Cl i n i c a l Pha r maco k i n e t i cs

Con cepts ond Ap pl i c o t i o ns

T h .1.. On _

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ALOS- 706- NZWP
Cl inical Pharmacak inet ics
Concepts and Application s
third edition

MALCOlM ROWlAND, Ph.D.

Depomnenr of Phormocy
University of Iv\oncne$ler
fvlonchester, England

THOMAS N. TOZER, Ph.D.

School of Pbcrmocv
University of California

San Francisco, Cclnormc

A Leu ..v... Febiger Book

.e1~ LI pPINCOTT WILLIAMS & W ILKINS

• A Wollen Kluwef Company
Philadelphia • Ballimore • New York • l ondon
Buenos Aires • Hong Kong . Syd ney • Tokyo
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9 10
To NIorgarel ond Down
 PREFACE

PURPOSE 01 TIXT
The rhin l l"tlitioll. in kt 't' pill~ wtth tilt' fi o t hm ("l;lilions. is a pn nu-r in p harmacokinet ics
\\i th a n t' llI ph;l~i s 011
clhucn l applica tions. 111t' Ix)ok should hl' useful to ilny student. pmc·
tulom-r. o r rt'sl'ard lt'r Willi is in f('rt'slt'() o r t 'llga~("ll in til(' dt ·" dopllll'u t , e-....uluutk rn. o r II!\('
of nu-dn-im-s. SIl('h !W n;O Il S illdlldl' ph annac1sts. physicians. vete rinari ans. pharmaccuuca l
scn-nt tsts. Im:ieo lo)..,'i sls, al1 al~1 i{Mu1chemists, luoc hennsts. and d ink'al chen us ts. It is a n in-
troduct ory text ami tln-n -fon - pn 'slllllt'S that tilt' n-ader Im." littll' or no t':qx' n t'IIl'(' O f k nowl-
( '(I~t· i ll lilt , an-a. Previous ('xposnn' 10 certain aspects of physioloK\' and pharmacclogy
wo uld ht' 11I·lp(1I1, hilt it is 1101 ('Sst·utia!. SOIllt' kllowlt'( I~(· of calculus is also dt 'Sirab!e .
Our intent h to ln-lp tilt' n-ader lenrn to apply plranuacokincncs in therape-utics . To this
r-nd. W I ' I'lIlplJit\il l' {,(lIll,('pts t l ln )ll~h problem solving \\i th only til(' essence of requtr ed
marlu-nuutcs . In tllis respect. til(' hook is a p ro~r.lI n m {'(II t'am inv; text. AI the bt";ll11i n ~ o f
I';u: h d lapll'r, ohjt'(:liH's art' !-pH'n 10 itll'lltif)" lilt' s aln-nt poin ts 10 be learned . T o furt her
aid in !e;ln-illl-: tln- man-rial. examples art' \\urkt'(! oul in del ail in tilt' text , At tilt' {'ud o f
t·ad. chapter, t'Wl'pt tilt' first. then- an' problems thilt allo..... I!l1' reader to v;r...' p tilt' (,(JJl{" pts
o f tilt' chapn-r ,Illd In lnukl 1)1\ man-rial ¢ H'n ill previ ous chapn-rs. nit' u n !t' r of tht, prob-
k-ms in I'a('h cliapter n ·III'(1s cousuh-ratiou of both t1HIi(1111)' and how WI·I\ tlu- problems
apply tn chapter principles . TIlt' questions sta rt wi th theless difli tult O Il('S and those thai
t·. llplmsi...x- tlu- principh-s.

ORGANIZATION AND CONIINT

As in tilt' s('('(md t'(lilioll , 11\1' I)( M)k is t!id t!('(1into fiv(' St,'<.1inllS: AbsUlVlion and Disl'll,).'i itinl\
Kim'lil'S. T ll{'raj'll,'lItil' Hl'¢Illt'nS, I'hysinlo¢ c COII('('pls and Knwttcs . Indhi tluali...at iou. ami
SI'!l'(1t, ! Tnpil'S. T lmst' \\i sllinl-: to ~<ti ll a ~1· Ilt· ral oH' nil'\\' o f tlu- sllhjl'<.i. 1It'(, ! on ly siudy
SI'('tiollSD Ilt' alld Two. fl,!-:t'lllt'r \\i lh Chapter 13 , Variahi lity, and C hap ter IS. \ Ionitoring.
S('('lion Tlm'(' dt'als wi th til(' phys iolc ~(' co ncepts relevant to an umk'rs tamli ng of the
Pl'Oc:t'Sst'S o f absorptmu. dtvtrthution, and climiuanon. T his section fo rms ti lt" basls for an
app reciation of tilt' mat{'ri,tl ill Sect ion Four, whid. is conce r ned \\i lh the idt·nlifieltion.
c!t'Sl'riptiOIl , and at'('(llllltilll-! o f "Iriahility in p atients' rt'SI)(JUst·s to d rugs. Coven-d hen- are
~(' Il l'ral ;I' pl·(.'h o( va riability, (ollm\"(, 1 by {,(lIlsidl'mtions o f ~(,IW lks , age uncl w(·i ~h t . dis-
t';I<;t', in lt'mdi lll-! d m l-!s. and lI\(milu rinl-: of dftl.e: concent rauous.
SI'('linll Fi\"(' contains sch -cn-d topics . These- <tn' ill!t'I\(II'(1for Ihust· rt'a tll'f1i wi\()wts h 10
~aj ll a mon- t1f'lailt'(l i ll si ~l lt into cu rious uspect s of clinical pbannacokim-tics . 111t" topics
an' d istrihulioll kim·lk'S. plla rlll an Jlt ~(' rt'SI)(J!lSt' . IIwtaho lih ' kim-tk-s, doS(' and Iillll" dt·-
1)('IIIII'I1('II'S, t U nJO\"N l'()IIl'('pIS. ami di:J)"sis, Eud. Inpk' is K{· .lt' rall~· st·lf-<.'(lIlta int, !; tllt'y
ImH' unt 1)( "11 arnlll~l, 1 in any part il'u lar st'lllt·m'(·.

CHANGES IN TNIRD EDITION

T Il(' fl.y('a r ~a p hdw t"('11 tllis thinl ("(filion and tllP st,(,(lIld . puhlish,"(1 ill 19MJ. is shurt t'r
tlla" tll(· 9 YI'af1i hd \\l ,,('U til(' st'(u nd alltl firo;l 1, litiol\s. nlis shUl1t·nillJ: o f tilt' Iilllt· spa n
 Pl!EfACE

IM'tWl'i 'lI ,·d ilium rd ll'd s tln- l'\ l' r-J,:atl... rill ~ P,I( ~ ' of p" ~n'Ss alld a pplil'atioll of ehnical
plla rllla(~lki ll d ics . D,"pill ' IlIi, J,:m\\11i. which Ila,\ n'( lllin "(l Ihe inclusion o f 1I111ch new
ruatr-rial. ( '\('1"\' dfort Il,L' IM"( 'II matl(' lu (~lIIlaill tln- over all Si"A' of Ih.. book. This. in 11101,
lias meant Ih,;1 SWill' lIlillt' rial llas lIad III Ix' ('o llde llS("(! or dd t'lt'(l. It IIlLs also n's1l11("( 1 ill
a muc-h j,(n'all'r u,,' of "hhn ·"ia!ioll' . (·'I)(... · ial l~ for un its .
T Ilt' 11I1I1l1M 'r . topn-, alit! S(" IUI'lll'(' of chapters have h('('11 kept ('Sst'lIl iall)" lilt" ~1 1Il (' ,L~ ill
11.1' \('('(Illd , -c Iiiion , IIIMl " I'r, r-ach chapter has b("('11 ('l\lt'nsi\"d )" n-visc..1 am l up(lalt"(! 10
I'IlSUf(' 111;(1 IIII' I',-,unpl,·\ n-lnn- 10 l1IITt'lIlly prescnlx-d dmg) , A part kul,lr (' Ilu rt h,L'; be-en
IIMd,· III ind lill.' vtr-n.. It' I I I· lII i~ I T\. n,( ~~l1 i /il l C: Ihal Isomers ma v Imn ' dillen'nl kinet k-s and
a(1i\ily. Tl l('n ' h "I"' l ('t>I I ~id('r,~!ioll o r til(" iJl(:n',l~ill~ Il llmh(·~ of IXllyp','pti d, ' am! protein
dmj.(s ,·IlII·fJ..,'iIIl! [nun advances ill mol ecular hioJ, ~ and hiol ('('hlloll 'K\-" ' AItI Il)U~h the ki-
Iwl k· (lllll",'ph an' lilt' sallw. 1111' phy, i ll lu'~i ~' halllllilll..:: of macmmoll'(11 lar comp ounds is
' lui'" dislilld from that of I ~pi('al slIIall lllol''(' lIlar \\t·it.:lll dm ~s .
TIlt' pn-wutation of lilt' 1M10k h'LSa["'1IM'''II ruar]« .. I1 ~ illlprowd through Ih(' Ust· of (:olo r.
TI ll' mort- nuportuut ("Illalions art- IIOW lIil..:lllighl1'd bv means of color. C hapter number
;111.1 ~'('1i' 1I 1 Ilt';\llillg IIlIWalllM 'a r al 1111 ' It Ip 'If ( '01(·11 p'I,l. ::" b~ nu! to assist ill (' mss- rt' fl· n' lIci ll ~ .
.-\ lahll' of fn 'lllwnll.\ tN·d '~'llI buls hlL.. IIt·('1l pb( ~ "(II It 'I;lTt . Chapter 1 10 fad lil;lle n"tldillin ~
w mlltlk wln-n IH "~ 'S"IT\ ' .
T he ralll.:1' alit! uumla -r of p robk-m-, al Ihe e ud of ('adl chapter and Appendix I (total o f
";7 III'W pruh[('Ill';) Ilan ' 1"'1'11 , " h, tallli,illy extem h-dto itssisl in 1('itm illlJ: p ruh l('m SU "; I1~
ill l)haTlna,~,ki lll 'l i('s , 'I(lsi Ill' lilt, addilillllal problem s an' taken Irmn hterutun-, rather than
Sillllltt"'i!. Ib t" ,
T ilt, thtrd , -c [itiou (1J1llaill\ 102 IWW fig ures anti 20m'w tables, n:'l1('(1 in~, in large P;lrt .
Ill,' atklllt'(', ilIad" ill n"t'('111 ~" ;I rs ill 11liT ~'ll lwll'(I~(· o f 111(' pharmacoknu-ttcs uf dn l~s . Tln-
mun-rtal 0 11 "S mall \ 'UlllllW u f Di ~ 1 rihlltiull " thut compns,-d tilt' ttsl chapter of tilt' second
,..[itlon II '~~ 11t"('1I illlUTJMlTakti intn C l.aplt'r W . D istrihulioTl , atul :\ppc.·lIdh I-F.
\\'1' (~llIlilllll ' 10 adopl a umfonu st'l of svmbols 11m! 10 II...• lIlilli.t.:r.ulIsIliIN (mwLl ,lS
tlu vtaudard 1H,'aSl lW of couceutranon. \\'e do rt"l.1lj..'fli7'(·. however. tht· illl'n·,t\i llJl; trend
towun ] tilt' atin plillil of 1lI0lM Illlil\ lind haw' pn l\itl'''tl a fad or for conversion ht'!"Wi'('1I tht·
two lIllils of nu-acun-uu-nt ill til(' ('ll,'rt iIlPIlI fiWm· captious. \\'t' shall un l~' il(' convtnced of
IIII' virt m- of ,,,I,,\y lISi ll~ lilt" molar s~"Sl p lIl of mcasun-ment wln-u dm ~s an' pn-scnlx-d in
~ Ild l Ilnih.

ACKNOWLEDGMENTS
\\'1' \,;sh to th ank all tilt· Ulall)" silltipuls lind rea tlt·rs w!lu pn l\itl l"tl inpul thai Ilt'lp' ''lllis
sha pt· Ihis Ihinl ("(!ilio n. Their 1·lllhIl Sia.SIIl ami {"m"llll r.t~{"IIWIlI haw ' 11t'('1l lIl,mlillllal st.ltln't·
of salisfill1ion . To 111(' 1It'\.\· n·ilde r. Wt· hnpt· that 11... IItMlk \\i ll su('t.'t"("f. 1 in IlI'lpin~ ) U U
<I....-dop kil)('l k- r..a....mill~ Ihal ....i ll hI' of personal \,.Iul' ill ) 'tl1tT p m f('ssio nal p ml1il"(' ,
\ \'(. hOI\"(' h("('11 (' llorlll(msI~' ~nllifi l"(l hy till' \\;de allli d i\"l·rst· n ·mlership of IIIl' fir.-t Iwn
t"f.lilions o f tilt" h(ltlk. \\·t· ....,) \lld lik(' 10 ht'ii('\ "(' Illat lIlt' IItMlk ha.. 11t'l'1I ins lmllll'lIt ai in
fllrtlll' ring mliollal lllilllav;en)(' 111 of dm~ t1lt"rdp)', Wt· sinl'l,Tt·ly 11Ilpt· tlml Ih.. thi nl t'(!ilion
\\i ll l'tllltilH l(' 10 do st.1.

,\loltcllt'-d t"r , £1IJ!lom/ \l a!t.1,lm H()\,·land

San Fm'irl~('(J . Calijonl;(/ l1 Ullll ll'i~ . T oz('r
 CONTENTS

Definition!> of St:ibols xi
1. W hy C1inico l P ormocohnerics? _ _ 1

SIOION I. "'SORPTION AND DISPOSITION IINIHCS

2. Basic Ccn stde rcno ns 11
3 . Intravenous Dose 18
4 . Extravascular Dose 34

SlUION II. THIU'IUJI( IIGI.IN5

5 . Therapeutic Response and Toxicily 53
6 . Constant-Rote Reg imens 66
7 . M uhiple-Dose Regimens 83

SECTION III. PHYSIOLOGIC (ON((PTS AND IUUTI(S

8. I'v'lovement Through MemblOnes 10Q
9. Absorption . 1 19
10 . Distribution 137
11 . Elimina tion 156
12 . Integration With Kinetics 184

SECTION IY. INDIYIDUALlZATlON

13 . Variab ility 203
14 . Genetics . 220
15 . AgeandWeighr 230
16 . Disease 248
17 . Interacting Drugs 267
18 . Concennctio n Monito,ing 290

SECTION Y. SEU CTE D TOPICS

19 . Distribution Kinetics . 313
20 . Pharmaco logic Response 340
2 1. MetabOlite Kinetics 367
22 . Dose and Time Dependencies .. 394
23 . TUfnovel Concep's .. , , 424
24 . Dialysis ,44 3

SEUCTED lEADING 463

APPIHDIX I. ADDITIONAL CONUPTS AND DUIYATIONS

A . Assessment 01AUe 469
B. Esnmct.on 01Eliminalion Hall·life flam Urine Dote .47 3
• CCNTENf5

C . EstimaTion 01 Absorplion Kinetics F,om Plm mo Concentration DolO " .. ,." 478
D. f'.h:Jon Residence Time 4 85
E. Amount of Drug in Body on Accumula tion 10 Plateau 4 90
F. Oislribulion of Drugs Extensively Bound to Plasma Proteins "' ,4 Q4
G B!cxxi 1o Plmmo C o oc eollO tjon Rolin 50 2
H Esllmorion 01C,eohnine Clearance Under Nonsleody-Stote Conditions ..... 504

"rINDII II. uswn s [0 PlOIUMS SOl

IlIIlI.L
X - "110
586
 DEFINITIONS OF SYMBOlS *
Amoullt of dnl~ in hody. 1lI~ o r
umolo.
Atl Alliount of t1nl~ at ubsorpnou
sit(· n' m ai lli n~ tu he.' absorbed,
1ll~ o r "UIIO]t' .
C UlIlulathl' amount of dnl~ I' X-
e.'rd("(,1 U1l('h atl ~('t 1 in th(' urine,
Ill~ Of j.tlllo le.
A d (", ) Amount of lllt'ta!xl iite ellmtnan-d.
1lI~ or umole.
CUlIllilati\'{' amount of dOl!,!: ex-
{·rt'h,,( ! ll n{' h;U1~(,,( ! in rlu- urme
dllrin~ a dusill ~ interva l at sh ';ldy
stun-, 111 ~ Of umok-.
C umulative amount of d m~ ex-
(: rl"lt-c. I II Ile.·h;U1~t'tl in tilt' urille to
lilllt' infinity aftN a ~i ll~!e duse ,
mg or j.tmolt,.
A (", ) Amount of md"hulilt ' in Ixx!y.
1Il ~ Of j.tll1ule.'. • a specific time Interval. e .g,. dos-
TI\(' min imu m umouut o f dm ~ in
Ixltly required to obtain " pn-de-
tennim-dh-vcl o f n'spoII ~' , m ~ o r
"U Il O!t ' .
A y ...... : ~l ll\i ll1 11 m am i nununum
A,\',.."" amou nts of d m ~ in I)(ltly afh' r th e
Xtil duSt, of fi.'H't! sin' ,wd ¢\"1'1I
at a Iixed dosill~ interval , 1l1 ~ or
umoh-.
"\\'., Amount o f dnl~ in I)(xly at tilllt' t
aftN till· Xtli " O\t', 1Il~ Of umole.
Amount of t1m ~ (t'maining to he
t'xI'n'It-c.! ill umn- arkr a smglc
dose-, mg or umole.
· C."..I ""iI' " n ' 10"''' .
A... Amount of dnl ~ ill Ixxl)' at steady
state.' during con stant -rate mt rave-
1I01lS in fusion , mg o r IJIllO]t' ,
A...... A\'erdge amount of dnlg in Ixxl)"
during a dosing Interva l at ste ad}'
state. mg or umole.
A..,......: Mali:imu m and minimum
A..... ... amounts of dnlg in Ixx!y during a
dosing Inte rval at sll'lld)" state on
administering a fiu'tl dUM" at a
fixl-c.1 dosing Interval, m~ o r
IJIIlO!t· ,
A.... Amount of drug in body at lillie t
\\ithin a dosing Interval at stt·ady
state O il ;u!millish'ring a fin-d
dust, at a fi\I-c.1 t1os in ~ Interval,
Ill g O f umole.
AVC Aft"a under the plasma drug con -
centration-nm e curve . Total un-a
fmm tinll' () to infinity is implied
unless the local ('(mt('lt indicates
ing Interval, mg-hr/l , Of 1J~I . h r.
AVC" To tal area under the blood dnlg
concentrutio n timt· curve , mg-hr!
L or p ~ l . hr .
A UC(m )An 'illlm l('r tlw plasma rm-tabo-
lite co ncen tra tmn time curve.
mg-h r/L or IJl\I ·hr .
AVC.. An'a under the plasma drug ( '( )II-
cen tranon time cu rve within a
dosing int erval at steady state,
mg-hr/l . or IJM -III'.
,\ V.\lC Total an-a under the first mo-
mont-time curve . mg-h.-2/L or
1J ~1 -1 1 .-2.
c Co ncentration of dnl g ill plasma.
mwL or j.t ~ 1.
..
.. Df fN1X)NS OF
C (O) Initial plas ma eoncentratkm,
all)' obtaintod b)' (' d r oiplKdHflll to
time 7...-ro. mw'l. or J.l M.
C 1:C2 Coefficiellts with units of <:(m('('I1-
trarjon, m ~'l.nr p M.
C. Ceucentration of t1nl~ in fluitL.. 011
the ;j,~lTptiOIi ,itt·, IIlWi. o r ",\1.
C" C.tllK't·ntrolltnll of dnl ~ in arterial
blood , IIlgfL or J.I \1.
C, ('.ou('\'ulmIKlIl of dnl~ in h lood.
mWL or J.I \ 1.
CINI CotK"t"ll lmfinlln( bound d Ol I-:: ill
plas ma, IllWI..o r ~~1.
D nl g l'lIIK"t'n lratinn in c li a l)~I I ('
C 'J
Ic'a\i n~ d iOllp N . mWl. o r J.i ~ 1.
(;1 CtJlK't'nl rllfiun nf inhibit or of II1t'-
ta bohsm. 1Il1i!. or ~ \ 1.
CI. Tot.al clearance of J mg fmm
plasma, l A ir.
CI.." Toeal dt"ar.lIK't' o f Jmg fn)lll
hlt:n.1. l A ir .
~'5is clt-anuK."'(" ba.~ 'tl Oil dmg
Cl ..",)
l't"K'(·ntr.ttioo in hluu{!. LAir.
CL" II Hepatic d(~.u-dIKT of dnag from
hlnnc.L l A ir.
CI.~ Ht"taI d('llrdlK"t" o f N\·dlillillt-.
Illl/min eN" l A ir.
c t.; Dial)'5is dt'drdlK't' ba.'\t'll 011 dmg
couceutrateon in pla.SIlla.. l A ir.
C/, Clearance a\sudaftoe,l wit h Forma -
lion of a mt1a!J,olitto fmm a dmg.
l zhr.
c t.; Hepatic dt'a mnn ' nf d n lg from
plasm a. l A ir.
CL"" l nt riuslc ck-aranee of dm~ ill or-
~an of t'l im inalioll . l A Ir.
CUm ) Tot al d (';\mn("l.' of a rm-t abolitc.
lAir.
Peritoneal dialysis dC'ardlK"t'
CI· ,.u
based o n dOlJl: ("II1K't'llfrdtlon in
plasma. l A ir.
CI." Renal clt".uaIK"t' of tlmg. tAn .
CI..fl C k".u-d1H.,· of unbound drug.
l A Ir.
C(m) CAIIK."t'nfrdholl o f ffi(1ahofil t' ill
pLaSIila. '"WI. o r 1-1\1.
s,r.w!O.S
lISU - C_ lI i~ht', 1 {Im~ ( ' U ll ( 't' u l r.l!illll lll ..
~'nl'tl in plasma follcJ\\ill!{ad-
milli,tralioll of an t'xt m''lL'ol'1lla r
tic .....•• mWl.llr JI\ 1.
e l m).. C Olll't'n l rd lio ll o f a IIIt·l al. llih· al
\tt ·;"ly ,t.aft" d urin£: a ('(m..tam-
rate illt rd'l'IKlU" inf"sinll o f dnl~
IIIWI."' J.I\t
C_ .. \ l illi u llI lI l ('1ltK't'nt r.tlin n n"Cluin'tl
10 ohtain a pn'tIt.It'nuint"l! tnten-
"ity o f n~llClIIs(·. mWi . o r J.I \ I.
C ,\ _ .: \I.ui lllll lll anduuniunuu ulII<.'(' n -
C\' ~" tnutons of d rug in plasma afll' r
Iht , X III doS{' n n ;td r n i llh ll' ri n~ a
fi.\t'tl d o S{' al cquul dos i ll ~ inh'r·
vak IIIWL or J.i \ I.
c.; CUlll't ·ul r.lliun of t1m~ ill Ill'rill..
lll'lll l'a\i f)·, IIIWL nr J.i \ I.
C. CmK't 'lIlmtiull o f dm~ ill plil-\IU;.
al ,11';11.1)" stOlf(' during a n msla nl-
ran- inlr.l\1:"IlCItIS infusion, mWJ.
ur J.i \ 1.
C.. _ ,\\l' r~{' tln lg conc eutra bcu in
pld.\lIl4/, clu ring a dosill~ i'JlN\~J al
stt-....I)· slalt· 011 d(l lII i n isll' ri ll~"
fi\t"d diN' a t t'{!ttal dosi ng tnn-r-
vals, mWJ-,. or I-I \ t.
C..._.: ~ l a'{i lll lll n and nuninuun t'(lIl(,'I1-
C.. _ Irdfiems of dmg ill pl.tSIIl;& af
Slt';lcl)" slaft' em adminis!t'ring;&
fi'{{oe,l dust' .II equ a l clus ing int e-r-
vals, m!ifL o r J.i \1.
C, ,\ \'{ ' m~t- courx-utrutjon of d nl ~ ill
111li,Ls uutshh- plasma, IIlWL o r
JA M.
Cl'" J) n l~ ("IJ11c't'lIlmfifn) IIl1hollllcl ill
lol al hoc.I)· wate-r. mWI-- or pM.
C.",....- ~1 a.,i Ill U Ill a nd m inimum limits
C"....... for p la.'lIIa dnl~ ("Ilnn ·n lrdfMms.
1llWI-- or J.I ~ I .
C" Unbound dm~ (·ollll.'llfr.t tio n ill
plasm a, mWJ.. or )1 ~ 1.
CII, Unb ound plasma (.'t)lK't'lll mlioll
of illilihilllf, mWJ. or 1-1 \ 1.
C,_ C.tIlK"I-utr.lIMlIl of dna,:: ill \"(' llt MIS
hlcMII1lIIWl. o r J.i 'l .
 DEfWlONS Of SV.YaQlS
IJ,. Luadi ll ~ dose. m~ or ~.IInClI(' .
\ laintl'llalln ' dn"", of a f!Wtl.tlOSl'
IJ"
n-WlIll'll. 1Il~ o r ~ullolt"
U __ \ t u i lllll lll mai nft-ll<.IIK,(· du!>(' 10
v
r-u..un- th .d tiM.' plasma dm~ con-
('OI'ntrat ~ >II " 'III;UII~ \..ill.in C..,.,,-
and C.lo ....... Ii mils tillrin ~ a (k)O; i ll~
Interval at st eatl~' ..tat e. 1Il~ or
~Illlllt"
F. E,tr:.K1illll ratio. 1111 units .
IX :',II {;onn'ulratioll ~i\i ll~ one-half tiM.'
ma"iIl1ll1llI'lT('1. IIlWl. " I' ~ \ I ,
E" IIt'pal ko l' \ l md iull rutio , TlU units.
f:,..... \ I,l\ illllllll ('lTl'1 , uutts of re -
SI XlII M' uu-asureuu-ut .
P H illa\~li bhi li ty fir d m ~. uo units.
h..1 Ratio nr I XIIIIIII til Ini al d m~ con-
l'Ol'lItmtilllls ill pl.eeu a. nil units .
Di al"''iis cl..aram'e- as a rrd(1io n or
t" tUlal' cleamno- dllrill~ a (Ii al~"is
In'a lll MOlIl, no units.
F ract ion of t1nl~ "'~.... te-uuc-ally
fi·
...."".liLahlt' 11Iat i", l'uTt'!l,lun-
t·han!:t'll in urine. lin uuits.
FEV, Forced (·xp i rdt () ~· \UllInK' in I
second. I ~
Frecnou or tlnl~ t'likrill~ tht'
"'" live-rtha i Ml'ilp' -s l'limi rlalioll 0 11
singlt' I'la.Ssa~l' t llnlll~h th ai o r-
~all , 110 units.
Jm F"rad:iull lOr IlnJ!!: sph" Illit-; J I~'
;l\'ailah lt' tha i h t'(lI\\'('r11' ! to a
IIl1'l:llx,lilt'. 110 uni ts.
f ill Fract ion or ..d min i..lt' r,,1do!>(' or
dnl ~ that l'nh'f'!i ti ll' J.:t' llt' mlcir-
l111..-liou us a nu-tabolin-, no un its .
F Fraction of filn-n-d and !>('(:rt'It't!
• drug reabsorbe d ill tilt" renal tu -
bu lc, no units.
ft· Rat io (If unl .Jl.lIltl and toral dm ~
('OI.IK,'n t r,dion~ in plasma. no
umrs .
I"' Ratio or un!'numlilut! hltal dm R
('OI K'('llt mt ioll~ in pla...ma Ulld("f'
t'Uullililll\s or a1tt'n,1 bintlinR- no
units.
.~
t". Ralio of unbound co ncent ranon
in pla.\ lUiI and lotal dru~ (,(JlK,'n-
tranou in blood. un uni ts .
ft·, Ralio of unbound and total sih 'S
a..'iLil.r.bk fo r bint lill~ nn a pla.\IlU
pron-iu, 110 units.
Ratio of unhound and a\'('r.t~(' tl..
J"ff
tal dm~ rono-ntrations in intra-
t, 'lIl1lar "uids , no units.
Ratio of IIllhoulltl and to tal dm ~
f liT
conccntranons in tissues (o ub idt'
plasma). 110 uni ts .
y Shapl' fact or in conce nt rat ion-
rt'Srx)IJ ~' n-lanonship. 110 unit s.
GfJl Glllllwmlar fi ltration rate. 111 11
mill or l;1l1'.
k Eliminati lln rat e constan t, hr - I.
/; AS\lx1ali oll co nstant for tilt' biml ·
• i n~ of dr ug 10 prot ei n. 11 1J1olt' ,
ka Ahso rption rat e co nstant. hr - I.
k" Ehnunatjon r.lIt' constan t whilt' a
P"'tiMlt is undergoing tlialrsi'
In-aIIlM.'nt.1Ir - I,
k. U rillal)' escn-non rail." constant.
11f - I ,
kJ
Hatt' constant ilS-\lldatl'll wit h l1.t '
formatio n of a metabolite, 111' - 1.
/; , Inhihitio n t"fluilibrimn constan t,
mWL or ~ ~1.
k (m ) Ralt' constant for th e d ilUina! ioll
or a lIll'taholitl' , hr - I.
Am M k hiU'IiS·\h ·uh 'u coust aut, mWI.
o r ~\ I ,
I'm ' \ l ichal.'lis·\le ule n constant. t'X-
pres sed in te rms or lot al plasma
concentranon. mgIL or p \ l .
Kp EqUilibrium dist ribu lion rdtio or
dmg ht1\l.'t ... n tissue and hlc...1 or
plasma. no umts.
k, Fr.K1tonal rate at which dm 2
ko""'S tis~ut' , hr - I.
k. Frat.1tomll tUITMI\"t' r r.tle , h I'- ',
)...; )-t F.\plnt' lltial coefficit'nls, ltr - I.
. Iv OE fNllCl!"iS a S¥MaOlS

'" Slope of Iht' center of It... inten-

..i~· of n.~polIst· \"t' nus t.. ~ con-
'." DumtMlII of a constant-ran- infu -
sio n, hr .
('t·n l r.d ioll ('1II'H ', units of re- Tm ~ 1 a.U Ill II Ill rolle of tlm ~ t rolll~pllrt
.. 1'11111 ... -. (w't.Tt1 km) into Wllm tnlmM',
.\lRT \ 1t~.I11 tin"" a 1IIC.lI'..,IIt· n -skk-s ill mwllr ,
lJ( Jl.~·. 1.1. H alf-lift'. hr.
.. :\ unilk" .. nu mbe-r. '''' Turno..er time, hr.
v :-':1111I1)1;'" o f ( 1tN-~ . no unus. "I ' \"0111111('of ( Ii~t ri htlhon (al'lp .. n 'nl )
f I'I'nnt'abili~' {'tIll·ffi dt·llt . rm/mln ha.' l'll Ull
tlm l?; (llIK'l"ntrollitlll ill
0 1' (:lI VI. r, ptl~III'l. L
V Blood flow, 1) lII ill CIT 1.1111'.
{>" I>i 'lly~.ah· How in Ilt·lIIullilIJ~ ...is
I'
• \"ululllt' of (listrilK ltMIIl (a pp a n 'n t)
based on ( l rtl~ (1l1l(1'ntm fio n ill
ws n-m . ml Jmill (II' IAlT. blood . L
V/ Hall ' of filtm lt·lI11w fmlll ulu-ru o- BlocMI volume, L,
filtr.tliull S}' h 'm, m l/mi n Ill' l zhr.
I'
• " ollllllt' (If d iah'!lall' solutio n (111·
J le-patu- blond 1l11\\' (port al vetn \'"
V.. It'(1t...1 duri ng ~ helllo(lialp i.s
plus IU'p alk ark !')') , I/ m in or tre-atme-nt , l ;
lA,r.
e Hiltin of conc eutra nou ill blnnd
(, '11 10 thdt IIllhutllltl in plasma.
", \"Ullllllt'
partme-nt. L
o f in itial d ilution ( 'lJIIl -

\ '". ~1 d.U lll llln rate of IUt' taholi..m I,:,'

"- .\ ("(.'11111111a lio l\ r,olfiu (imlt·'d . 110

uui t...
all r-nzvmati call.., mediated n'''''''
lion, 1I~~/hr u r ~mok~lr.
&I Ratio o f u nhuulJ(l c k-aran o- of an
\ '( m ) \"olllnl(' of di strihlliion (ap pan'lI t)
Individual patk'Il1 In that or a ~p-
o f a Illt1 aholite 00.'\(...1011 ih
M panem. IlU units .
KW
pb.-una (' "K't' ufrdlkm , r,
1ft' Itt- nat fUl K.1KIII in .III indi\iftual
p;.d it·nl a.~ a fr.K1iun u f n-ual I 'r PIa.~lIla volume-, I ~
flllK.1iou in a t~'Pkal l);dit·nl. no \ 're \"OIIlIlW of dial)"Satt'"ithin lilt'
units. pC'rilulJ(·ll! cavi ty, L.
It l le uf l'tlll~tani intr.l\l.'nul!S in-
1("
fll ~ioll , 1IlW'1r.
I'
• Ali"t·tlIlS " U llllll(' of illll'al,'l1nlar
fluids. I ~
II, Tu rm wer rate. 1ll~/1.r. Pt.)'Sioll~c ..." lu ln(' Clllhic lt·
-' Salt form factor. lUI units. "r plll-'mla in ln whi(·h dm~ dtstnb-
S/\ Surfaet· urea. m Z, li lt'S. I ..
of di strihu tiou (appa n ,n l )
t

'-,
I)o sinv; lnte-rvnl. hr .
~ 1 ;l'lii Ill U Ill d ns iuv; inh'1"\1ll ln n--
"• \'I IIIIUl('
uml t'r sn-edv -sta te C't)fuliliom
lII11i n " i th in (."." .... " Iltl (.'"....... lim- 1~l-'l... 1 o n ll~l~ (.'lJlK't'nlrut!on in
its , hr. p!;lSmOl, 1..

'_. Tillie "I which lht' h i ~ht'l>t dnlV;

(11IK't·ntr.d ion occurs follu"ill~
\ ' rw ."-q ut·o tls volume oulsklt· pla...ma
tuto which dru ~ distrihules , I ~
al lmini"il r..lioll o f an extravascular
\ '" \'olulllt' o f dlSlrihulioll (aPlldn -n u
cl.l'\ot' , min IIr hr. 1Ja.'oC'l1 011 unbound tlnl~ C't.lIK't'U-
Im hull in pl,uma. L.
'J Duration of ('fTt't.1. hr.
 WHY CLINICAL PHARMACOKINETICS?

T IlOSt' pat ien ts who sufli-r from chronic ailme nts SIICI. as d iaht'h' s and t"pilers), lIlay han '
to lal.:" drugs ( ' \ 1'1)' day for the res t of their li\'l'S. Al the other extreme are tho se who laJ,,(·
01 si ll~l l' duS!.' uf a tlnl)!; 10 n ·!it·\ t' a n occasional headache. 11l(' durattcn of drug therapy is
Ilsu ally IM·tWI,,('U till'S(' (·xl n ·lIlt -s. 111(' mann e-r in w hid l a dmg is taken is called a d tutl /!.(·
"q~j"U'II . Bot h tI\I' duration of dmg therapy and the dosage regimen depend on the t1W T·
apt'utit· ohj('(1iVt's, whith lIlay 1M' t'itlll' f ti l l' cure, the mitigation. or the pn...-e nnon of
t1iSt·;L~(, . Bt'('illl'>(' all d m~s ('xhihit undt'simble d T('(1 s, such a.s d ro ws iness, dryness o f the
mo u th, )!;;Lstruin lt-sti n.J irritation, 1l<1\ISl.'a , and h)l x)k m ioll, succe ssful dmg therapy is
"d li,,\","(1by opti mally halandllg til t' dl·~i mhl(· and tht, un des irahle- ("rTed s. To adli("\'(' op-
ttmul tllt"r.lpy, Ilu- appn ~ui at(' "d rug o f chotec" mu st he select ed. This decision implies an
accu rate d iag:uo~i ~ of tlu- disease , a knnw!('tlge of Ihe climcal state o r til(> p atient . and a
s(lllml U1u le nlandi ng: of Ilw phartuaeotherapeutk- man agement of thl' disease , T hen tilt'
questions How much? How ortl' n? and How long? mus t 1)(· answered. n it' qu est ion 1I0w
mudl? n '<.1tgniz('s thai tlw ma gn il\l(les or the the rapeu tic and torte rt'spon St'S an' Iunct lons
or tll(, doS(' gin'u. TIl(' qll('stioll Hew oft(' n? ~i7.es the importance uf time, in thai tilt'
magn itude o r tilt" effect ("\'('lIluall)' declines with tinll' follo""i ng: a single dose o f drug. Till'
fillest ifm lI ow long? n't"tlJ?;lli1A'S that a cos t (in term s of side l' rT('<.'ts, tCl\id l)!, ("(111l1ll1lit'S ) is
incu rred with con tinuous d rug urhniui stration. In practice . the se quest ions can not 1)(' dt-
\lIn1't1 Imm otu- auotln-r, fo r exampk-. thl' convenience or g:h i ng a larger dn"l' k-ss fn"
I I I wilily lIIay he mon- than ofTSt't hy all increased incidence of toxicity.
In th(' P;l\ I, tilt' an swers to lIlany import ant tln-rapeu tlc questions were obtai ned hy trial
and error . TIl(' dose , Interval between do ses. and ro ute of ad ministration wen- 5(,ll"<.1('(1.
and tl.l' !lalil'llt's pn~rl'S S followed. TIle desin 'll effeceend an)' S i~IS of toxicity we re ca re -
fully noted. anti if nec essary. lIlt· c1osaJ?;t· rt>¢nw n w asad jush'll empirically un til an accept-
ah lt, hallUll"t, 1)('I\\1.'(·n ti ll' desired erred and toxici ty ""~.L~ achieved . Eve nt ually, afte r con-
sidembl!:' experinu-ntation n il ,I la~e n umbe r of patients, rt'a.~onabl l· dllsagt· rt-giIllI'1JS were
l'sta blisllt'll (Tablt· I-I), hut not without some rt-gi UW llS p nxi lld ll~ excessive toxidt)' or
p n J\ing ine rTl'('1 in'. \lon 'lJ\'t 'r, the alxJ\"(' em pmcal app n "ad l left lIlany ques tions umm-
swr-n-d. \ \1 1)' , for exam ple, doe s tet racyclin e have to be g tcc n l"\"(" )' 6 to H hou rs to I)(!
t,rTt'<.1i\"f.', whill' diJ?;o\ in can he Wn' lI on ce dail)'? \\11Y IIIIISt ox)'teK;n Ix· Infused tn trave -
nously? \ \ 11)' is mo rphine mo re I'fTedive given int ramuscularly thall wht' n giwn orally?
Furthe nn nrl', this ('1I1p irical appnJl\('h contribull's litt le , if all)t hing, towa n l estahlishing a
saft" I'rTKi in' tlosagt' n-gitllell of lInolhl't (In lg. TIlal is, our hasit' unde rstand ing of dm~
h,L~ not 1)('('11 illCrl"l<;('t1.
Tn 1J\·('ft-'UlIll· SIlIIIt' of ti ll' limitatiolJS o f the e llipirical app m;ldl allli to anSWl'r Slllllt' o f
ti ll' fllll'stions miSt'll, it i~ fll"(1'SSllI)' to dl'k t· fnrt llt'r into tht' t"\"t'llls thai rollow d mg: ad -
ministmtio n. III rifm and i 'l ri t:t) studies show thai the ma~lit utll' of the rt'SpOIls(' is a
fundion or the l1ml1-'ntralion o f d m g ill the fluid b<lthing the site(s ) o f aliion. F mm Iht·S(,
(JilSt'l'vations th e snggt'stion might 1)(' mad e that thl' tllCnlpl'ulic Objl"li i\'l' ('all 1)(· al'hit"\"t'll
hy maint aining an atl('ll uah' t.1m('t'utr.ltio ll of dmg at tilt' sitd s) o f act ion for till' d Ur.ltioli
2

o f tlwrdpy . II n\"'{."\'t 'r. na n ·I)" is a d n1lo': plat.'t-d at ib silt' of adjoll. Indee-d, lIl(l\1 d m~.. a n '
goen orally, am.! }'('I tlM:.,.· ad in fli t" b rain, on t ill' he-art , at the II t 'U n llllllSl'u !ar jUUdHlII. or
t'!........h e re. .\ d Ol!; m u..t th e n- Iore m O\"t" fro m tilt" ..itt>of ou.llllini"lrJotion 10 the sitt" ofaction.
SimultiUK'OIls1y. IK,"'"'\·...r. til t· d m g di"lrilmlt~ III all ndK'r ti....1WS i n<,JlIdi ll ~ ttN....• orga ns,
nntab~' tht· lh'N ami lIl(' kidneys. that eliminate it from the IlOl. l~·.
F igu fl" 1- 1 iIImt ra te-s III(' cwnts occerrtng "ftt'r a tte~· of d nl~ i!'i ar. lmilli..h- n -d or...Jly.
n it' rate at whk·h dm~ init ially enters the bodv ('u't't'tu its rate of eliminat iun ; tilt' (1)11 -
('t'nlroltions o f dru~ ill bit..;! ul hN ttssues ri M:. nftt'll ..uffidt·n tl)"hi~h 10 d icillht' dcsi n-d
and
tht-rolpl·utic t' lTl"(:h and sometimes even to pmtlll(,(' to,ilir,'. Ew:·n tu all)". ellt' rod,' of d mg
r Jjmination cxl'l."l"ll, t1.~. roth' uf its eleorption. and t1lt"rt·... In-r. tilt' ('OTK'I.'ntrJ.ti(m of dnJ~ in
" "til blood anti t&SIl~'S (1t'Clint"S a nd th e e fTl"(1(s ) slIlxidl'S. To administe r dm~ optilll;lll)'.
therefore, knrM·I,'d!{~· is Ilt"l"!t .. l nnt o nly of t h~' 1ll 1.. .han i...ms o f d n l ~ absorption. distrihu -
non, and elimlnanon hilt a1 ~J of till' kineti cs of thl'\(' pnx"l'S<'('S. th 'll is.IJIum llllCl.lkl,U1iN .
TIll' application o f phann'l("l.kindk principles 10 tl.l· tberupeunc lIIall;l~I'lI1 t'llt of 1l<ltit'n h
is r/lll ico!plwml(/('(Jkllll ·' lc.f .

Trealmenl 01 lnf.ect>onl.
T_~

250 "'9 ~ 0-8 lit

l)go>:;n ArneIOOfO!oon 01 ~
cc-dcc fo;~
"'"
"'" I 5-2"'9 ,ntt>CJly o- 2.4
Iv. li'>e<~ 0 25-0 5
"'9 once 0 cloy
0<,00<- Ir.c:I..oon and rno.ntenonee "--'-' ....,.,
o 2-.4 ..........'Ii/rr"n by
""',..,.. ..... '" """"
~e1oe1 01 _ e po,n InIrQI'nuSCuIa< 10 mg ~ ~

"'" Nor recom....e..d.,d becocse

oIleduc ed ~

tl«. 1-1 . PL..".... " "1l' '11!r·' '1I'' ' .J

I hn>rh~ tli,... In il.,, 1'i"1 (.. llo... ·h .lt....
unl ,10...,. of a fil. ).n' lt tnulrullo..I·Il"-
lo'iI-\l' (un llul..liull. Krfof't" lilt' 1"'..1< i\
" •• -I..-d, tI ... r..I, ' ..f "''''''l>lic''' " l '
('1 h Iha l of t' h minaliu" . Al 11,t'
1 It. tI tv... r..to"f a " I',..]; II..·.....
..firf'. tI ralr of ..Iimi ljun Mt~b
1...., ,/ .u-...''T''jr", IRr<.I/lrOIm fn ....
s..ut..... R.. St";ni)""l. \'w.. Dl1rtti.
E .• tMhm . A., ilml S-ch"k II U.:
f'nov-n l;d'iono( ,",-,k, in hi<....lui\...-
rD:T_bn.. lnl I . an. f"hann....1
n..-r. TOlicul.. .)'} s;~. IWl.1

o 12 24 36 46
Hours
CHAPTf i I 3

11lt" events f(l ll(J\\i n~ dnl~ admtutstration can he d i\1d("(1 in lo two pluse-s. a IJlwnlulC(J-
ki"l'I ic IJlww . in which ti ll' 'KljllSta blt." elements of du'l' . dusagt.' fon n . frt"'llIl'II(.')'. am i mute
o f udmuu strunou are rt..lated to d nl g k-vel-Hm e rdaliollships in the hudy. and a 1"l lln lw-
('Ilfl y" mll k pl lfls(·. ill whidl th(· 1"ll1l('t'l1tmt iun of d nlg at tilt' sih'(S) of at.1iou is n-luted to
tln- nmgn il mlt· o f lilt' (·fTt"(1(S) pmd ul"('tl (Fi~. 1- 2). Om"(·IM,,1I of these phases han' ),t't'11
dd il\('(l. a dOS;lgt· Tt-W lllt'll ca n 1)(· t!("!iig1lt't1 to a/: hi(...·e Ihe 1!It'T;lI)('utk ohy't.'t in' . I)('spi h '
tilt" grt'a h' r amount of Infonuanon req uired wi th thls upproech. it has several ad va nlag;I'S
o\"('r rlu- empiric..tl app n ",l'i l. Flrs t. aml most ull\ i lJus. dis tlnction l'im ht· III;K!(' II(,t\lol't'lI
ph am l'K'tl).;illdic allt l Jlll anllal't )(I~llalllit· causes of all unusual dm ~ Tt'SpOIl'l', Se<.'Olld, Il.lt..
IliL\k- concepts o f phannacokiuerics an' co m mon 10 all dmw;; illfon llalioll ~ai l\('ll uh out the
plmrm au )l..i nl'l it.,. of 0I1t' linl g 1..11I ls-lp in ;lIl lici pal i n~ tilt' phann;K'tllciul.tit-s of allot lJ('r.
Third. Ilnd('rstalld i n ~ tilt' plum naco k tncncs o f a dru g oftl'n expl ains till' manne r of its list·;
()('(';lsio llally snell all 1II1tlt' rstalid ing has savr-d a d nl g th at otl J('rnist' llIay h'l\1;' 1)( '('11 dis-
cank-d or lIas 'ill~t''ih'tl a more app ropriate dusa )!;l' re)!;inw n. Lastly, ).;J1(J\\111F; the pilar-
mal'tl).;illdil"'i I)f a dmg ititl\ tln- clinician ill anlidpiili llg th e op tima! tk)Sit~c n -W lllt'll for 0111
im ih iti llal pal ient am i in prt't:lil1in ~ what may happen when a tlOS:l)!;l' regimen is changed.
;\ llil\ ic tenet uf clinical plumuucekim-tics is th at the- magn itutk·s of hut h tht' tkosin 'tl
rt''i!JlIII'>t' <lm l lo'l;idty an' fUII11iollS o f tln- tln lg coucentrahon at IIIl" silt'{s ) of 'K1ioll . Ac-
l'(lTtl i ll~ly, tlu-rapout ic failun- O'SIIIt", when r-ither tilt' concentran on is too Inw, ghi ng in-
t·fT(,(1in · IIlt"fiIpy. or is 10 0 Iligh. pnlC.llld ng unacc cptahlo tod d l)'. Be-tween these limib of
concent ration lie-s a regton a....ocian-d wi th therapcuuc success : this n ,.;on 1lIi1)' 1)(' regarded
us <l " tln-rapeutte wtndow." Han ·ly can the co nce nt ration o r the dmg at II.It' sill' of ,K'lio n
1)(· 1II(';l\1I0't1 di rt't:1 Iy; im h-ad til(' conce-ut ratiou is lI\('a..lln 'tl at all ah t'm ati\ 't" an dmore
al'('t'ssiblt, silt'. ti ll' ,Jhtm Ul.
B;l\t '(1 OIl tilt' fon 1:0illg conskh-runons. all optima l dO'i<tF;1' regime n miglll he defilll'ti as
one th at maintains Ill(' plasma ronceutration o f a tlnlg wi thin thl' tbe rapc u nc \lo1lldow . For
lllallYtl m,gs. this the-rapeutic o!ljt"l1in.· is nu-t by ¢\1ng an initial duo;« to ad liMt · a plasma
conce-ntration within till' t1lt'ra pt'uti (' window and then maintaining this coucentratiou by
n 'plating rln- ;llllount u f dmg lus t with ttmc. Om' pupu lar and ('tIll\t'llil'ut lI\('an", of maill-
!t'llalll"(' is to ¢ \"t· a duS(' at d ist'n'!l' lilll(' inf(·rvaIs. Fi ~ In' 1--3 illllstratlos tht·llil\ ic (t'atu n'S
;l\\l)('iah't! \\1tll this appnlildl h~' (It'pk1 ing the I"(JIll't'ntrdlioIlS tlmt follow the ad mi nistnltit)ll
of hm n";II1I'US, i\ a ud B. 11l(' dusing; inte r..al is tilt' same hut the dust· ¢ \l-'u in rt'WIIll'1I
Ii is h \11'(' tha i ¢WII in n 16l1wlI A. Brt-aIlSC SUIllt' d m ~ ~'a'"!i « 'mains in the lui,· fm m
pn't."('tl ing t1U'lOS, iK'('lIIl1ub lio li ()("l.' urs unti l. witll hl <l dusing inlt 'rvd1. tht>amuunt !()'it t,,( plals
tile' <lOSt' ~ \'t'II ; a dlar.K'!I,ristk' saw·tc)()tlw'(l platt'au is tl wn adli("\1't!. \ Vith n ";Il1l'1l A,

Pharmacokinetics Pharmacodynamics

Plasma
,,
~- - -- ---

Site
Dosage ,
Regimen
Coneen-
Iralion
,, at
,1_ _ Action
Effects
____ _ _

,
,,, ,,, :,
,,
, ,
~ - - - - - - - - - - - -~ \~ - - - - - - - - - - - -~
t 'l " , 1_2 . .\ n ~ I'pr"",,'h In tI... ,I." ;!C" fir ~ .I."'"l(t. rt;(i mrn n it, phartn;K'<lki....." lUItl tI... "'........ ,_~ ~.....Illit.. fir
II.... I", ~ ~,..' fi...1 c "·fillt ~ l . TI It'n. ,'itl" 'r Ill.· rLl.nu d roll: t'<M ItVlltnttlfln ·li mr data fir tI..• r lTt't1. plulllt't'd lIll' u"' '11
r,...
via p1,~ nnat~ ok; rlt-tit .... . ~ ~I1 ....·~ (o Lt.IIt~1 11"... \ III IlMltli l)' 11... l lo: ~· " Wmt"fl t" lIt-l,.......upti m,,1 tI..-r.I~·'
• CHAYlH I

'i('n-ral IIm e's had to he ~n'll before d nl ~ uccunurlatkui Wit.. sufficient 10 product- u ther-
apt'lIlit' concent ranou. Hill! the rapy 1,( '1.'11 stop pe d hefnre 111l'1l. th e dm ~ lIli ~hl have I)('(,u
l holl~hl im,(ft"'l1in' ami perhaps ahandoll('(1 pn.·maturt'ly. Altt·Olillin .·'>', larxN closes lIli~hl
ha n ' 11('('11 tried , (' .~. , rq~i llll'1I H. Ah holl ~h a th erapeunc rt'SPOIlM' " 11111d ha ve h"'('11
<tehit'\'!, 1 fairly pmmptly. toxicity woultl lmn' ensued \\;111 l u ntillll('(l admin ist ration when
lilt" cone-utr auon ('x.<'('('{!t'{ l tllt' upp«'r limit of ti l l' tln-rapeunc "imln\\'.
'111l' S~l l t1 lt"l il' an timalariill aKt' ll t. quinacrine, dt...·!'lop!,'{1 t1 urillK \ \'m ld \Var II to suhs ti -
tu n- for til t ' n ·lativd y sca m - quinine. is an example. Qll i ll<ll ' rilll ' wa-.. either iud TI'<.1 h1.'
at'ult'1y a~a iTlS I u mb ria or .."",>nlu ally p roduced IIl1ilt't..'t· pl;tble loxidly when a dnsill~ rate
sllffid t'nlly h i~h 10 he d Tt't..1in ' at'l ltd y "'~.L~ maintained. Only afn-r its ph;tnll;IC.'t)!cillt'lks
had 11t'('1I t1t>fillt'(l W lL" Ihis d nl,g Wit'(l sut't.'t..'ssfllll)"·, Q llin<lcrint> is t'l im inaf('(! slm"'!y am!
at't..'lllllllb lt-s t>xh >nsi\,(-ly wnh n-pean-d d;uly ad mi nislration . 111t' allSV"t>r ""l'i 10 ¢ \'t> 1 1I ~t'
t111'it ' S l"'l'r lilt" firol fl>w days 10 nt pid ly at"ilit'\'t> therapeutic Sll{.'t..'t,.'SS, foll"wt'(l hy small daily

clo se-s 10 muintuiu ti lt' p l,L"llIa coucentratiou wn hiu thr- therapeutjc wi ndow.
TI lt' plalt'au situation in Fi ~. 1.....1 shows thai ho lh IIIl' widt h of lilt' Ilw ntllt>Ulk window
ami lilt' sp' 't"fl o f dm ~ elim ination gm 't'm IIIl' Si7A- of lilt" Illainl t"nann>do~ ' an d 1111' Fn-,
qm>IIl'" o f administration. \ \1 lt"1I the \\; fI{!ow is uarm w and the d m ,g is diminatt"tl mpidl)·>
small doses mu st 1)(> ,gh l.'!l ofkn 10 ." .'hit'n' therapeutic s m't:'t·s~ . Bo th cvclosponnc- and
d i ~o'(ill lIa\'(' a narrow therapeutic \\; m lo\\', hUI hl 't:';IIISf,' t')'{:II)SIX)rillt>is e1iminatt"f!Ill11t·1I
num- m pidly than d i ~()\i n . il hils to 1)(' ,gi\1.>11 mon- Frequently. O \)1odn is an ext reme
exaruplc: it also h a.s a !l am JW therupe-utic winduw hil i is t,lim inalt'(l wit hin minutes . TIl('
1I11 1~' nwans o f m!("fillatt'l)" l> llS ll ri n~ a Ilw mlx 'utic concentra tion of oX)1ocin Ihe rt'fort' is 10
illfu ~> it al a p rt'(; ~> am i cousta ut rate d in't(1 1)" into lilt' blood . 111is dt"gTt-'t· of t't llllmi is nol
IXJSsih lt>\\; 111 utllt'r Illud!"s of ad mlnis tmtton. Bt·sid t>s. had oX)1odn 11t'i:'n ~\1.>11 o r ally, Ih is
I x ,l~lx-p titlt> hc rmom- \\1Juld 1.01\1,' IX'i:>n dt'sl rt'~1,'(1 by tln- p mlt,(,1)"1ic (>UZ)ll1t·S in ti lt" gil'"~
tminn-stinalfhuds . ~t Olllh i ll e , ~Wll orally. is also t1t·s ln ~·t'i:l substantia lly before (>n lt-ring
th e gt'lle ral circulation, hu t fo r a reuson <IilTe rt'nl from that of oxytoc i n . Mo rphmc is ex-
tt '"si\"d y nw lalxl!i7A'(1 o n I);'l"solge t hmll~h the liver, all urgan I~; n g be tween lilt" g:Lst n, in-
n-snnal tract ;tlltl tilt' gt'lw ral circulation.
Awareness of tilt' ht'llt'filJi of llndt>r.;landilig pbannacoktue-ucs and coucent ranon- re-
"I)tlllst>n 'latin nships hilS led in n -cent )"t'il ro 10 the exit-m in> app liC'"dtioll nf sucll in fnnnal io n
by tilt' ph arm m.'l>ut ieal ind us try 10 d m g dl'si~ l , Sf,>lt't.1illll, mltl d l'\"t'lopnwlll. Fo r t·xalTlple ,
a IXIlt-nl t"flm lxl\Il\(l fOIlIlt! to l)t> pno rly alit ! un n >liahly ahso rh('(1 and iu lem lt'1l for oml
ad m inislr.\tioll llIay lit' sl1('I\1,'11 ill fa\1,lr o f a s<llIlt'\\'hal It>ss polt >ut hnl mort' (>xtl'll sh1.' I~· an d
rdiahly ahso rl)('(1 t'tllllf'l"lllIld. Also , IImllY of tilt" hll"je p n ll1.>Sst'S l'tilltmllin,g IxlllI phanna-
t"flkind it's alltl n,>sIXJIlst> art· sim ilar at'm ss mam malian slx't.i('S sllcll lhal dala eml II(>..>x-
Inll x llated from animals to p n '(liI1 1Iu:lnl ilalh l.,ly tlte likely he h;t\; or in human s, T his lilian·

" ';!it. 1-3. \ \1..." • •Im )/. i . ~ ...n in

• 6"'11.10...· .,..1 at Fi",. 1ti nK' inlo'r, Therapeutic
..... 1. (.I.·,.. ot,,,1 l~' II..· .1Tl",,,l. il . .. Regimen 8
Failure
(~lIl1l1lah .. "ilhin 110., 1...ly "ntil ;t

i. n ·'...~ .... I, Will, n 'Kin..·" A.

pt 'I" " "
11"" "P""Ii<' " KU .... i, . -hit'\,,1 ;U,
' 1....,)1.1, ,..ot inili.J ly. Wil h ..,;""'" H.
II..· lI"' r"I','uli<: "1>;....1;\1' i, ...-I,i,"\.,,1
''''In' <i " i.-l, ~' . 1."1 II..• pI..., ,,,,, ,In, l':
" .....·" I... titll' i, t1h i n"'I" ~· " •• Itij.:h.
Therapeutic
Failure

Time
CHAPTH 1
•
titatiw fnllllt"'\~lrk improves rhe chance-s o f sdt't.1i n~ not only tht" most p mmi sin~
(,( 1 1ll 1)( ltl ll{ l~ h ut also tilt" corn-et nmgt· of safe doS('s to first tes t in hu man s. lncorpo ranon
of a clement wi th the-se t·arly Phase I stud ies, usually in he-althy su bjects,
phan ll a('t Jkin('ti(~
h~t'tll(' r \\i th assessment of any sidt· effec t s produced. helps to define candidate d(Jsa~t·
forms and rt'~i ll l('IIS for evalua ttou in Phase II studies conducted in a smal l 1I1111l!Jt'r of
patie-nt s. Th e M' ph,l\(' II stud ies aft> aimed at de fining the most likely safe and e ffic-dliolls
d()54I~t' rt'WnwllS for use in the subseq uent larger Phase III clinical trials, o lten i ll\ul vi ll~
ll1a n~' t1lollsalld s of patit·nts. Ultimately. some com pou nd s pmvt' to ht· of sul1k i t"llt 1)('llt'fit
and safeI)-' to ht· approve-d for a particular clinical iudication hy dmg rt'gu latUfYaut hori ties.
Evt-n then tilt' d m~ n ndt'~ot,S \i rtually continuous postm arkt'li ng surveillance to Iu rtlu-r
n -fim- its plmnnat'tltlwnlflt·util' profile. This S('tillt' nce of events in d m g dt...-elopmen t and
evu huuion is dt pil1t-d sdlt·matim lly in Fig . 1....1.
o

FiK\lrt· 1-5 Illustrates an impo rtant problem idelltifit><l du ring t1mg dt...e lopment and
tilt'mp)", vuriability. Tlu-n- is a " i de ran~t.' of daily dose requt rem ents o f the oral annco-

PRECLINICAL CLI NICAL (HUMAN) TEST ING

TESTING
Dose (Cone) Population PKlPD
Response Trials Characteristicsin
Large EfficacyTrials Post-
G=v PK-gui• •• c;;::::J fi ~ = Marketing
In vitro PKlPD
Animal PKlPD
Dose escalation
Safety ~ Dosage
Efficacy
PKlPD in Special
Populations
= Surveillance

<::::;:7 Assessment Selection

Toxicity Patient Variables
IAnimalTeSting)
PhaseI

"lit. 1- " TIlt' d' '''''~ '1l11 '''llt and ",I lll.'Il1 lIlark.1illll: uf II ,Iruli:. TIll' pn ·lml1lall .lata l...Jp:.lo it"'lI lifnm"ni~! nl:,
'''''''I''MIIKL, and h. '''~.'''t "'.,fu l.Ic (; If I"'hlll:, in huma ns. Pha..'S I. II. alld III or human a,""Ssnlt'ut 1:.t'1lt" r...r~·
n ,m "p'nK I I" II..· 6"" ",I",iui, tr>lli.lt' I" I,,",, ;tu pot'''''''',
ri>. ... ...Juah" u I" .. 4.'11.'(1 ;1.11<1 II..• 1a1'):t4" In..ls.
"""I" '(1i",I~'. I'I"' nm.....l<ir..1k (1' 11:1 ..",I (W'arm" lyruunicc (1'1» ,;t 1:,a11,,·rnl.1 urinli: ..JI I'I......... uf dnJli: .10.",..4·
''P'' '' '" I t,,·11' ,,, "fJit:i" n'I~' .1.·61,,' ... 1'•• ;tiKI ..If,oct!,,, dma."" .. ,.,,,,, for "pli mal i", b'id u..l ' lOt'. 1'. ..tU...n.rtllli/:
. " ..., '1 l1allt.... II.·II" ,,, ..·6,... ,I..· I' K!I'D inf"mla li.." ,

~
25 "'111:, l ....s. TI,... Iai ~' .Ie...•..f ",oufan n n'(l"in'(l l" p".I".....· , imilar
pn>lh rornhin Iim.'S in 2lXl ••dnll p;<lio'nh ,'ali(.. "'ic"'~" ( I '''WI . ..
~ 20 3.3 ","I t l K.odl3lloll from K()(·h · W.~'r . J.: TIlt' serurn 1t.... {·1ap-
1' '' _ '10 t.. jIKIi'-ic I"a1il,;tlio>llUf ,ln' lI: .Ic""lll-'t·. Enr. J. elin, pham...·
~ 15 ....1. 9:1-'l . Il:l7S.1
D
o
'0 10

5
o N OJ OJ OJ OJ OJ OJ OJ Ol Ol Ol

V ~ ~ ! 1 I ~IJ:~~
Daily Dose (mg)
• O WTUI

a~lIlalll wa rfariu Iw('(I('d tn p n l(lm."l· a sim ilar pmtlmnnhin ti mt' (an md..-x (If h1()oc:llua~.
uJ.,hilily). SUlln:t'lIo of \"" riability ill d m g n "!'r_n!'iot' indmk' tilt" p"titonfs agt". ,wi~llI . t!t"P'''C'
(If ol: N.'\it~' , '>1)(> alKI dt-,:n't· o f M"-'{'ri l)' o f tl.t· c.1ist·a'W ', th"'Il;dit'nl's Rt' Jwtk lIlakt'tlp. ut!K'r
( I OI ~' ("II IK' IITt'n l l " adlllinL\ll -c.l. ;,u K.! ("m; nmmt'ut al Iactors. Tl a- n";lIlt is thai a sta ndanl
on

do ...agt· n ' ;IlH"1l t;rd dOlI{ lIla~' p rtl\'t" tberape-eric ill 'iOIIW patients. itw ff......1i\l.· ill otlH.·n .
am i tovic ill ..till or hers The Iwt....1 to adjust the (1oY.~(' «'; IIH'II of a dru~ for an indi\;<!lIaJ
rolli" nt i.. ""\'((('111; thi s 1It 't"t! is clt-arl) ' Wt'at~t for d mgs that han ' a narmw t1w nlpt' ul ic
"imln\\". Ihal ('xhihit a slc't"p concent....d io ll- Tt':'ipem.....• cu rve, am i that an' ('ritkal to (I m~
t1H'rdI'Y' E.\;ullplt"i. an- lli~n:in , u<ortl 10 t reat WIlW l-anliac di ",unk' n ; pI M·"~1 oin . IN.-d 10
p n"" 'nl ('pik-plic- l'On\lll!iion!i; tI"" 'PI1~lI i nl" !I!iol.. 1 to dinunish d lTonic airn'll~' n-si!ililIKT in
a,t1llnalk", ; alltl ('·yl'Kt<r>pJrint>, a n illlllllll1o"iupprt"S.'\il1l1 11...... 1 ill lI~an tran"'planta tion , \\i tb
tl. t"\(· t l m~ . a nti with rnan~' oebers. variahi lilY ill phannscoktre-ncs Is a majo r "iOlHU.· of total
\1Iri:,hili ly in tl m~ n"'p:lI1'it·.
It ... hll'l.·Ullli ll~ iIK"1l·a.\in¢y l'Ofll,nOIl to v;ain a.s 'IIIK'I. infonna tion o n va riability a'\ Ixn-
..ihlt· t1l1riult dm~ tk"'l.·lopllwnt l~' j:!;atht·rillJt. allJt"it lilllitt'ti. ilKIi\idual pla.'IIJd t·olK"t"lItr.lIion
;IIKI n... p:lII.... •tla ta in a t ug,' (lllJlulal it m of patit 'll t", tlllli lll't Ph;......• I I J d ini<"aJ t ria k At lt ' fIlph
;In' tllt'lI 11I.uk· til at'("tltlllt fo r th is \1lriahilil~.. ill te rms of sud, pa t....n t c hardll.1:t·risl in il.\ aV;t·
.IIKI wt'i~l1 t , 11k "\( ' IJ>t.1"ulntilm l')h a n nal '01J1K-ticl pI Jdn nal"tKI).T1Clm k shKlin Iorm a Il;,l\i "i fo r
tic.....,.... • n-,.,IIII·U recomna-ndatlons in di nit-a! pr.Ktic:t·,
Coatllllillidmtitm of \(·n:·r.t.l dm gs til a pa twnt , pn.",a lt·n t in chuk-al prdll.1:kl.·. can IXJ!i("
p mhlt·llI"i. ,\ It l.t M I~' tht· rt"lip lllst· produced by f"'"d('" h dm~ alrnw rna>' ht · pn'tl it1:aIJlt·. that
p",tIlK'(..1 I~' tilt' t'(, mhillatinn mOl>' IK' 1l"">S certai n a nd (It,(,"d.\ionall).· 1IIlpn.'tli ctilhlt·, Keto-
t"(IIIaJ'.ok· . (IIr t·""mpk·, d t....,)jd of iIllIllUlKlSuptln .......llt ac.1i\it)•• plllh'ntia tt'S tt. e dTt"t1: o f
t;'l.,It)'l;lx ,rillt·, I't ~ sihle t'UII'it'S uf thi s lind of e !Tt"t1: art' U14U1)" , III th is in.\laIK' ·. il\ in man y
o tllt'f'. ti lt' Inn-n....1:iu n iIlH'!\l."S a dw. Il~(" in phamlat-"t)!.;indit:s. SUlllt' t1 nl ~ stilllulatt" drug-

n it· 1-6, :\ h l OW, II........ ~ pL..t , p!-""" •

'~ .......Ir-.I.... , ,,( 1 ~t, lIin Irt..10 I" i' ~..... ,""It. 50
II"" .I."U'll: r.l,' , II re- I~ ('(......I.-nhlr >...u.tion In
I '''' Iwlth .... ,,;&/, (O" r m~ •• 3.Ir. ",M.1 ( Ro..
•
t1 n fn,m 1.", ,,1. I ~ : t:lT.",'h o( I'hrt,~t•• n in poo'
h ,h WIlt. rt"I.,,,y In ~ , Itl it. .""" "('''1...1;'...
111 1'1..."", I n KI" It",.-..I . :fT 1~"( Dn'lt' I" ft,·L. I ;' >II1
In TI lI" r 11.... ".. C.. nn.. ,IM ""'" E.I,I,..II " , D ,S, I).. . •
''1M .. ,,, I II , ~ C. I'rlt:l ",..I. M..... li ILu., 1 ~ ""I. IIl' ",.,j

• •••
1l"'ll1~I ,,~r. U173 . I'l" 227-2.1.>1 ,)
•
• •• •• •
•• • •••
. • ••• :!.
• ••• .!J•••:
• ••

·:-. Iot'."
.~
..... ~},.;~ ••

o
ii•

··.Ii. .'( ~
5
••
• ·1
• •

10 15
DaI ~ Dose (mglkgl
 7

1Ilt"lal x llizi ll.lt (' II7.)lJlt'S and hasn-u lim /{ loss: o t lw TS Inhilut I ht"~· {' II7.)"Il1l·S a nti slow ('Iillli·
nation. Still others interfere with drug absorption. SUt'1l iutr-ract ious are grad ed. tht' d lilll ~t'
in tht, pbe nnaco ktnencs o f 11 elm !!: va r ies ('on li llllc)IIsly \\ilh llit' ph..ma ccncenrration n f tin-
illtt' nK1i ng dm~ am i IIc'II('(' wil h tum -, Inde-e-d, ~n'll in slIllk-it'nlly high doe-s. almos t allY
dm g cau intr-ruct with anot he r. It h al..... I) 'S it questionof dt"grt'l" Ultllt'rstamling t ilt" lilian·
lilali\"{' elernents of interact ions ('I\Sl1n'S tlw more rational use of d m~ lhal may ,wl'< llo
1)(· (.,();'ltlm inish'nr-d.
Fij..,1l.l rt· 1-6 illust rates a sil lml ilJll in which lI11m itl l ri ll~ of the dmg concent ration Illay ht'
bt'lwfid al. Ch'N the narrow mllV;t' of tilt' daily dUSt, of tlu- autu-plleptlc drug p llt'II)1uill, fi ll'
plalt·au ptt.~I1l;l t1m ~ l'C lIll't"lItmlio ll varu-s 1ll00rketlly ""i l hi n Ill(' p atient population , Yd till'
tlwrspc unc ""indow of pht'n, 1oin is nar r ow. 7 to 20 IIlW[.; 1N." "I1t1 20 Illgll... tln- fn"' llIt'llt~·
and the <legrt'..• of Im:id l)' iuc n -ase- p n ~n'ss i\'('l)' wit h coucent ranon. H r-re again, pharmu-
coktm-ncs is tlu' major SOUn1" of variah ility. A p m~IJl <l t it' appmaeh 10 this p roblem wo uld
Il(' 10 adj ust till' dO~I~I' until tilt" des tn-d objl"l1i\'(' is uchh-ved . Control 0 11 a t!os,aV;I' ha.sis
ulotn-, hnwt...vr, h;t.s pr ocr-d difhcnlt. Control is achn-ved mon- n "adily and 1lt1.1lrllll'ly wln-n
plasma d nl ~ con ce m rauon d;ala an d the pl mn llal'C lkind it's of the dm,\?; are kno wn .
Dnlg st'!I'l1ioll an d tl ll'mp)' "a\(' Iraditioll ,IUy lll'('J1 llit."l'll so ld y 0 11 observutlons of tln-
d Tt'<.15 produced. In this ch apn-r, lill" ap plication o f p ha rmaluklut't ic p rinci ples 10 t11'li siu n
makin v; in d m v; therapy has bo-n iIlustr<lh 'tl. Bu tll appmadws an' 1\('('111'1110 ad'!I"'" optim al
dm v; therapy, T his book emphasizes tlu- pharIllOll1Ikillt·lir.: approach. It 1l('W1lS ""ith a con-
sitlemtiull of kinetic cOlIll'p h IIll-s il' II) phann:Jl1,khwtil'S and r-nds wi th a Sft-1 iOIl n mlaini nv;
~· I('(1('tt topics .
 , Section I

ABSORPTION AND
DISPOSITION KINETICS
 BASIC CONS IDERATIO NS

OBJECTIVES
The reooe will be able 10:
Define rhe following term~:
Phatmocokinelio. inkO'oU5Culor cod ell,lroYo:Iculor odminiS ll"otion, absofphon. drsco
sirian, distribJllOO, metabolism. excreeon. fif$l-pOSS effect. enteroheparic cycling. com-

IX"""·'"
2 , Disom the limilolionsro interpretation of phormocolinetic dota imposed by ouoys!ho! fo,1
10 diSlinguish berween cceccords odminislefed le.g. R· and 5-isomet'sl Of between drug
and melabolite
3. Show the general contribution 01 moss balance concepts to drug ObSOfpliOn and drug OM
melobolite disposition _

Phannacoldnencs hit.' mall)' uS{·flll llpp lk liliu llS that skill from ba., il· L'tJlll't'pts. Tht ·~ · con-
cepts a rc dt...·t>!0IX'l! in this ~'Ct iOllllf the !XX)". 111is cha pt e r sllI:'li fieall)' dt·filws ! ('fIll S and
dt' S('rillt·s a basic model for d nl~ ahso rp tiol\ and di sposition .

ANATOMIC AND PHYSIOLOGIC CONSIDERATIONS

~ 1 (';l-s u n' 1I 1('1I 1 of 11 dmg in til(' " ud)' is lilll ih'<IuSlIlllly to hlo(1(1or plasma. NOIlt't1wlt·ss. lilt'
infonmllioll obrahu -d has proved \"t·f)· uS(·ful. Sudl !lSt,fuh U'ss can b - t'xplaillt'(l hy ,Ul<tlo lllit'
and physi ()I(~c ft,,,tu ft'S lha l aOc'('t u dm~ follll\\in~ its ad ministriltinn,
n llJfltl lIr pl ~l-'Ill a, in mld itilJlI to hl'i ll~ a p ract u-al and l'o nn'n it'nt sitt· of nwaxure-ue-nt.
is III(' most 11 ~1-al nue fo r t1t·ten n i ni ll~ d m~ in III(' I M lt l~' . n lond rece ives dm~ Irom tl«- si!c'
of ad ministration us we-ll us {'a nit's it 10 all the O~im s , ind uding IhoS(' in whkh tilt' d m g
ads anti those in whi<:h it is ehmina tecl. Thi s 1ll00'I'lllt'lIt uf d m~ is dt'pk11'(1 sd lt ' lIl;1l it'<tIl~ '
in Fi ~. 2- 1. This scheuu- forms a basls for " /.y." if l/o:z,ic ",ofl~ 'li llc. ill I1JUlnllll nikilll'til'," , SII("h
Illnd('l in~ has applications not on ly in clmical p hannucoktue-ncs hul ill d m g d.'wlo pIlWIlf.
\1.'terillary medicine, and in iLsS('ssi n~ risk ilssot.:iilh'(! \\i th t'xl'll,sun's to ('lI\; n llllll('lIlal and
tll"{'ullilliunal Sl l hstill l ('t~ ,

Sites of Administralioa
Then- an' several sites at wh ich d m gs an' I'(JII1 ll1tmly adminisll'n'tl . The-se- sift's lIlay 1)( ,
d 'ls, ifit.'tl us t'illlt'r int r ava scu lar or extravascular, t ' lt m n I.Sl1l/u ,. administratiul l n'(t' rs ftl tIlt·
place ment of a drtl~ t.lin-c:tly into the hllMJfl, t·itllt'r inl 1a\'I'nlJllsly or inlm-arh'rially,
Extmnl.';{'u /a,. IIlIMlps of administration indlltll' 1111' oral. sllhlillWml, buccal. int nuuuv -
cular, subcutaneous. dermal. pulmonary, ant i n -ct ul mull's. To enn-r Iht' hllMJf!. d m g ad -

11
12 BASIC CONSIOU .6.TIONS CHAYlH 2

m in i"II'n'(! e:dJ'<I\"<l.S<.11 Iar ly IIIm t he absorht'(l: :\'0 a bso rpt ion sh'p is n '(I"i(('(1 w ht' ll a d m~
is adm inislen'(l inl ra\"\.s<:llla rly.
Dm ~ llIay also hI' atl llli nish'(('(! r('Kinnall)". c.~ .. into IIIl" p le ural o r peritoneal cavi ties or
intu tln- l'f:n·hmspi nill ll uid. Ik ¢ o nal mlmuustration includes iutru-artcrial injection inlo
tl.e \'t'ssd l('ad ill~ to a tissur- 10 he treated. l' .~. , mu- l'olll"in i ll ~ a ( 'lUll't' nJUS tu mo r. It is 11
pon-utialnwans of ~ai ll i ll~ a sd l'l."lh "(· tllt'ra pt·ul k· advan tage. 111is ad\'allta~l' . ill comparison
\\i 11l ut lll' r routes of ad m inistnllio ll. comes alMlllt by i!wn ';lsing d mg ('ll.pm urt· !oe..:Jly. wlw n '
it is lIl'('(lt'(l. a nd dt'1.·n ·ilsin ~ o r p lll(lnd np; tittle or 110 d MIlp;t· in (-'l)( ls lI n' tllm up;lu lIll til('
n-st of the IMltly. wlll'r(' i t is not wanted.

Disposition
O lin ' ubsorbed. a t1m ~ is d ist rihllt t'tl to tb l' various o rgallS of tlu- IKltly, D isl rihlllioll is
iullueuc......! hy how w('11 ('at'l. organ is pt' rfllS('t1 \\;111 bloo d. orgall sizt'. hilJ(li ll~ of d n l~
wi thin blood am! in tissue s, ami pl.'rnlt'ahility of liSS1U' 1llt' lllhr.ul('s.
T Il(" two prtm-ipal O ~;lIl S of elimiuatiou. tln- livt'r and Il.e kidlleY". a n.' sl.t M11 sc purately
in Fi ~. 2- 1, Tlu- k i d n(~ 'S a n.' III(' pri ma ry sih' for excretion of thr- dwmi t'al ly unaltered, O f
III l("han ~t " l. d m~. Tlu- lin 'r is the- us ua] orgall for d m~ lIlt'tilIK,!iSIll; l.uWt'\"t 'r. ti lt' kidneys
am! other n f~a ns can also play un im portant metabolic 011(" for {..-rt ain dnl j.,"S. nil' IIl('lah.
oltn-s ~, Io rnu-d art' elther furt her lIlt'f ahnliZt'{1 or t'x("rt.'lt'{ l ll ndl;Ul~t'{ l . Tilt' lin'f lIlayal.""
St't'n'\(' llll{'ha ll,l!;t'{l d nl~ illtn lilt' hi ll' . 111(' h lll ~s an'. or llIay be. au important route for

t·'R, 2-I . (),K" a/ N ,rilt',J fnom .IlIY of 1111' (lI;UI~ )i h'~

"f ...h"i"i,lr"I'''Il. ,Iml.! i. t' '''\1~.'tI I~' hle...I ,,, all ' ilo'"
"irl ,i ll 1I,,·I ly i' K'hlllill lt ,I..• ..(i ",ill.,li ll ("f)(..Il• . Sil .""
" f ... [mi"i' I ,,,.., i'Kl " .Ie,: a , ..,1" 1)": h , 1"·" pl..·....I -..ill '
c. 111" ·1..· " ,III '111>..,I" ' II't..I ' II..."" , ,f,l ll "~' "",I ",1:""
lro: """ I "" t! 1.-...1. 11..· .Ltrk_ " ,111 li~I'I .... ,l..,". 1 li'K'" Heart
" i l h "m","" n'f"r I " II.., ", ,,,, """·,'n,,·,,1 "f ,In'lt in
hle . "I .tI,,1 in 1"Ie,. " ...I.....1i"·I).·. 11... """" ",,·,,1 "f vrr-
I" ...n., .. ,,~' .Im( .".." h., f"ll.."" ..1 fru", ~i l,' uf ...l",in i. · .c
Ir.d i" " I" " I,' " f ,·lim i" ,,'" '''' •a Other •b
Tissues

.. Site of Administration

U Enterohepatic Cycle
Kidney

• Routeof Elimination Renal Excretion

Gut
Wall
Gut
Lumen

Fecal Excretion Metabolism

and Decomposition
 13

dilllilliltilllt \ulalile substa nces, fo r e xample, ~a.<;{,,(JIIS anesthetics . Another pot ential route
of elimination is via a motln-r 's milk. Ahhough an i llsi~ni f1 call l route of elimination ill the
mot lu-r. d nl K in till' mi lk ", a~' lit, {"Il1lSU Ill('( ! in suffkit"1l1 tlua ntit}" to alTl"<.1 tilt" slIc kling
infant.

CHIMICAl PURITY AND ANAL YTlC SPICIFICITY

A gt'lll' ml stah'lI ll'll l 111"('(1... to lit, miltll' about th t" dll'mical pu r itj-of prescnbedmedicnes
aud t ill' spt·t:ifki ly of cln-nucal 'lsSilyS.
Ove r tilt' years , a major thru st of till' pharmace utical indu stry has been to produce
tlll'rapt'llli e agents that art' not on ly as safe and dTt,(:t i\'t· as poss ible hut also an' well
e!la rat'leri7.l.'() to ('lISure rcproducibk- qualities. n it' majority o f admtntste red drugs today
art' tlwrt·fon· ('sM'llliaJly pun' materials. and coup led wit h specific analytic techniques for
their det ermination in bi tJlo~ic fluids. dcfinitjve infomlalio n about their phurmacoktnetics
mil 1)(· ~ai llt'tl. II 0wt' \'('r, a la~t' numbe-r of d m~ substa nces art' not si n~le c hemical e ntities
bul rather uux tun-s. This particularly ap plies to ste reoi soun-rs am i protein s. TIlt' most
com mon stereotsomers found tc~d lwr in medicines are optical isomers, o r compounds for
which their struct ures an' mirror images: tilt' drug subs tance is usually a r acemate, a 50 :50
nuxrun- of tll(' H- and S-iSCllllt'T'S, Soim- d mg suhs ta nces contain gpOIl1t'lric Isomers . and
still others. especially proll'Ins o f h i ~, molecular weight dl'ri\'t.-d from natural products or
Ihmu~h fermentation , lIlay IN.' a mixture of struct urally n-lated . hut d ll' Jllieally disttnct,
l'tIIllI'N IUmk Each dWIllil"a]l'ntity wit hin the dnl~ subs tance ean haw a d ifTl'n'nt phar-
mal'tllowe, toXil'tl]o¢ e, am! pimnnal'tlkilll'lic profile. Somethnes Iht,Sf.' dilTen'll('('s an' small
ant! inl-'tmsc·cl" elltial. utlil'r tunes Ihe difTl'n'IIl-,('S l'lUi ht' therapeutically important. Fo r
t'xample , dext roamphetamine (S. jso mer) is a pOle nt central nervous stimulant, when-as the
R-('nan tiollwr is alm os t d t'\uiclof such activity. Desptte such differences , mall)' commonly
('mplll)'('ti clu-mtca l :L\sayS do 1IC11 d istinguish [x-twee-n stereotsome rs. Oll\iously, und er
Illest· cirx-umstauces, alk mpting 10 ' lu,lIltify the various pnx'('SSf.'S anti to n-late plasma
coucentrunon to respClIIM' has llIallY p roblems with no simple solutions, Notwit hstandin~
Ihest:' problems. spc.'(.i fk Informat ion about eac h chemical ellt ity should he Sf.)u ~h l whenever
possihlt·, h ll·n·'L\i ll ~]Y, sten-oisonu-rs an' hei ng produced as smgle chemical t'nt itil' S, such
as S-n<lproX)ll . whit-I. a\uid tln-se problems. In contrast. mallYnew prntein and pol)llt'ptidt'
d nl ~s are b(' i n~ intr oduced that may. ill mallY instances , lad purity. Furthe rmore. these
suh stauo-s an' o ften measured by assays that lack Spc.'Cifil:ity.
An added problem exists rollll\\ing d rug ad nnntstration , namely. lilt' for mation of me-
tabohtes. To 1)(· of value, all a l\al~1 ic' proced ure must dislinguish between drug and metah-
olit l'(s). Today, most assays 11:1\ '( ' t1lis des tred speci ficity. eXl't.·p t for some of those 115('t1 to
nn-axnn- lll.tIIy protein s and !'Nllypt·pt idt·s,
A pon-nttal pmhk-m ex ist s wheu using radiolabeh-d d nlgs, IlIl"CII'Pn r,ltioll of 01 1(' Ill' mon '
rudiouuclidcs. 1l.'llall~' He and ' II, into the llIolt'(.·ular stnll111re allows for simple alld n ·ad),
de!t'dioll \\i thill a lumplex bio]oWl-' milieu. h nl nol Ilt'(."('ssari l)' o f tht' ad minislt,l't'tl dntg,
COlllplt,lt, n -c.'tIH'I) ' o f ;III of a md inla!)(·ll'd dosc' in UrilW, follu\\i ng urdl llmg adlll inistrdtiun,
is lISf.·flll in i dell ti~\i llg the lI]timall' ],x·ation of d n, g-rt"latt.cJ matl'rial bill lIlay prmide liUlt·
to no information ailCIIII the' dnlg, For example, a1mosl all of ,III ord lly ac.lminbtc'n-d d m g
lIlay han' !ll,'t'n dt>slrcJ>·t't l in lhe ga.stroinlestinal tml1 , fm m whil·h t hl~ dt'gnulatinn pn ll!ul1s
c'IIIN Iht' hoch' alld an ' ('\'t'nhtallv t'.\cn·!t'tl illllrint'. A b:tsic lesson is leanlt"(l liNe. D islin-
K\lish l"lll't·full)' ht'I\\'('t,u dnl~ ami IIIt·taholile(s), ~l allY lIIt'laholilt'San' of in!t'n'Sl. l'S{X'(.; a1 ly
if tl.ey art' ad!\(' or toxic. Each d\{' mi(-d1 !;'util) ' lIlust lit' ("Cmsitle rt"d Sf.'par,ltt'ly for kine·tic
dat a lu he nlt'anin ~flli.
 14 CHAPTE R2

DIFINITIDNS
" h htlu ~h the- p rnn ·s ~t·s of aleorption ami e-linunation l ift' dt·M·rip ti\'(· and their II1t·allillj.,~
an.' app an'll! at fi.....t !{hUll...-. it is n nly wit hin lilt' context of expc-rtun-n tal o h'I: I"';llio ll tha i
th"y (~UI ht· '1IIillltirit'd (Chaps. 3. 4. a lld 6). G t'llt' ral dcfiuutous of tht' P OIl"-'"St·s follow.

Absorption
AbsOIvt iull is dd il\l'il i I.' III(' pm<:t'SS lIy "bid l Illlt:h;IIll-tI'l! d nl~ pnM.,,'tls fru m stn- of ad -

lIlin isl m t io n 10 silt ' of IIW;lSlIrt'lllt'nl wi thin till" hutly. To illm l mlt· why llhscllVti ll1l is dt·61\('(1
ill Ihi'. Wot)', 11l1ls itll' r the- ,'wills dt'p itkd in Fi ~. 2-2 ;L" a t1 m~. ~\'t" ll mall)" moves fm m
IIn- :0;111- o f ad m in ist rati u n tn 1111" !{t'llt" m l ci rculation. Then- a n" S(-"\'(' m l pnssih lt' s ilt's Ill' los s.
{)111' sill ' is l ilt' !{'lst miute-st uml lunu-n whe n - d t'l"lllllpns il io ll lIlay oc cur. SlIp pllst·, however,
that a t l m ~ sll "in'~ dt ost n l(:tiun ill IIIl' lunu-n n llly III1M' ('(lIllplt,!t,ly 1I1l't aIM,li:l.t't1by t'liZ)1 I1t'~
:lS it p;lSst'S 11J",u ~h till' me-mb ranes uf l ilt' ~,lstmill!t's l i nlll tract . One \\'lIl1ld as k. h tilt'
dm ~ ahsorl wd ? E n ' n I llo ll~h lilt' d m~ k-aves lilt' ~;lst nJi n lt'st i ll al Ira ti , it would lIu t
t11'1t'{,It'd in t ilt' gencml circulation. I1t'J1{1.', tln- d rug is nul absorbed sysh 'm im Ily, Taktng
"t'
Ih is a r~"' I IIlt' nt (lilt' ~ II'P fu rt her. h tlu- d rug ahsnnM't ) if all of the orally atllll inistt,rt't I t1n l ~
wen- til 1l<I' S Ih mll ~b ti ll ' 1llt'lIlh r,u lt's of the ~,l,l ",illtl-s li ll,tl t ract inlo the po rtal vetu o nly
In 1M' T1lt'l a IMlliI"A't1 ('(lIl1plt' tt'ly 011 j);l'S lllg: Ihn)lll-':II tlu- lin ' r? In an t'·' Ilt'rilllt' lIl p t' rfll rllll ,{!
i/l .. itn. ill w hi d l l ilt' 1 ); 1'S;I~t- t ,f iI d m~ ,I('",S\ tln- iu!t'Stin al lllt"mIJnlllt's is studn-d !'> t'j);tm ld y,
tln- answer \\lII llt1 IJ(' IM)sil in ' , If, how t'\1.'r, ,lS is ('(IIll IllO II , h lond or plasrna ill all arm vein
is lilt' silt" of me-asun-me-u t, tlu-u. IJ(,{",III"l' nu dm g: wfJllltl lM' detec t ed. tlu- a llw, 't'r \\1Iu ll!
1M' III"gillin', IlIdt't't1. 10'S ut allY silt' p rior 10 lilt' sitt' of measurement contri butes to ;1
d l'{"rt',l'il' ill tlu- ~ystt ' lTlk' ahso rp tiou. 11\1' ~;I' lnJ i nlt'sti llal tissllt 's and ti lt' liver. in particula r.
a n ' o fIt · II silt 'S o f d im ina lioll. 111t, n ''1ui n 'lllt-nl for a n orally adlllin ist l' rt "<1 d n l ~ In ll;l'S
l " nJtl~h Iht,"l' liss\lt,S, p rio r 10 rt'al,:hillg: tbl' silt' o f rm-asun-nu-m . makes Ihe extent o f

Gut Wall

Liver
Portal
Vein

To Site01
Measurement

Metabolism
Metabolism

To Feces
HR. 2-2. " tlnJ~ "" " 11 a.. .....I..\, ,'rK~""'''''' ",,,"-r.J h...rri<·n ..", I " I... .. f ...., ill ih "'~ I'H'" li;d " " " 1'T,,,·,,1thlli ul:
R.."o-"""..'j" ,01 "1""'1lti..,,. 1"'." "'1'1.1,' "j
" r I,y ""~ ........ ill tI.., ", ll w.. 11 ..,... (.,.,,,
~ " li.. n. 10M' ' 'Io...hll"I I', ·n''' ·''''ihl~·. "",I ""1..
fi,,'
f PO'''' ..t......p li" " . H,' ",,,, -..I "f ,1",1:.... it
1>,.".", in II..· "' 111" ""'11
1"'"' .... 11In..,!:I, II.., 1M "
f"rllo .', n ~ I,,<~, . ..l""'1ltit",
CHA.PTER2
"
ahsorption dcpondeut on d iminalion. T Il(' loss as d Ol ~ pa~S(·s . for the firsl time . th rull~h
sites of d illlinatioll. sll(:h as tln- ~:l~t mi n lt'sti nal membranes and the liver, d ll ri n~ abso rption
is knowu us Ill('jin t-IHlu t1Ji.'l1 .
Absorption is nol res tricted to oral admiuistruno n . It occ urs as w.:-II follouing tnt ramus-
<'11Iar. slll)(:lItall('tllls, and other extra vascula r routes of ud mi uist r ation . ~Ion itori ng Intact
d Ol ~ in hl(1l 1l1 or plasma olTers a IIst'flll nwan s of a..sess illg the ('ntf)' o f d m g into the syste mic
circulation .

Disposition
As absorption and d imillatio ll of d Ol~ art' juterrelated for pl l)'Si (ll~c ami anato mic n -a-
SOilS, so too art' distrihutioll and elhmnanon. O nce absorbed . a d m g is delivered sim uha -
Il('tlllsly hy arterial hl()()(1 to all tissue s. incl lldin~ organs o f elimination. D i still~uish in ~
lx-twec-n e-huuuution and drstrthutfon llS a ('U II st' for a decluu- ill concent ration in blood o r
phsma is nfh'n t1iffil11l!. lJisIXA\·ltioli is tilt" term IIS('(! to em brace both pnx'(·§.·i('S. Dispo-
.~it itm lIlay 1)(· defiued as all Ill(' pn x'('Sses that occur subsequent to the absorption o f a
d m ~. By d t·finitioll, lIlt' l11mpu m'Ilts o f disposition art' d istrihu tion and elimination.
D ist ribu tion. Distrih utio n is the pn x't"ss of rt's"ersiblt" transfe r of u d m ,; 10 .md frnm
the sih' of measurement . usually Ihe blt)()(1o r plasma. An exemple is dis tri bution !Jt'h\1't'n
blood ;llld musek-. Th e pa thway fo r ret urn o f d r ug 11("('1.1 not he the sann- lLS that !t'a\; lIg
tln- circulation. Fur example, dm~ llIay he excreted in Ihe bill'. sto red in and rt.·lt·.l.....-d From
tilt' ~all hl :l( !l lt·r . t mllS i t into tln- small intes tine, ami bt· rea bsorhl'tl int o the circulation. B, ·
doing so, til(' t1m~ complet es a (")"(:11', the l'tl tf'mlu1H1tk C1Jcle (S('t. Fig. 2- 1). If all tilt' dm ~
is rt'absm !J('t1 in this manner. hiliar:v sccn-ttou is not a m ute of e liminatio n: till' ()t·ling is
then a component of dist ribunon. n i l' situa tion is analogo us 10 Ollt· in whic h water is
plllllpl'1.l from om- n -senotr into unotln-r, only 10 drain hack into rln- origi nal n -w rvot r.
Biliary v -crenon is tr uly a mu te of climmntion only 10 tilt' extent that the t1mg fails 10 lit,
ft·ahsur llt'1.l. Th is Iailurt- llIay result fmm dcc omposttion in IIIl' intestine, p' xJr absorption
d Jar.K1('ri stit'S, or otln-r complica tions. Uncha nged drug in hilt' thai is nei ther n -ahsorl x-d
nor dt'l'(,ml)()St1.1 ill tilt' intest inal tract is t'\"("l1tllull)"excret ed in tilt' feces .
E limina tio n , Elim ination is ti lt' Irreve rsible los.~ of d Ol ~ fm m tilt" site of meas urem e nt .
Elimination occurs hy two p nx"l;'sS('5. excretion and meta bolism. 1':xcn1io/l is ti lt' im...ers-
ihle Inss of d lt'lIlkall" IIl1d lltllgt"t1 d rug. •\ln aboli.'01II is tht' conwrslou of one l'ht' mit'lll
,!)("{1t·S to anothe-r. Ck,(';lsionally. rm-tabolites are conve rted hack to the drug. As with eu-
I('mlll'pal k l.,"(:ling, Illis nu:ttllxuic illlrmml'f'nitm is a rou te of d imination only to the
t·\ tt'llt Ihat rln- I1lt'l al)( llill' is excreted or oth("m;S(' im"'1:'rsih ly lost from Iht' body.

BASIC MODEL FOR DRUG ABSORPTION AND DISPOSITION

TIlt' complexiu... ~ of hu man anato my am i phrsi o10r0' "'11111d ap pt'a r 10 make it difficult, if
not impo \sihll'. to 1II1)(ld !low Iht·I)(IlI)' handles a dOl ~. I't'rhaps surprisingly then, il is a
simp lt· ph armlll'()I...;nt'tit· !Il()(lt,l, depil1:t'1.l in Fig. 2--3 whit'll ha~ pm \'("{1 use ful in 1Il.1II) '
applieatiolls ami is t' mplla\i7.l.'(l lhm ug!lnul IImd l of Ihis " t)(lk. ~I on' ('()mple x 1Il(IlIl'1s art:'
IIt'('('ssaly 10 t!(·St:rihl· till' pha rmiK1Ikint'til-s of SO lnC dmgs. Examplt·s of sud l llltlllt·ls an'
<!t'sl'rilJ('t1 ill C hilps. Ill, 19. alld 22 .
11lt' I)()\l's in Fig. 2-3 n:'p n 'S('ut cem II Hlrt r/U' /l ts Ihat logi('lllly fall into two d'l~S(·s . tmns ft· r
or
'lIu l d uolllit'ai. 111l'sitt· adm inistra tion. tht' IJ()(J:.·, am i t' xert'la art· d t·arl, · d im 'nont plat'los.
Eal' h plal,(' lII<1y lx' rt'fem'tl to ll\ a Itx'lliion or tra nsfer l'Ompartlllent. In l'OlIlr.1.sl. 1Ilt'lah -
ol islll in\l lkt,s a d n'mil"ll (1lUu'rsioll ; Ihl' ult'tal)()lile in tltl" I)()(l... and in t·xt'n·ta art· IllI'rt·-
fort· in l111T11Mrtlllt'Uh tllat di ITt·f" dl(' mim lly fm lll the d n lg. '
 .. CHAPTER2

Tln- Illudd is h..L\t "{1 U ll a mo unts o ( dnJ~ a nd nu-tabolue. lI uwt,\'(' r. t1H' amounts of dnl ~
ilm l lllt' t.thnhlt' ('l UI nlJ l~' lit, measured in urin e din'C:tl)'. '111' tnt"I IUIllMlIlf of dm/;t 11K-tal...
n lil.l.'1! illdmlt... IIlt'hthnl itc'!i in , a.\ ",..J I as el inunated fro m. !II(" I..dv. nit" a UK)U1l1 in the
h()d~· is mll.llly dt"lt>mlint"(! {nlln measure ment o f Iht> hlond o r ph, ;na ('U IK't ' n l ratiu lI . F~\·
lilllah'~ of t lm~ ill III(" ahsurvtiull l"Olu pal1 mc'n t art" ..tso mually mad. · int lin't11y from either
hle. .. I IIT urne - (Lila. DnJ ~ at d lt' aho,()rptio n sill- inC'llldc", that w hidl is IIt"'-'t"r absorbed. for
,·u-m pl.·. d nJ ~ th ai is 1I 1 I i lllah'~' de c omposed in tilt· ga.\lminh"s lirwl trolC.1 or 1m! in th e (c"(1;"S
.Ifh"r oml .\lJ lIlinbt rJ.tiun .
n it' mod.·' is rt·;" lil,"visuahzcd from mass haliUK't' ('(lIIsick· rdfto lls. 11 It' clu!>t" ts al'l'Ul.llllro
fo r 01.1 au)' O Ut ' trme- ~: til(" molar amo un t o f suhslall(.,\' in ( ' al-ll of Ill(' ('u m pa r1nwn h :

Amounlof Amount Amount Amounlof Amounlof

Dose .. drug 0 1 + of drug + of drug + rnelobo!ile + rnetobo! ile
o ~ ,ite in body excreted in body el iminated

11M' ma.'I.'I. haldfK'f' nf dm~ a mi related mat erial \00; 111tum- is SIM"' 11 in Fi ~. 2..... . SiJl('\' tlie
SIIIII o f ti l(· 11K"''' a llMllm h of d rug in transfer anti dM'mie-<lI rom part nK'n ts is r- qual to tiM"
lll r'l.ol'. ttM' '1.11111 o f tilt" ra te-s o f dlall!2:t" of Ihe (Im ~ in th(."\C' l·ulllpart nk"nts m ust IN.' equal to
7~ ' nl 'Io() th'lt :

Rate of change of Role of Role of

drug in body "" absorption el imination
2

n it' n ·latiu lI'l.h ip'" (·\ p n...._ 1 in (-:'1'" I am i 2 apply lIIKIN all ti n.' llUstarK'l'S. n~anlk'Ss of
IIJI' narun- uf tilt' absorpnon and eliminatio n p nx'-~'S . 111l')' an" part in lldrly 115(·flll in
dl·n ·llIpi ll ~ mon- o unplex IIl(Mk-1s for clua ntil).i ll!2: drug absorption ami deposition . Phar--
"llln,1.:I Ilf1 ;c~¥ is tiM' quant ttanou of the- tune- (, )UI'1'e of a d nJ~ am i its llH'talxllilt'S in tt.(·IMKly

Drug at Drug in Excreted

Absorption Site Body Drug

Metabolite Eliminated
in Body Metabolite

nil:. 1-.1 , ,\ ,lrull. ,. "m"II"' I.... a1 orf....I"'lo II t...h · ..."d ..Ii"'" rn .", II to. ._""....., nort ,l,.....
n p" '""" .,r ...t"'''I'h''ro ~ 1 .....'tal n' ~ i....Iil. ",It. anuoo,:....t , <:t ,poort "'ilt.
t n " 1""" ,10 n-pn--.__ dtffi-n.nf 10 ohrf..n.nl d "'il. c. _ ~a1.oLl..).
\1t1...t..",I I"'''' , n.....·.. ....., t".· f,,,"h.... ~..t.oL .. n tn<Jt oh<...n l .... ("\("ft'f.", .
CHAPTER '1 17

100 Filt. 2-4. Till..• t~"l"" of tln1lit "' ..\ "....

1..""li'.. i" ......., "f tI... mlTlp"rfn"'llh
/ Drug at Absorplioo Site i., .•
.t.o.. I" Flit 2--.1, n ..· .. rnc"lllt .~ d ,
'~""I rtn ll Ii ...1' 1i1.. .. 1"·n~·"I..~·
75 of , ,1c lOIl i"i."· l. In "'i' M.ilrnl,k·.
Eliminated Metabolite ..II' ,1< I " •.,rl I,
~
8
'0 50
/ Drug in Bod~
"
~
u
~
~
0-
,I Excreted DrlJ9

25

o 4 8 12 16
Time (Arbitral)' Units)

.uu l tilt' ck-velopment (If appn lpriah ' lIlotl.·]s In dt·S(.'ri! ll· ohservatious and p rt'1lil1 out comes
in otln-r situatio ns.

STUDY PROBLEMS
(Answers to Srvdy Problems ore in Appendix 11 .1
I . Defino' 1111' tenns lish ..1 in th p fi" t o" jt'('fiw at tlU' Ill;;nning uf thi s chapter.
2. Brit·lIy sia l(' why an unalyncalmethod thai do!;'s nol di slill~ui sh IX'h\1't'1I n· and S·i·
SUIlI,'rs can I" atl lu pruhl" lIls in ti lt' interpretution uf plasma data follo\\inJ: admtnts-
tr at iuu of a met 'llIk mixtu n-.
3. U...illJ: F iJ:s. :2-.1 aud 2- t slx'(1Ib l(' 011 how an .LSSilY thai measures tilt' ...11 111 of d m~
and illat'fin' 1Ilt'lal ll)lift, llIi ~h l inllllt'I\('(' a cc rrela tton I)('t wt't'll p!'lsma concentrauon
am) tlwm p' ·lItit· n·s lxlIlsI·.
.1. Follf)\\ill ~ oral ad millist ratioll of a t1 m g lalx-led with a nlditl<lt'fiH' alo lll a II (If tilt' v

mdio;ld i\ily is n -covert.. 1 in un lit.... Can on .. conclude that tht' dm ~ is ,'(,mpl,·,,·ly :1'"
so rlll.'t l?
.5. Answl'r I'ad l of tilt' follO\\i llg fllll·stioIlS. wlak h n-late to F i~. 2-1 aut! Eq s. I and 2.
a. D{ll's a 100'l n'{'(ln : ry of luwh an gl'tl dnlg in urin e ftlllowi ll ~ oral adrnlnistranou
illlli('ilh ' IhOil d nl ~ is t1ll1lpll'll·ly ahsn rh:'tl and not 1I11'Iaholiu 'tl?
h. \\ 111'11 dl x's d m g in lxllly reach a peak fnllO\\i ll~ admmfst rat ion of an oral do....'?
I" C'\l1 lh,· uuunmt of dm ~ ahsur lll't i up 10 u h";\l'n ume Ill.' det .. mnnc.. l?
d. \\111'11 is mho of d l'llIJ:t' of d m~ in IXKly equal to nih' of dmg d iminalinn?
P. \\'l lt'li dOI ' ~ ran- of ('h a n ~t' of dm~ in h,x ly apprna,.'h nit.. Ilf absllrpti()lI?
 INTRAV ENOU S DOSE

OIJlCTIVES
The leader will be able 10:
1 Deline rhe meaning of holl~ife, eliminatiOn rcie ccoscot, li/$I-Older prOCMS. volume 01 dislff-
butiOn. clearance. renal clearance. and f'ocllon excreed unchanged
2 Estimore the vo~ 01 holf·liIe, elimination rote ccoscot volume 01 di!>tribJtion. and clearance
from plasma Of blood ccecerecnons 01 0 drug following on intravenous dose.
3. Esllmote Ihe vo~ of half-life, eliminatiOn rOle conslon'. ond frocliOn excreted unchanged
f10m ulinory excretion dolO following on inllovenous dose .
.4 Estimate The value01 !he reoclclearance of a drug from conbioed plasma and Vfine dcrc.
5 Cokulole rhe concentration of drug in the plasma and the amounl 01 d".'9 in the body With
lime following on inlToveoous dose. given -..alUM 101 the phormocokinehc pClfOme!ers,

:\d lll i ll i ~h'ri ll !!

a d nl ~ illtrd\1l-"C:11Iar ly ensures that 1111 of till" d OM' enters ti ll' ~l·Ilt'm.1 d R.·\!-
larion. Uy rapid injection . ele vated co nce ntrations of dnJJ,?; in tile hloo d can I){' promptly
adl;t'\l'(1: bv infusion at a coutrolh-d ra te. a constant eoncentratton can hI.' rnalntalned. \ \ 'ith
/ltl ot lw r r oute- of aduuuist ratton can blood co ncentruncn Ill.' as prolllptly am i {'mO('IIt1,.
conr mlled. of tln- two illtm\';L..culur rou tes. tilt' intravenous [ t.v.) one is the most Fre-quently
(omp lo}'("tl. Intra-arterial administration. which 11a_" gIl'ah'r Inherent lllanipu lat h'(' dange rs.
is n ·S(·....·("(1 fur situatio ns in wh i(:h dm ~ locahza non in a spt"t-; fic o~all o r tissue is desired.
T ill.' (iispos itiull charactcristlcs of a dmg lift' ch-fi ucd hy allalFjng tilt' tem po ral changes
of t1mg and meta bolites in blood. plasma . am i ot.'(-d..\ ionally u rine follo\\; ng i.v. ad m tnist ra-
non.
lI uw thi s infonnation is ubtaillC"tl fol h""'i ng a rapid injection of tilt" d rug for ms the IllL~is
(If thi s cl.epn- r. The- rt' lIlaini ng chapte-r in this Sf.'<.1in ll d('als wi th (...-ents folloy,; ng an e xt ra-
\1l-<;1:1IIar tlmI.'. 111(' pliarmacokim-tic informatio n so dt'ri \'("tlfon ns a bll-..is for maki ng ra tfoual
c!c"(; sic)IJs in tl ll·rap(·utks. til(" sllhj('t.1 of sllhsc'tlllt' nt se-ctions.

DISPOSITION VIEWEO FROM PLASMA

St"n· m l ult't hocl.. an' t·lJlp lu)l."tl for grllphkally d ispla}i ng p llL'ma conce nt ratton- u uu- data.
O m' t'(IIII IIIOII method. shown wit h t11l't lpl.)'lIill(' ill Fig. 3-1A, ts to p lot concentration
again..t tilllt' nn rt':'llar (C llTIPsian) gra ph Illlpt·f. D l'pit1("t1 in th is manner, tilt' plasma
{'o n('('u ! rat io n is nhst ·....·('t l to fall rap idly imm("tliat d y aft e r a 500-mg bolus. in th is <:a 'i(' [rom
appm\illllltd~' 2~J to 18 IIIw'L wi thin 3n min . Th ereafte r. ti lt' ra te of t!1"(,lint' become s 11111<.'h
slower. tilki ll~ almos t a nother oj 11I's bc fo n- th e ('()11('('ntriitiflil falls 50% to 9 mWl.. Anotl lt' r
111t'!I1od u f d isplay is a p lot of the sanu- dat a o n M·m iIOKdritlulli<.' f'<llx' r (F ig. 3-1H). n it'
ttnu- scah- is till' sanu- :l-' lx-fo n -, hut nnw till' ordinate ( '(lII('(' ntmtion) scale is It~ari th lll il"

II
 19

S ol il't· t il(' sha rp hn-ak at ahoul I hr wln-n tilt' plasma conce-utrut tou is ubout 16 IllWL.
Bf·fon· lhi ~ tune, tilt' fall is ra pid . Then-afte r, tilt, d l 'i ...hm- is s IOWN and . Oil thi s wnulo ga-
n thmic plot, appt,';m; 10 l'tmtilllll" lim·urly. 111t' ea rly phase is l'll llllll(m ly r..llIl'() the tlhtrl·
Imtion plum· an d the latter, th e e!im;Flo titlll I,"ast'. 111is di stinct ion i.. sometimes flot clear-
cut . an ' <'' 1)('(1 more compk-n-ly d ist"IIS'i('(! in Chap. 19, Distrib ution Kinetics .

Distn'bution Pfluse
TIlt' distrihutioll p!l;l'i(' is so ea llt'l l be cause distribution primarily dct emnnes tilt, (·arl), rapid
<!ed im ' in plaSIIl<l concent r atton. For Ilwophylline. d ist ri buti on is ('xtrt' IIlt' I~' ra pn l a mi oc-
cu rs siKll i fi{,illl t l~· I"'·t·1l hy tln- time n f tilt' firstmeasurement. 5 min . This must be so bec ause
lilt' amount (If theophylltue in plasma lit tilt' end uf this p -rtod is onl)' gtJ 1Il~, n lis value is
{'a l('ub led hy lIlultipl);II~ tilt' hi~llt's l plasma concentra tion. 33 mw'l.. by tln- plasma volume.
3 L. Th e Illiljo ril)', .to I Ill~ or 80% of tlu- total (500 m~) dose. must han ' elreedy It'ft tilt'
pLL\rna und Ia-cu d islrihult't! into et her t tssncs. Amoll~ these tiSSUl'S an' till' hvr-r and tilt'
kitlrlt'ys. whtch also clear d rug fmm the body. However. althou~h some dm~ is eliminated
dllri l l~ 1111' t'<trly monn-nts, tht, rr.1l'tin ll of tilt' atllllin ish·ft't! dn....• In..t d ll rin~ tilt' dis tri bution
phil"l.' ts small for th t't)phyllint' andlllan)' ot he r drugs.

Elimination Phase
D urilll-: till' dtstnhunon phil~" changes in tilt' concentration o f tim )!; in plasma ft'fI("('t pri -
marily movement of drug within. ruther IhlUI loss from. tht' hnt ly. Howeve r, with time .
di stribut ion ("fltlilih rim n of drug ill ttssuc with that in plllSJlla is t'sla1J1ish('t1 in mon- and
mon- tisslles. and t'\"t'lIhmlly, dlan,l!;t's in plasma concentrat ion rd lt"('t a proportional dJan~t'
ill tlu- (UlI("('ntmtiollSof tim ,!!; in all otilN tissues and , hence . in lilt' amou nt of d mg in the
IMM.I)'. D lI ri ll ~ th is propo rtionality phase tilt' IMXly ad s kin('ti('ally a.s il sill,l!;le containe r OT
('(Impartlllellt . As dt't'lillt' of tln- plasma coucentranon is 1J(J\\l due on ly 10 elimination of
dOl~ {nun tilt' 111M(1)' . this phil'>t' is ofn-n called t ill' elimination pllll"l.' .
E lim inati un lI a lf· Life. n it' elimination phase is d,ar.Il't('ri7.(""I IJ)· h ' 11 p<tr.lI11('t('f!i, lilt'
l'/illli,wtioll Iwlf-/ifi' (t !12 ) aud thr tJp1'nn'nt uAtll/U- of d;'~t riJ",tioll (\ 'J. n it' eliminatinu half-

A 8
40 100

~-
~og, 30
} ~-
~og,
>-E >' E_
~- ~ -~ \ . ..............
... - 20
~ c
•• ~ c -
00
~
~
.-
~ ••
~ 2 !1 10
..... e g
...........................
~ -
E ~ • • E " ~ ~-
~ u ~u
c 10 • • •
• • a:8
~
"- ..,
- 0

0
0 2 4 6 8 0 2 4 6 8
Hours Hours
.'1 ". 3-1. ,\, I'L"" "" "" Il~· "l r"t il " ' (If tl..~ '1"I~lli .......uh Ii" ... aft..r a 5ln-mJo: 1.\-. 1.,,1,,\ 1";'''''1i1111 into a 7O-l~
1);lh"lIl, H, l11(' ,Lila ill" an' " "" li'rla~.~1 a' .. "'",i~'lo:"r1II""k r~ >t . S ,>t.. lhr .t .nrt .li'lnl>" tilll' p1w.,,' (I "'WI_ ..
.';,5 /1 \ 1). ( \I , " Ii fi.~ 1 (" ' 111 tl..· .L.ta "f \1110"111.. .. PoO' " 111111 ( ~"w. RI .: Phanll;lll~>kin.'tK" o( i"I""""II'''' t lw.~'1,h .
yll ulI·. el i", l 'II;<",l;II"" ~ ' l1...r., f.I .'\U\h "i13. 1l1i3.)
20 INTIlA'/ENOUS rose

lift' is til(' time taken for the plaxmu concentration, a.s well as tbe amount of thl' d rug in
Illl' IMM ly. In fall by OIlt··half. TI lt' half·life of th eophyllilll" determined by the time taken
to fall (m ill I fi to " 1Ilw'L- is 5.11 !In; ( Fig. 3- 1B). l 1lis is tilt' s am e tmu- that it lakes for the
(1111{'(' n t ra t io Tl 10 fall Im m 12 10 fi IlIWL. In otln-r words, for theophylline at till" dost"
ad m illish ·rt"tl. tilt' r-hnunution half-lift' is illtlt ,!lt'IIt1t'nl of lilt" a mo unt of lim p; in the hody.
It follo w .., tln-nfon-, tha t k-ss dn l~ is l'Iim inah 't ! in each su('(.'t"t·d ing haIr· lift,. In itially then-
are SOlllllg in Ihl' hody. AflN I half-Iif.· (5 hr ), 250 IIlg rem.un. Afh 'r :2 half-lives ( Ill hr ],
12.') lllg n-nnuu. am i after 3 lla lr· lin·s (1.'5 hr). 62 .5 lllP; remain. In pratiil,('. all the dmp;
(H7%) lIIil)" I~ · n-gMd t't! as " <Isi ng lx-en d imi natl"tl by 5 halr-IiVl"S (2.') hr ).
Vo lume ur Distrih utio n , 111t, conce ntration in p l'l'lma adlieH -'(1 ufter t1istrilmtion is
('(Im plt'l c' is a rum1 inll (lr dosl' undexn-ut or di stribution or dnl~ int o ttssu cs. 111is extent
o r distribution can 1M' d l'h 'nnilil'(l by rl'latin ~ tilt, conc entration u btail\('(l \\ilh a known
amount o r dm~ in the hody. This is analo~~oll s to lilt' ck-n-mnnattou or til(' \ 'O IIIIllC or a
n -servotr bv d i \idin~ tilt' am oun t o r dn ' ad dt"(l to it bv the resultant conceutr afiou . artt-r
t ll(lnm~h ' ;li\ill~. 111t' \Ullllllt' IlW'l..ur;-'(1 is, in dTc·l:t. a' d ilution spa('('.
TI l" ,IPIl;l!"f'" ' \nllllllt· illln whi!'h a d nL~ di..tn hun-s in 11ll' hCMI}" at C'llllilihri UIlI is ca lk-d
/1
the- ((lI' / lIm 'Ilt) ( "( 11", /11: d istriJ", t; Oll . Plasma. rather tha n b'OIM!. is usually measured.
CC III.o;t;'I!lIt'lllly, thc' volunu- or di strihllliCJIl, V, is tho \"u lllnlt' o r plasma al tilt' dnlg ronre-n-
tm lioll, C, n-quin-dto al'('u unt for 1111 lilt' dOl ~ in ti lt' body. A

v - Ale
Volume of .. Amount in body
di~lribu lion P1a~ma d rug ccocentrcfico

Volunu- or d istrih llliOll i.. IIst·rul ill c'stimatill/{ plols ma concent ra tion when a known
amo u nl or dOl ~ is ill till' IMllly or, l'()IJ\'C 'rlit.'!y, in c'stimal ill ~ lilt' dost, reqnin-d to uchicve a
~\l '1l ph\lIla e uu vntranou.
Calt'u b liollllf \'C IIUlIll' or d islrilmt inn n-qui n-s that di strihutiou equilihruuu hc' adlie\l'll
ht'twc'('u cln l/{ ill tis'llit'S alll! thut in ph~llla . Tilt' amount uf c lm~ in tilt' hCIl!)' is kmJ\'11
illllllt'(liall'ly afte-r un l.v. ho lus: it is the dost, admlntstr-red. Ilcl\\·t,\·l'r, d istribution t'f!lIilih-
rimu ha s nnt yl'1 11l'l'1I adlit'\ '/'l!, All t'stimall' is Ilt,('l lc'l! or III(' ph~Ill;l concentration tlmt
wuu ld h;l\'(' n -sulted had all d rug spontaneously c1htriblllt'll int o its final volume or distri -
b ulioll. To dn th is, list' is madC' o r till' linear c!C'l:lillt' d ll ri n~ the t'!iminalicm plul-"l' st'('n ill
till' sl' m i lo~a ri t i ll n ic plol (Fi~. 3-1B).
!>C'l.'IiIU ' in plasma roncent r at ton dunng tbe diminal io ll ph a.o;t;, ca n II(' d mra<1t' rin'l! hy
thl' linear t'fj1lalio n

InC _ lnqO) _h 2

wlU'rt, k is thl' J>lopC' or tlU' lillt, ill Fi/{. 3-- 18 am! C (ll ) is till' n mn' ut mtioll /lIlC' wu u lel
dt'lC'nJlint , rru m this t'filialiou at ...c'm tilll(', 111t' nq.~ati\"(' s i ~ 1 aris c's Ilf'l.'UlSt' ('C lIK'C 'ntra lio n
dc'(,1illc's \\ill. tilllt' , TI.t, te rm C (l l) is an t'xtrapn !llh '(l \"alm' lind is all t'stimatt' of tlU' (1 )Jl -
t1'lIt m!ioll wllil'h whl'll llHlltiplic'll hy th l' \"ulllllll' It'nll , \ ', al'l.'C lllllt s ro r Iht' duSt, mlm ini s-
tt 'rt'll. i.l' .,

Do.. - V · qOj 3

In tl)(' c':\<I"l p lt, " i tl. Ihl'l'phyllim' , C (O) is IS IlIw'L . Sint"t' .son 1Il~ Wll" ,1l!m illh l!'TI'f! ln
tit" !liltit'llt , tilt' \Ullinit' or di.~trihlltiOIl o r tht '(}ph)'lIillt, is 2S L. K Ilt J\\i ll~ tilt' \llIUIll(' or
d islribution . ti ll' amuu nl in thl' hotly ( "II IInw 1M' {'stimah'(l al any tinu.' c1l1ri n ~ Iht' c·limi ·
 2.

nanon phase. For esamph-, w hen tilt' {'1II 11'l'n l m t iull of th ' 'l'phyllint' in pWTJliI is 5 mWI..
'hNt' art' 140 m,.-:; in tilt" IXKk
VnlUlIIt" of w stribllHoll is 'il Jin"'(:t IIWClSUnc- o f tht" ('" II'nl of Ib~t rilllltjon. II ran-ly, ' It,"'·
t"I1·r. corre-sponds 10 a real volu me , such as plasma \ulu nM:' (3 1.). n.t rdCt"lIula r water ( 16
L), o r total hod). wate r (42 L ). DnJ j?; tli\trilHltion ma~'lrll ' to al l)" utlt' o r a comb ination of
tht- tissues and fluids o f tilt ' bud)" F urtbe rmon-, himhng 10 lissm' l'Om porwn ts rna)" till' ....:,
gn-at thai tbe \'olunlt' of (Lst rilm tion is mall)" t illlt"S tht· total l...~· ..i7.t".
To appnocialt" th e dTt"(1 of ti' SUt· hindill~. ('o nsid(' r the di'!>trilmlion of 100 mg o f a {Inag
in II I· L system com posed o f ....-ate-r and 10 R o f al1i\'ah'll d lan 'o al and ....iw.>n.. 9'9'1- of dm~
is lIlL'il,rbe.-d ont o the cha rcoal. \\l l('n til(" charcoal has !\t.·ttlt-cJ. lhl' roncentratson of tl n l ~ in
tht· ;l(]lIt·ous pha..... would ht, I mWI..: th us, 100 L I)f tilt" a1 11lt"lK'S phasot' ....,ou ltJ hI' n "l lnin'll
to lK,('CIu llt for all lIlt' dnl~ in tilt' ~ ...te-rn, a vnluun- IIIl1t'h Jtn'alN tha n that uf tilt' total
5)";h 'lII. Vohmu-s o f di..tnbunon fo r M,II"C.1 t't! dnl~" an' ..h U\\11 ill Fi ~, 3-2. nit, l'<lUM'S for
dl is "it!t, ra n~t· (If values an' di scllss("l! in Chap . 10, Disiri llllt io!l .
F in t ·O roc r E liminatiun, Why tilt' r-lhninatton fill' tl woph)'lIint' (and for IIK",t " IIIN
dnl~s ) is hneur when d ispla)-t'(l st' m i lo~~a rit h lllimll,· l,<1II lit, ap pn-cian-d a.~ Follows . Tlikill ~
the an li lo~arith lll of hoth sltlt'S uf Ell. 2 ,i l'ltl~

c -qol ·.-" 4

A _ Dc». . • _ b 5
"------'-
silK'l' C ' " and C(O) , " art· tlK" illll(KlIlt in th t· IJ(JtI)' allli tbe t!tlst' ad mmlstered. n ""'I'M "l··
th't"I, ·, Equanons -I a nd 5 t'nahle the concentranon and amull nt ill tlte hod)' at ioUl" h lllf.' tn
Iw.' esti mated . \ \11t'1I tlt'(..lim' in tilt' pl asma tUIt(.'('n trdholl or amount in tbe btJti)· l'Wl lit,
tlt~I'M"'I1 h,· a sinJtlt' MpOlIt·ntiai n-rrn a... ~\l'1I II)' Etl s. -I anti 5 , it is sait! til ht·
(1lI0IK)K'xporw ll tial. SilM.'l' ti lt· dimimll io ll half·lift· (frl2) is the time taken fo r t he ('(lIlt't' n ·
tration a nd th e amount in tilt' IKJti)' to fall by OI1(".lIalf, I' .~ .• fn JIII C (O) to 112 C(O), it fol1..,"""\
from Efl_-I that :

o r, on ill\l' rsioll

TakinR the natural Ic~aritlllll o f buth side-s,

~ . 'In - In 2 - 0 .693
Oi l«' nh taill5 t he important relanonsbip.

0 .693
'In - -,- 7

Alt"ou~ t he constant k is i ll tilt· t'\ pollt'n t in F.,+ -I and <-.III II(' calculated fmm F.cl' 7. ih
lIlt"a.llin~ may
1M.' ht1tt'r uncL'nttoo lJ)' ex.a.mi n i ll~ tl H' rat e a l ",nil''' the a mou nt in tilt, 1.0,1,.,
A , is dlan~ll~ with time. ntis is ohtaint"ll ll)' t1ifft'n'lltioltin~ 1':'1. 5.
22 INTRAVEf'..0U5 D05[ CHAPTH J

dA
di - 8

but ~i nl't ·.\ = D cl'il,' , ., - h , it (nllnw<ithal

dA
di - - k· A 9

Tln- term 0 11 lilt' left-hand sid e of Eel. 9 is rln- ra il' (If (:hanKe' uf lilt" amount i ll tilt" hud)'.
T his is also tlU' mit' of clnninatkm o f dnt~ fm m tht· heMl)'. Pn xx-sses such as this, in which

Volume 01 Distribution
liters/70 kg Drug liters/Kg
50.000
Quinacrine 500

20.000
Chloroquine
200
10.000
100
5000 AmiodalOOlI
Doxorubicin 50
Onipr~mine

2000
ChlOrpromwne
20
Nortriptyline
1000 MlfIoxi<!11
n Jt. 3-2. 11..• "'I'I>;U'O'nl ".I""". mt" "'~,kll 10
,Inol:' ,Ih ln h" k , ...rit~ "'itlo·I~·_ 500 0'001.111
Qiltlaum
5
Verapamil
Morphine
200
Raflllidine 2
100
DiazePim
EryUlromycin
50 Phenytoin
Theophylline 0.5
Ampicillin
20
0.2
tbupreten
10
Warfarin
0.1
5 Erythropoill'1in
0.05
3
CHAPTER3 INaAVINOUS DOSE 23

Ih", r ate of rt'ac:1:iu ll is pr oportional to ti l(' amount pn-se-nt, art' known as ji n tofmler li me·
l'_n~',~ .
The pm pmtiollality const an t is know n 1L~ Ih(·ji n'-t,,.,/f'r rate n llu to " t with dinn-nsions
o f tuue - I . Bec ause I.: cha racn-nzes till' eliuuuation pnl('t'ss. it is known us t!J<> r [i mi llotil m
rate n m_~t(m t . Sill(:t' ti l(" rute consta nt can also he denllt'1.l hy ft'arnUl~ n/;!; Eq. 9 to yk-ld

k _ Ra te of elimination
10
Amovn t in body

til(' eii nuuatjou rate L't mstanl lIlity sim ply 1",-' ft1!1lfll('t11ls 111(' jmctiOllfl1 m re {if dn,1!. w/JI onl!,
Fo r e xample. sint't' Ih(· half·li ft· o f IIlt'uphylliJlt' is 5 hr . tile va lut' o f its e limination ran-
constant is 0 .14 h r - I . II t,IIt" . lilt" sp('('1.l u f tilt' d im illati,," pm('t'Ss n f theophylline- c-an ht"
dlamd eri 7...('(! ('itl wr by its half-Iif(', S hr. o r hy sa~ i ll ~ thnt tlte Fructional mil' o f r-limlnatton
is C),I " (o r '4% ) o f l l l(' d Ol ~ ill III(' bo(ly p('r hour.
Fruction of Do<;(' Remaining. Another view of tln- kin etics of dru~ e ln nln anou lIIay
I I(~ ,::ai,wd by l''tlUnillill'::how tilt" fraction of tlu- do ">(' n' lIlai n i ll~ ill the body (NOose ) varies
"'i tlJ tiun-. By (('ft,rt:'lll't.' 10 Eq . 5.

of dose
Frac tion A
11
remaining in the body - Dose -

111t" [ruct ion of tiu- doS(' (('Illai ll i ll~ is. llwrt'fo ((', ~\1 '1I hy {, - lr. Sorncumcs. it is !I'w ful ln
( ':<P (('SS time ft,l"tin' 10 the ha lf-Iifl". TIl(' valur- o f dn in,:: SCI is S('(' I\ by letti ll ~ II ht' the-
mnul e-r of llalf-Iin's (,lapS('(11Iftt't a IMJIIiS tluS(' ( II :::: tit 1t2 )' 111('11. 'l S k :::: O.69:Yt 112:'

Frac tion of dose

12
re ma ining in the body -

Fracti on of dose 1/ In 13
re ma ining in the body = I 2

111l1S, 1/ 2 o r SOli u f tjn- doS(' remains afte r ' ha lf-lift', <lJl( l l/~ (1/2 X 1/ 2 ) o r 2.'>% n-nuuns
afte-r 2 Imlf-Ii\1's. and SCJ on .
Total C le a rance . Jml .lS the pa(;mlt'l('r vnl uuu- (If t1istrihulioTl is 11('('(1('1.1 10 n-lan-
concentrat ion to amount ill th t' 1)(1(1)', so 111("((' is 11 Ill't't l to ha\1' a p ararm-tcr to n-late
rmrce-nt m tion to rate o f dnl ~ t>l imillalioll . Cleumue- (Iotal). dt'(Jot('t1 hy CT. , is that p ro -
po rtionalit y f'Ki m . Tlltl s,

""' ",
o, e '''el imino tion - CL· Conce""' .,o,Ii,O,,". .
.." o .... 14

111(' uut ts o f eleanmce, like Iho ">(' o f [low, 01(( ' colunn- I)('r unit tune. Fu r example, if the
d ('amn('(' \111ue is I l zhr , then al a concentratiou o f I IIlWl.. tilt' rate of dmg d illlina tiull
is I JlI ~/hr . Ortlillllrily, us the- conccut renon of 11 dm ~ i1wn '11.S('S, so dot'S its mit' of dillli-
».
1I111iull ; ch-amuce rvmafn s ti l(' s ame. F r om EII- mil.' o f r-lhrnnatton :::: k . A . Sillt't, A ::::
v C; From Ell. I. il follow~ that
Rate of e limina tion - k · V · C 15

C omp arison o f Eqs . 14 and 1.'5 !('lI<1 ~ 10 tlw n-lattousbi p

2. CHAPTER3

Clecrc oce • k . V 16

U sill~ ElJ. 16, tlu- Itolal) dl·amll(:t· of t1lt'ophyllint' is calculated to lit· -I l Air o r 67 flit /min.
So 11m! at a (11,'-\ 111<1 coucentranou nf I mJil .. t· .~ .• t jn- ra lt' of d ill1inatioll (If tht'oph)1Iillt"
(mill t ill' hO: Nly is -I III Whr.
C learance and E lim inatio n lIa lf-life . It is mo re l "Ollll ll O Il to refer to tilt" lI a](·Ii f(·
ruther than III thc elumnatton rail' cons tan t uf a t1nl ~. Hccallthut ' \12 "" 1I.69.Vk . so tha t
half-lift· is n-lan-d to d t·;lr.lflc(' by:

0 .693 • Volume of distribution

,1/ 2 - """''---'-;'C''''::'''
Clearance ==== 17

Equation 17 is p Ulvosd y arr.Ul ~t '(l in Iln- abo\'(' 1lI,U1Ilt'f to stn-ss th ;11 hillf·)if(' {and d illli·
mlli on ra il' constant } rt'llt'(1s rat her than contro l.. \, IIUIIlI' of d islrihut inn ami cleara nce. two
ill(l" I)I:II(I"nl pammdt·rs. To show lilt' app lil'< llioll o f Eq. 17, l111lsidt' r the lise of creatinine,
a product of ruusch- cnrubohsm. as a marker of n-nal fum-non. C n 'alln!IIt' !la\ 11 clearance
of -:.2 1)111" am i is t-n 'nly , listrillllh>il t hmll~hullll h,' 42 L o f total hudy water. As t'X))('(.'tt>i1
hy calculatlon m inl-t E' I. 17, its half-Iif,' is .. h r. Inulin, a pn lysal'd mrid,' also 1I.\t"t1 to a\M'SS
n-nal fUlld inll, has lilt"sault' t.,lt·;lr.1IIt.1' ;\-\ creatinine, I!OWt"\'N , inu lin hlL\ a half·lift· of nu ly
1.5 lrr !1(>i';lIh" il is n...tri(1,'(1 to Ih,' )6 L u f exlm' 1'Iluiar wa ter.
C lt.· arance. Arc" . a n d Volum" o f Distrihution. 11l11s far , cleurunce has )1('('11 ..-sli-
malt,) Fnnn !lalf· life alltl volunn- of d isiri butiu li. Clearaue - can he better t'slilllaftotl iu
OilillthN way. H)' n'arr.U1¢ n~ Eq. l-t. it lV,lII be seen th at d \l rill~ a small interva l of time, tit,

Am ount elim inated in interval dt _ Clearance ' C · d, 18

whe-n- tln- product C ' tit is tilt, l, )m'sl)( md i n~ small an-a under the plasma co ncentratton-
lim!' t-urve-. For r-xuu ph-, if the- d,'amllt" of II , I m~ is I l z min and lilt' lIn';t IIl1d r-r IIIl' l'll r.,'
1)(,t\\"' '('11 flO and 6 1 mill h I 1ll ~-m i l\/ l ~ tlu-n tht, a mo unt Ilf d Olg r-lhnlnat cd ill th ill mhnnv
is I m ~. 11w lulal amount of d Olg ('n 'lIll1a11y ('lim ina l('(I, wllid l for an i.v . bolus ("(Iuals the
do \(' atllllinisl...n-d. is ;l\st'ssc'(l hy m ld ill~ "p 111" inftogmtillg tlu- alllllllnh ,'!illlina!t'() in each
finu- Interval, Fnun limt' 7.t'm 10 infinite tim..., and therefore.

Dose - Cl ' AUC 19

when- A L'C is li lt' lolal a n-a und er th r- concenr rutton- unu- curve. 11111s, mu-e AVe is KIUJ\\ 11
(Ap!)('mlix I·A1, clearance is rt';ulily ralculated . ;-';u!t' th ai IlwIT' is lUI needto \..110\\' til,' half·
lif,' or vnlunn of t1ist rih ulilln 10 calcnlan- clearance. Furthermore, th is l,;,!t"ulatillll of d ear -
unce is imlt'!w lltlt'lIt o f the shape' o f lilt' coucentranou-tinu- pmfil(-.
Ti ll' rdatillllsiJip !K'I\\'t'('n are-a lind ehmluntiou ran II(' applied al auy linw fll!lo\\i ng d mg
mllllinisimiion , as Illust r ated in Fig. 3-.1. Thus , IIm llipl)illl-t tilt' an-a up 10 a giwn rinu-,
[A L'e (f), t JI hy dt'amlll1' ~\'t's lilt' amount of , Inag that has 11('('11 ...hnunan-d up to that lillit'.
:\l lt'mati\"...Iy, wlu-u lilt' area is ('xp n 'ssc'll a~ a fr.tt1iull of II.... tnt al AVe . IIIit' o!'taillS 111('
fral'tion o f tlw d oS(' d imina lt'll. :\ml th... fr.it"tion of til(' Inial art'il hl')uud a g1wn lilll(' is a
1ll, 'a.~lI n' IIf tilt" fmt1 inn o f dllst, n 'lIIain ing In l)t, ,'!illlill;llt'(l. Fllr t·X;llllp lt·, in tilt' eoL'it- uf
tll' 'l)pllyllillt'. hy ,1.6 11 1" tile an'a is 4U% of lilt' tul al AVe , allt l lll:'lIl't" 4O'.t, o f th ... mlmillistt.·f('(l
5()()-lllg lIost,. or 2()O mg. h;l~ 11('('11 ...Jiminalt'll fn uu Iht'! I(KI)'; 3lXl mg ha~ )'('t 10 ht, t'lim -
illah 'l l.
\ 'nl ulIl,' o f d islri lm lio ll { \1 is IIst'() 10 n '!alt' p t l\lII;1 l1ml'('llt mlioll to amoull I of dmg in
Iht, IItKly d uring Iht, dilllillalio ll pha-"" , of"'''11 111(' \, ,JIl" obtail l(,(! by ,'xtr.tpolalioll (1': '1' 3 )
CHAPTE ~ 3 INTRA-Vi NOUS oose 2'
is a rt"L\(mahlt, t'slinm!l' of this \u11l1l1l' tcnn. Ot't'l.LSiOmllh·. when t'slt'lIsin' r-lunmntkm
occurs in tln- dislrihlltillll ph'N" it is not . The lM."st 1I1("IIIoc1 of t'ak'lIlatin~ \1IIUIII(' of dis-
trihutlou is to d h id(· d l'anllll,(' bv r-lunmauon run- con stant

v .Cl . Dose 20
1 AUC ·l

Unhke extrapolation, this method of t'stilll atill ~ \ ' is not restrit1t... l m the l.v. bolus situation
hilt l',1Il hc' usc... 1unde-r a \'ari dy of conditions, t' . ~. , long-tt"nn i.v. infusions . Cm lsc'C!IU'n tly,
lilt' valuc' of \ ', t·stimafe... 1 n sill~ Eel' 20. is app!it...1throughout th ... n-nuunder of thi s hook,
alt holl)!;h olhl'r voluuu- n-nus are t·x.ullint't! in Chap. 19 . Distrihution Kiuet k-s.

RlNAl ClEARANCE
Elilll ina!iull CI('(· U "" hy n-nal excn-t ion ,md extmn-nal piltl l\\1I)'S, n.sllally IWpiltit: IJlt'lall(llism .
~(JI onl., · is n-nal r-xcn-non an important route of t'limillalioll for lIIany d m gs, bul IIsc'ful
p llanllal'llkil1t'l k iuformutiou run iJ,t' ohtaillt'tl [roru analysis o f urinarv dat a. C""lllml lo this
analysis is lilt' t'l)JIl'!.'pl (If ",.,IIlJ f'!nlnlmY' .
"\ l1 a l0l-~lI ll s 10 to lal <'I t·arall('!.'. n-ual d t'a nlllt1.' (CI. R ) is d l'fill(...1 as th(' proportiouahty
n-nu l)('t"'I"1I urinarv excn-rion rate- ami plasma l'Ulll'('lIlmliull:

bcretion role • Cl// . C 21

lh-na l d t'a nllll'l', lilt· total dl·ar'U1l't·, h,ls nnits of flow. usually m illilil(·rs!lIlinnlt· or hn-rs/
hour.
Pnldil'al pnJb le'ms ari se, howt'\"t'r. ill t's timalill)!; renal d t';tf"d llt'l'. Urine- is lu llt-c1l't! cvt-r
a finite IX'n od , I· . ~ .• -I hr. t1l1rin~ wllk-II tilt' plasma conce ntration is dmll~lI~ l'o lilinllu llsly.
SI.(lrtt ·lI ilJ~ II.t· (u llt'1.1iI1ll pt 'rind reduces tln- dmll~l' ill. Jl1;l~ma coucentr anou h' ll iu(·n·, tst·s
till' IIIlt't·rtainly in tln- t'Stimat e u f excre-tion mit, o\\ill~ 10 incomplete hladdt' r t·lIlpl)ill ~.
Tlus is l·sl)(-c·ially trm- fur urine- (u l1t'l1in rl inn-rcals of Il'SS thau (,') min . 1 ,(' lIhrt l lt' n i ll~ tilt'

t'l ~. 3-1. A li".·;O]" pi". "r,.... sa,,,,'

I,LL, ,,,;c (~ "K ~·"lr..' k"H jl!"· ,LoI;c rfl r
'I"'0 l'''~ lt i ll'' ..s .lhl'l..~ .·c1 ill t"i" .
:J-I,'l. n it·......" lip In 3 6 Itr i . 411'.
"i tl..• ,"• ..I .U·C i,.. lin alilll: IlwI 411'.
of II.., .Ie · "'lmini...·rt..1 ha.' 1" '1'11
.·1i1rlin;ct I I ~' 1I,, ·n . n ..· ;crt·;( 1 "~lJ'MI
.1.6 hr rtllrt... ·nh ,I..· fill'l- or ""Imin.
i'lI .r"I II....'1II,~·Il; , ... n·,,,;cininj( In I ...
,·li", ;n;cl<..1

o 2 4 6 8
Hours
2. C HAJ'T E ~ 3

collection inte-rval, 10 avoid t ilt" problem of iuce mpk-n- t·lll pl~;lI g . rt'(juin's II II1 fl(lifit '(! ap -
p reach for tht' estimat ion of renal clearance. 111is app roach is analogous In th at tak('n with
to lal clearau ce-. By rt"arrdnJ.,tj ll~ F.A!. 2 1, duri ng a \"t'f)' small int erval of Ii me, tlt..

Amount excreted '" CLI/ . C .. df 22

when' C . (Jt is the l,(JlTt-'sp:m<lillg small art-a unde r IIIl' pJ.L~ lII a dmg conccntrunou-nme
curve. The mi nt' collect ion int e rval (de llo ll't! hy t\t ) is compose d of mall)' slJl-h n'l)' sma ll
lncre ruents o f time , and ,ht, amount ( If d rug excreted ill a collection interval is thl' SIII II of
lilt' amou nts excreted in eac h of th ese smal l mcn-men ts of tum-. that is,

uc
co 'lee,'
Amoun t excre
' t
ted , in .: CLI/ " ( A
Of\ In efV(]
WI
lth In
l mle rvo I) 23

Th e p roblem in ca I('ulalill~ n-nal dt'am.I1(1.' then-Ion - n -sts with t's l ill1 atiu~ tilt, AUe
withi n ti lt' ti nlt' int erval ( St"t' Appt'mli \ I-A ). TIlt' a\·I'rl.l~t' plasma drug conceutratfon du ri n ~
the (1.1Ilt'('!ion int erval is !-?WII by «AUC wit hin inlt'mt! )lN ). 111is awmgt' plasm a (1.)II{1.'II-
tration is neit he r the value at tln- ht' w nnill g nor at tht, t' nd o f Ill(' (d lt"('!ion tum- hut at
some inlenl\('tl iat e po int. By asslllllillR that IIII' p h SlIli' rmu-eut rution dl;lllgt'S lillearly with
time , ti l l' ap p mpriatl' concenrranon is that at tht, midpo int of the (d ll'('!iull interval . Ix"
cause the plasma conce ntra non of drug is in faet dlan!-?Ilg t'Xpo lll'lltially with titue, thi s
assumption of linear change is reasonable oll l~' when los.s d uring tilt' tnn-rvnl ts small. In
practice, til(' Int erval sho uld ht, lt,ss than an elim ina tion hal f-lift' .
EXlt'liding E(I. 23 11\ " 1' all t tn«- Intervnls, [rruu zem to infin ity, 1I1ll' obnuns tilt' useful
relationship

, Total a mount excreled unchang ed

ena c ecro nce - AUC 24
"

when- AUe is the total area 1I11dl'r tilt' rl.lsma t!rtl g concentratiou- ttuu- ('U I'\'(' , T o apply
Eq. 24, can - mu st hi' taken to eusu re thut allurine is colh-cn-d an d for a su ffidt 'u t ('Jt'rind
of tilllt' til gain a ROIIlI es timale of tilt' total amount excrcn-d u nd langt'tl. In pruet ice, the
pe-riod of tune 1I111s1 1)(' at lt'il-st 5 to 6 elimination half·li n 's of tilt' d m~ (st'(· Appt·nd ix I- B),
1111I"', if the Ilal f·lift" of it drug b in till' unlt'r of it fl:'\\' hOlln. , IlIJ p ract ical t1ifTk ·ultit·... t'xb l
in t' mllri n ~ urine collections taken 11\ '('1' an at!t'(lllah ope-riod of tum-, St·\'('rt' t1iffit'ulti l'S wi th
{1.lInp li'lI\l't, in unli t' collect km occu r. however. for d ru w; such ,l\ plwllolml'hil,(1 with ;l half·
Iifl' of abo ut a week, si ll{"t' all uri ne formed on'T a I)('rillli uf at 1I',l\ 1 1 mon th must lx-
collec t ed.

DISPOSITION VIEWED FROM URINE ONLY

Lac ]; o f sll ffidt~n t l)' sensitive ilnal)tic tec hniques cau and prt '\illllsly has prewu n-dme.eure-
ment o f the- couceutrauon of lIIall)" d m gs in plasma. In tln- ahst' lIl't' o f plasma tueusu re-
ments. neuber \ UIIIIlI(' of dist rtlmttou nor d ('amn('(' can 1)(' d('It'nnillt'll. :'\om-tln-le-ss. useful
tnformanon can still ht, ohlailJ('(l Irom u rine data alone, wllt'n sud l i.~ 1ll '("t' SSiU) ·.

TI lt' dilllinalioll half·li ft" o f lilt' ft'\1.'rsihlt, l'!IOIiIlt'sh' r.lSto inhi bitor, galallihamil u', l"itll I.,
l'slimah't l fmlll Urillt' data. TIlt' apprtliK'h is to plot ti lt' an'mgt' t'w n' lilm mit' agaillSt the
midpoi nt of tilt' (,(lllt'('!ioll tim e Sl' lll i l(~a ri t h Illi<.'lilly and . fmill t11(' slope o f t lit' stl'ili~h t Iilit' ,
(!-\APTER 3 INTRAVE NOUS DOSE: 27

obtain an es timate o f till' half-lift" I ll t ll i livt'1~·, tilt" approach is ('asy to see. Assullling that
renal d t'a r.Ull't' is constant . lilt, uri nal) ' excret ion rate is proportional to p lasm a con ce ntra -
non, and pl ott in~ uri nal)' excre tion rate a~.tillS t tune is likt" plotting plasma eoncent runon
a~aill s t ttnu-. TIll' half-life is then taken as the time for the urinaryexcretion rate (or plasma
l'(Jm't·lltr.ltio n) to fall by ollt··halr. For ~aJant ham iJw this is approximatt'1y 6 hr in a ht·alt hy
subject ( Fi ~, ,~ ) , COII,·t'~' ly . wlu-n a st r.ti ~h t lille is obtaillt'(l h)' plotting the urin al) '
ewreuou run - a~ain s t tlu- mid poi nt tune , l'tlllsta nl'" o f renal clearance is Inferred. '111e 11('('(1
for using midpoint tune follows fm m the previous diSl1lssiou; the measured u rinary excrc-
lion r ate n -fh-cts till' ;l\·l'r.l~{, p lasma conce ntration duri ng; the collect ion inte rval. Formal
pmo f uf till' fu rt'going diSl11ssion is !'in'n ill Appendu I- B,

Renal Excretion as a Fraction of Total Elimination

:\n impo rtant phan nal'(,killt'lit., paranlt'tl'l"is tln- fract ion of the amount enter mg the V;t' ne rdl
cm-ulunon that is exc reted U1ll'haug('(l.fi', II is a quantitative measure of the cont rihntion
of renal I·XI'n·tinn to (lw r:lll dmg eltm tnatron. KIltJ\\ing f e ajds in t'stablishing uppmpriatr-
lIlod ifil'atiolis in tIL(' IIsual dusa~(' rl";u\('n u f a d n lg for pa th-uts with \1u) i n,l1; degn "t's o f
reuul fUl1(1ioll, AIIlUll ~ d m~s , tilt' value offi ' mn gt's het\' 't't'u 0 and l.O. \\l w ll the \ 11111l' is
low, excretion is a minor path\\N .lYof dmg ehnunauon. Ol"l-d-sionaJly. n-nal excre-tion is the
on ly rout e of eliminat ion , in whic h l'a<;t' the value o f fe is 1.0. By ddinition the difT('f'('lIl't',
I - ft'. is 1111' fract ion (If II\(' amount (' n t(' ri n ~ the o rr-Illation that is elhnlnan-d hy extra re nal
mecluuustus. usually me-tabolism .
:\n ('st ima tl' offi· is most readily ohtalm-d [rom cumulative urinal)' excretion data Iol-
1 U\\i n~ i.v. admintstrutkm, since by defiuitlou.

Totcl d,ug
Ie _ excreted unchanged
Do..
25

In pract ice, ca n- should alw;I~-s lx- ta ken to ens ure complete urinal)' rt"t,,(J\'('l) ' (i.e., collect

1000 .'R,dn3--1,nn i/: ";ot.·h

rat..
,~.f'aI;:t"
,.. u rin.' ,og:n 't;on
Unlit'{·UII."'1ion m-
1"''''''/ afl.. r lU' 1,\'. I• .tll. J. of 10
ml/:of1/:;cl.."Ih>imi l"'lt> .. I lth~, sub-
100 j ..d . (R..,lr,,"'·n rm m 8i .·~ ..I, U.,

f:
-"
n ,,"n....'. T .. W,'h" T, W.. n..-Iwr,
J .... 801("' no, R., S ilT. ),1.. ..,,,1 11:....,-
il7., II . I'han ll... ulj",,'t~ or ~;u"
~ 10 Ih;omi...· in I"",,,. ns ..n<I ..... ~""" I .
a: inl/: ..t",li.,...I..,...., i"I,il,i!i,m. CIi" .
~
Ph..rm",'ol . TI,,' r.. ,S fl : 4 :W- 4 2~,
"
;u; 1Y91.1
w"

0.1
I
0 12 24 36 48 60 72
Hours
2. OW1H3

\II;m' fllr 011 It'll" 5 t'limillatiull h;Jf-liv('s), I" lilt' (~lW of ~al all t hillll il lt',fi' is app m"imah.ly
0 .2.'5 in sllhjt"t1s with normal n-ual Imu-t ion . AI any inslanL t llt' fr..u:lioTlfi' Illay II(' d l,fjl\("tl
ilS th e fatiu o f Illl' rate (If ewn-tion til till' mil' of elim inatio n.

11: 0 16 of excretion
26
I!:ole of elimination

Appmpriatt>l~· s ll "st it ll!ill~ (or IU.IIIN ato r am i ch-nouuuator ill Eq . 26 , it is Sl."t'll that

27

Thus. fi· liMy "lSI , II(' t!,·fillt't ! llmi l'sti lllah·d ,lS tll(' mi lO ()f n-nal am i total dt 'ar.tlll '(' s . l'lis
is pa rtit'ulany useful in Il lOSl' situation s in whit-Ii totul u n l it' l '(IIII't:IiOIl is lint po ssihlt·.
III p r act ice, estimates of e l . and CJ.x ;In.' u h tililll't i di n -ctly, w!lt' n ';"->; ex t run-ual t..lt";tr;llil't'
is dt 'h ' n uilll'l! hy d ilTl'T('!It't·. 11 111s, extran-nal dear-lIlt't' is ( I - Je) . CI..

ESTIMATION OF PHARMACOKINETIC PARAMETERS

To apprr-cian- how lilt' p hann<l('Ukindie ll;lfillllt'lt'rs dd illi n", d isposi lion ure l'slimah,1.
constder tilt' pla_'imu and urine da ta in Tabl e 3- 1 oblai nl, 1 follo\\i ll~ an l.v. holus doS!:, of
SU Ill~ o( a d nl~.

,.We 3-001 . Pl._ .IMI UrI_ ..... 0W-1...4 ••II.wI.., •• I.. . . .1• • 0._
08Sf N AOClN TI1MMEM C# Dolo'' '
1'\.A.S.Y.A (),Io.' ''' lJRf",((),Io.''''
CCN:f:NTU 'NO.N
TWf 1NTf1V"I ,~ '" " (tfIl D C UYU./l 11VI
o ccec
"""" ...
="",,,,0 "VCWlT~ ~""-'"
..,..... o ...
CO<f..... N""

I
"'roN
'0" ''''(}-2
' 2'1.13
~, ""
120
""" N " "
"''''
133
Im ....Tf lll,'A!.
("'\J"/ll

' 00
...
....J!NA!.
'
'6 0
H C91flO

160
3 2-4 180 50 226 00 250
5 010 , -<> BO 63 14 0 56 30 6
7 0 43 .>-8 340 10 0 66 34 34 0
10 0 20 8- 12 178 18 0 80 32 372
18 12- 2.1 2 0 43 391
0 0 25 ' 50
"
Plasma Data Alone
A p lot o( p!;Lsma concentranon versus lime illdi("lill' s that IIII' \·alll('s an- dmppin~ p n ~n's­
sin,l)", hilt o nly a(h'r tln- da ta an' ploltt'( l S<' lIIi l()~ari tl ll n it."lllly (Fi ~ . 3-.5 ) 1·1111 til(' !tal(· li(t'
and elimination r.lt(' constant 1M.' n-adtl v de!t'rmilll,(1. 111<' Ital (-li( ', 1;I)(('1l a\ Ill(' tiul(' (or
til(' l'lIl('('n lr.tt ion to fall in hal( ( '.~.' from I .U to U.S 1lI""'1. ( I f U.2 to U. I mwL), is 2.S hr .
so that k is 0.25 Ilf - I. Clear-lII('(' is t1t'lt-n nillt'(l by t1 i\itli n~ doS!:' hy AL'C. 111(' Intal.U : C ,
esli llllt1I,(!lIsi n~ Ihe trapczoldal m il' (Appe nd ix I- A), is 10.2 1Il ~.ll r/L and wlu-n di\itlt'(!
into the dos<' \idds a value of 4 .9 lA ir for clennme-. \ 'olulIlI' of distrihutiou. ,'sl im a!('(1
From CU I. (E:I. 20) , is Ihe n -(on' 19 .6 L. Tht s value is \irtll;lll)" id, 'utiedllo Ihal calouluted
hy ((hi d iug duS(' h)" till' Intercept l'tJ!l('('utmtin lJat IA'n l ti llle. !M.'(.'allw no t1i \t ill('1 tlislrilJ1tlitlll
phase is appa n 'ut.

Plasma and Urine Data

Bntlt p (,L'ima anduri ue data an' n 't illirt't! tn ('slimalt' rennl dl',mUl(" . T his pamnlt'h'r can
I" , nIJl:lim'(! {rom tilt' sln j'" of a plnl o( Ihl' amoun t e-xcreted \\il ltin a " 11l('(1inu interval
CHAPTH 3 INT RAVE NOUS DOSE

a~aill \t ..\ L'C within tilt' sann- tim!' i llft·...... 11 (Fig:, 3--fi), TIl(' \t r.ug:ht Iiiit' implit'S thai n-nal
dt·ar.lll('t· i\ con stan t and illtlt'pt'ndpllt (If plasma concentration . TIlt" stolx>o f tilt>liue in-
dican-s that tilt' n-nal d t'ilr.U1{,(· of thi s dOl ~ is -I IJhr, ES.\I."lItialty the sann- \lllllt' is o!Jt<lill(',d
hy 1Il1l1ti pl)i!l ~ total d t'ar,IIl{,(' (.5.0 IJh r) hy fi ' (O, i S) (cf t:'I' 2i ), TIl("{'u mnb th "t· amount
t'xn t'l t'{l is 39.1 1Il ~, so rln- fraction of the delS(' t·X(:ft'tt'(l lIn(:han ~t"(J.f(' . is 39, 1 mWSO mg:.
or lI.iS.

Urine Data Alone

TIlt" elimination Ilalf.lift>of tilt' dOl~ (';1Il ht· ohtatncd from either excretion mit' or <'1 1111 11-
latin' cxcn-t ton data. TI lt' app r opriate nu-thods an ' dt'all wi th in Aplx'llflix I -H,

3.0 H It, :J.-..5· St,,,,il"Kantlullit' r~>t u(I Il. , rt.....ltlat" " .

2.0 n '"lralilM,· li n M· , Lola Ki'n , in TaM" .1-- 1.

....§.z: 1.0
0.5
~
g
e
c 0.2
~
y
~

u
0 0.1
0
0
0.05
C5
~
E
~ 0.02
" 0.01
c,

0 4 8 12 16 20
Hours

HK .3-4>. n... an MM",1 f"un 1... 1i. ,liW<1h·

r" '1M.Ifl i1Moal In fiM' ,-\l 'e: ""·.... un.. l " "'f"T 11M'
""'M' tulJ..-c1i<M' in l....\;a] . 1"" ,,;</ d.·;oralM.... i.
!V'•." h~" tl... .I"p.' uf II... li' M·. Da l;o (n" "
T ;</,J" .1--- 1.

o 1 2 3 4
Area Under Curve Within
Sampling Interval (mg-hrlll
30 lNn AVfNOUS DOSE Cl-W"TE fl J

A Question 01 Predsioa
Had vnu , tilt, re-ader, p lolh-d li lt' sa m,' data and eak u lalt'( I III,' phurmacokine-nc parunu-ters,
~' lll lIIay ha\"l' ohtaillt"tl a nswers that d ilTN Irom t!loS{' ~\"l·11. Thi s is 1101 unusual and " i ll
U('(1Ir in llIa llY case-s when }llll dWl"k }llu r uu swers 10 l ilt" problems a l tilt, ('11(1 o f ('adl
l"h<lplt'r a~.tillS l tho S{' ~ n' lI ill Appt'ndix II. 1111' reuson Iii 's in d ifTt' I"t-'IJ('t ' S ill th e d r-d"in~
of a Iilli' th mll!-:h data. aflN 111(')" ha\'(' lx-en plolh'd. alld in roll lldi ll~-Orr numbers . In
addition . all 1IlI' ;LSUrt'II\I' UIs han' errors lLs s.od a l l't ! \\i th all al~ t ie methods. t l lTlllitium (If
, t(J"'~I' . ;ull l l l;U1d li ll ~ of ....mpk-s prior to iUla l}1iis .
:\l sc ), 11ilt! tilt' sl udy ju st ('o llSidl'I't '( I IJ("('1I rl'pt'ah '1) suh">("(llIl'ntly ;n the "lllll l' indtvtduul,
tilt' ,",limah'1,l half-lift' ilia)· haw ht'f 'n :U hr instr-ud of 2.S hr. For almust all d illiC'lll
situatiolls. IIIis t1t-grt·'t· of illinum li\i tlual variat ion is <ll1.'C 'ptablt·, To n-flect lilt' ;t('t'C 'plablt, 5
10 Il Yl variatjnu . mu st an swers he ft' a ntllhmu ~houl tilt' n-maimh-r of ti lt' hook an- ClIl I~·
¢ \l'!1 to ! \\11 or 11 10"" Sij.,'11ifica nl p lace s.
III this chupte r. mall Y s~lu hols an- ck-Hned. ll\ it is the firsl tune tlmt ti lt')"an- 1I ~,,(1. 11 1t'~'
s)1llho l\ a n - rt' u ~'t l ft>pt ·aft'tll)· I llft lll~hoU I Ilu- hook. To <l\1Iid l'tlllli lllmlly rt'tk' fi n i ll~ them
ill t...t·I')' chapte-r alltl to I"adlitalt' refen-nceto t hem, tl u- Definition s o f Symhols ap lx'a r j ust
IN'fo ft, Chapn-r I. StJlJlt' iufrt'(jllt'ntl,. Ilst'C,! S~l l1 buls Ihal occur tllll,. in om' d lap lN ma,. lIu l
ht' illd ml t'(l ill tilt' Dt,fillilio ns.

Measurement Fluid
So far, lilt' phartuacokinetk-s of tilt' t1 m~ wi thin Iht, INltl,. han ' lx-eu t1t'fillt'(l \\id l n 'f('n'II('('
10 d m !!: ill p l;l\llla. SUlIll'l illll'S tlu' fl.'ft,rt'lIt'(' is t1nJ~ ill serum Of wholt' blo od. TIlt' majuf
d aTt' f('II('t' " t'IWt'('1I p l'l-sm<l ami serum is tilt' n -moval of fihrifl(~t' n ill the- latte r t'a.'i(' h,.
doUi n!, of hIIMK!. alltl us mos t dm ~s do lIul h ind 10 fihri lJ( ~t' II , lin tlilTt' rt' lwt,lx,tw('l' 1I til('
('tlll<1'ntnltioIiS of d m !!: in plll-SlIla ami se-rum is t':\;I)('(1t'll. CnlJst '(l"t'ntl,., Ih mll~hnu t ti lt'
INM.k tilt' k rill 1"(1·\·" m is taL::('1I to illdllt!.. st'n llll.
W ith ill hlcMltl. dmg can biud to ma ny ('tlllslilut 'lI!s i ndlltLu~ plasma p mtr -ins ami IJltltKI
cells . 1) flI ~ ('o ll('('lIlm lio lis in whole hlotMI alit! p lusma can d im 'r. Ilwn'h)' )i(' l d in~ diffen-nt
vahn-s for ma ll)' phanna('tlkint'l i<-' Jlilflllllt'f('r.;, an aSI)('1.1 dis<-'usSl'(1 ill some dept h SUhSl··
Illll' lItl)' ill ti l(' IU lk (part i('u larl,. C hap . I I, El imination, an d C hap. 12, In!l'g ntt iun \ Vith
Kiru-tu-s). A ("t't ll'tlin ~l,., uul ike serum und pllt-s ma, h locltl allt l p l'l-\ ma cannot I)(! ('tJllsidt ·fl.'C.1
10 he.' equivalent, althc m ~h for man )' appl iedl iolls ill p lmnmK"tlkint'lics. ti lt" dilTt'fl'Il<-'t:' is
f(' I;ct i \l' I~· unimportant . B-t'lM dUst' u f t';lS{' of ehmcal anal)'sis, mml measurements an ' lIlatlt"
ill plasma, rut her than ill blood.
Stril1 l)' sl)( 'a "i ll ~. Clllt' sho uld uS(' the h'rlll illol c~· n mt'~" l t rtltilm of (1m /!. ill "ltwlu/ (or
hll N ~J, o r 1,lll.\·" u/ It·nt/'r). Fur (':\;pt'll i(·Il(')·, ill mudl of thi s dmptN lIml t hn ,u~ll(m l tilt' n 'sl
of tilt' IUIk. this plml"l' is oft ell shurtt,llt'(l lo , l/n.<lmn (o r 1JIc ~ ~/) tlm:.: n mo.'ul rtltltm . Illtlt'l't.l,
Ihis is S(lIIwti lllt'S e."'l'n fu rtht' r sl.o rlt' n('l l lo l,!n.SFlUI CC /llCt'Ilt m t/.c1ll (o r b1of ~1 n IPu-" Pl t m t lo ll )
ill mall)' (Ulll('\!s in whidi ('tm(, ..lltmlio li of a tl m~ is u ntl('r.-tIMltl. Simi larl,.. tht' pl ll1l\t '
llr/u " m l ill hotll) n.f( 'r.; In lilt" ;clllUllllt tlf d ftl~ ill Iht' Iltxl,..

Use of Computers
Tt ltla)' (um putt'r.- an.' \ISl'lllo all'IIF.t' p IJilnll1lt.'t,killt't i<' data alltl makt' prt'C.lidin ns. B,N .'l1
upnn slalistit'lll ('rilt' ria, Ihe.' pharma('tlki lll.'fit' l'ardlllt'It'r \·alm' s art' adjllslt'( l lo J:i\'t' llw I~'st
fil of Ih(' appmpri;lft' t'(lllalion 10 Iht' ('.\ I)('rinlt' lltal da ta . 11lis appmad l 1101 (111)' pnJ\itl(,s
the IN'sl t'\limalt' of Ilitf1l11wlt 'r.; b ut also in('f(';lst'S Out··... l'tlllfidt'!l<-"C ill t1lt'IIl. Alstl, appli-
('atioll of tilt' ~I m(' t'o lllp ult 'r p n J!.,'T;ulI fl.'sn lts in tll(' Sll lllt' all\"\o\"(' r.; inclt'pt 'llllt'1I1 of Ihe
0lwflit uf. This ('flllsistc'Il('''' (Mdllllnt h(' ad lit'\ '('t l h)' fitlill~ ~rdphi<-,<lI d ata hy t')·t' . MOfl.'tJ\"t'r,
u ntikt , an t'\I)(lIIt'nli,,1 t'(llIatiull. t11t'f(' ;(ft' mml~· sih mliu m in p lmmm('tlkint'Ii<--s tlml ft'(lllifl'
C HAP1f ~3
"
t'l!u atinm; that cannot ht· hm-anzed. 111('11, ohta inillg a lx-st fit hy 1')'(' 11l"<.'Olllto:; \i rt ilall~'
impm sihll' , 11lis limitatiuu does 1I0t ari se lISin~ a compute r: any equa tion can Ill' filtt 'l!
di rt"<.-tly In thl' 1'\I)('rill ]('lIlal datil. Xoucthek-ss. a ~n'ul d eal aillmi (Lila is lea rned by di s-
pla~ ill g " W ill gm phil'ally, 0 11(' gains a f('t·ling for tln- quality o f the dat a and thl' ('(!lIation
that is I11l l' 1 lil.t>ly til dt'S('ril ll' them app ropriatdy, 111l' pa mTllt' IN \11111t'S nhtailwd by t')'t·
also gt·'ll'r.tlly M'r\l' ;L~ su itabl t· slarting \'1III1(' s in a l'lJlIIputer pm~rmn. Because of IIIl' ~n'al
11l'llt' fih lu I( 'an l ill~ ph anllaml.int't il'S gaillt'l! by plntling data, tht s r-h-ment is Inco rpo rated
inl n lIl 'Ul~· p r obh-ms thnmglumt tln- book.

IFIICT OF 0051
An adj m tnlt' 1l1 in dOM' is ofh-n 1\t'('(' sSilry to achil' \'l' optimal d m g therapy. :\ dj llsl lllt'nt is
mad t, mon- n 'ud i l~' when tilt' \·alllt·s of tilt' plllln mu.'likillt·tit, p'lr.l.Il1l'h ·1'!i u f a dnlg dn lint
\'ar:' \\i lh IIm l' or \\i lll concenrra tiou.Tln- possibilif>' for a dJallgt· \\i lll dOM' exists . howt·ve r,
fo r ma ny reasons. and thes e an' dealt with in C ha p, 22 under th e utle of D UM' and Tim e
Dl'pl·IJ(Il'll eit·s. Tl m mg!1011t tlu- majority of till' book, huwt"\...r , pharmac okmc tic pa r.tl1ll'-
n-rs an' aSMIIllI'l! llllt to (.'hungl' wt th either dOM' or ume.

STUDT PROBllMS
(Answen to Stvd y Problems ore in Append ix n.)
1. G in 'lI IIlat till' t1isposilion l.int'l it's of a dm~ is t1I'Sl'riht'l l h~' a one-compartment Illtxlt'l ,
whid l O1I1'(S) of tilt· follO\\i ng statements is co rrect?
11.t· hal f-lift· of a t1 m~ follf)\\in~ tlw r apent ic doS('s in humans is oJ h r. the-refore,
a. 111(' t·lim inatillll run- con stan t o f this dm ~ is O.l i 3 hr - I.
h. It takes Hi hr for S' "S'.f of an i.v. holm dUM' to hI' clnninated.
c. It takt ·s ~\in ' ;~s long to t'l imina!t· 0.3.5 g fllll c J\\i n~ a O.5-g holm tIClS(' a.s it doe -s 10
t'lillli llalt· ll..'i g folltl\\i llg a I .~ tIUM·.
d. Co m pll'll' unnc ('lIIlI"l:lion np to 12 hr is 11('1"111"1110 pn l\itl l' a good t·slilllalt· of Ill('
ulttman- amount of d n lg ewn-n-dunchangcd.
e . T ht· fr;tl'li oll o f the admi nistt'n "ll tloS(' elhmnated by it gin'n tillle is ilJ(lept'nde llt o f
rlu- si....t· of til(' tIusl',
2. Cuk-ulan- tlu- foltfl\\ing:
a. Tht' f"'ll-tiol\ of all i.v. tluS(' rell lajniu~ ill the Ixxly at 3 hr. when lilt" half-lift· is 6 hr.
h. 111t' half-Iifl' of a d r ug, when IS% of th e dose re mains in till' hl xl)' -I hr aftN all l.v.
bolus dost·.
3 , l'n-pu n - a st' milngari llunk pint uf till' f{)lIf l\\i n~ plasm a conceutratlou-ttnx- relation-
ship :

C '" 0.9 e - 0 3.. 71

where C is in IIl WL and tinn- is in hours .

4 . A t1 m g tha i di splays OIlI··l'l Jlllpa rt lllt'1I1 disposition kmet tcs is adnuniste-n-d OLS a singll'
!MIIIiS dust,. 1>t'pi(-tt'll ill tln- left -hand graph of Fig. 3--. are the plas ma con centrations
o f d m g ohst'!yt'tl initially ( 10 IIIWL ) and 60 min later (2.5 IIIW!. ). Depicted ill till' ri ~h l ­
hand j?;rdp h of Fig. 3--. is the tot al uri na ry excretion of unchanged d r ug IAt'" "" 60
mg]. Complete tilt" fig un- by drawtng continllum lint'S thai t!t-pil1 Iht' fall of d m R
t1111('('lltmlioll in plasma ;lIld tilt' at."<.11Illulalioll of d m g ill u rillt' \\i lll tilllt' .
,S. F ru m 0 10 3 h r af!t'r a ,,)(l. mg ix . boills doS(' of dmg. lilt' Ave is 5 . 1 II1g- h rll ~ 111t' lotal
:\ l'C is 2:1,4 mg.hr/L and tilt' (11I11 ulati\l' amollnl l'"l'n·It"lllln(:h an~t'll. :\r " . is II m~.
a_ \\1lal I)('r<"t' nl o f 11.1' atl1l1i nisll'H'l1 tIoS!' rt'mains in th l' l x xl~' a<; t1 m g ill 3 hr?
" CHAPTU J

II. Ca l("ulafto total clearance.

c. Calculate tilt' renal clearance of Hu- drug.
d. \\lmr's the fnl11ioll of till' dost" tlml is dilllill <lll"d by n"nal l'.\{'rd iull?
fi. \\ 'hen 100 III~ of a dOl~ wa s Ji!;i\'l'll a... all is. holus. tilt' foll(J\\i ll~ p la.'Im<l (~ J I K't' lItrd t i oll­
tune rela tionship (C in mWL und t in hr } was ub!it·rn'tl.

C . 7.14 6- 0. 173 '

10
9
8
7
~
°E
2- 6
c;Eo;
.~ 5
~ "
-c..
~ c
~
y
4
c
0
u 3
c.
2

o
o 0.5 1.5 2 2.5 3 3.5 4 4.5 5
Hours

60 ~

50

_E<>
c _ 40
o~
o ~

~go
~2
> y 30
~ c:;:
-" =>
o~
E ~
0," 20
u~
y

"
~

10

0
o 2 3 4 5
Hours
CHAJ'ff R3

Call,dah' :
3. VOIIIIIK' of tli..lrihllhou
h . ElimiJl<ltinn hal f-life'
c. Teltal ."'UC
d . Tulal d e·.muK1·
e. n il' ple..II1 a coneent ra nou 20 min aftc'r a 2,)H- IIl~ i.v. hull l" du'ol' ,
; _ Tahl.· 3--2 "U lll llliui7.l~ pla...m a da ta uht aillc'l l afh· r a !Jui lis lie N:' of n·ft ria.\UIK', a ....-nn-
~ll tlK' hc l1-pl.aleJ!Opo rin antibiulic. in a »cwbom iufan l. (.... llapl t"C1 from SelliLltl, V ,H.,
lI a~1e m , \\".l~ . and StcJl"'l,I",,1. J.: .: Sinp c--tIcN:' l1·ft ria.\U1 Il- kinc1it'S In till' ,"·whon! . Cli n .
Pharmecol. n Wf, _ 3 ;:522--52'\ , I g.~') , )

,.we 3-02 • ..... _ C I - . .. c.fhoIw AffMo I•• • &4.1 1_".

1•• -.1.0 -.lkw) h . -
Time lhrl I 6 12 24 48 n Qo 144
~lmg/lj 137 120 103 76 42 23 12 37

a. J'n -p.tn· a ~ ' Ill i~ui llllnk pk Jl o f Ihc' plasma l11IK" lltr.llion of l't.· ftru.\OIIl- \I'nll"
tin K'. E..tilll;ltt" Iln - !aoLlf·lift· of I.... d m~.
h. Est ill\,;llc' ti ll' total A (:C of l1·ftria.\lJIll",
C , C.ak·t1lalt' lotal clearance.
d . C.ak' ilatc· tilt' , ,,Imllt." of d i'\t rilmtin n .
s. n il' tlata !{i' 't"u in T abk- ~ .tn· lhc· plasma l1 111l"t-n tnd iuIlS of l'K.~IIl· a.\ a flll"-1ie llluf
tillW aftt"r I." . ;tllm iui..tr.lliou of 3.1 m~ cocaine h~tt m('l.loride· In a subjt't1 . (Mnlt, 'u lar
w.-i~th l o f cocaine h)tlrn t'b1oritle' := 340 Wmn1e·; IUo lt" llar ""t'i~ 1 o f ('(Il'UiIW := 31).1
Wmo 1c',) (Adapt t"C1 fn un C IItJ\\', \I.J.. Amlin ' . J.J.. RUIl, T ,I" Alli nson. A,J.. B ow..la-r .
D.J., allli Fi'\(:luTlitll. ~I ,\\'. : Kitll'ttl'S of coc aine d istribution. •-liminatjou. al KI dlnmo-
trupk' d Tc'1". C lin . Ilh;.oIl."-'u l. Tl ...r., 38 :31S-.124, 1 9-~,) . )

,.we~. "-- c •• _IJ.U. . . . . c.e.I_ a ..... 11. .lel•• . 0.-" 33 . .

Time lhrl 01 6 0.5 10 15 20 25 30
ConcenIrahOn ~/U 170 122 74 45 28 17 10

Ol. l' n-pan - a '\('lIl i lu,.~a ri l " lIlil' p lo l of plasma lt ml"t' u l raliu ll versus lirllt',
b. E!otimah' ti ll' 1J1lIf·l ift' am] lolal clcaruncc of cocaine.
c. G i\,c'n tl lal lilt' bud y wl'i~" 1 o f Ill(' slIhjt'l1 is ; ,'i k~, m ll'IIOI h' Ihc' \'Ullllllt' uf d isl ri·
h utillll IIf l"tJl-ainc' ill l A Jt.
 EXTRAVASCULAR DOSE

OBJECTIVES
The leader will be able 10:
1. Describe me choroderi5liCS 01, and the di!felences between, lirS/"Ol'der and oZel'O'OIde1 ob-
5Ofption processes
2 . Oeiermine wherher obsorpll()O 01 disp<»ilion role limil!. drug e1,minohon, given plasma (orr
ceoecrcenee 0010 following d;/ferenl dosage lcems Of roulE!S 01 administrotlOn.
3. Anhcipolelhe effect 01 oflefing loleof absorptiOn, e'denrol absorption, clearance, 01 volume
ofdislr'bution on the pIo:.ma cceceoectco and crrooet ofdnJg in the body ioIbMng eeo
vascular odminislrohon .
4. EsllRlOle!he biOOYailobilityoi a drug. given ei!her plasmaccoceoncrco 01 ullncllyeXClehon
dolofo/bMng boIh exlt(M)SCUlo, and inlroYOSC\JlOI odmlni~ohon _
5. EstllTlOle the relolive bioa.ooilobillty of 0 dll.'9. given ei!hef plasma cceceotctce Of urinary
exclelion dolo following differenl 005096 forms OIIOUIeS of administration ,
6 . E~,male!toe renal clearance 01 a drug From plasma ccoceoecrce and Ullraory e>lCleloon
dolo IoIIowing exfrovo5CUIo, administration.

Fu r sys h ·mie.llly ad i ll~ dmhrs. abso rp tion is a pn-requisin- for t1l(' mr~ 'lIt i c adhity wln-n
Iher an' a<!minish'R'(1 exrravascularly, n it"
factors that inllm'lIl't' dm~ ahsorp tiull an' {'( III '
sidt'n '(l ill Chap. 9, AhsOIlll iulI . III this dmph-r tln- fol1l )\\ill ~ ;Lspl '(:b an' ('x;un illt"t1: Ihl'
imp,,(:t o f rate and extent o f absorptton o u lJott. plasma ouux-ntration andamount u f dm~
ill tilt' hody; tl.t' d Tt'\.1 of a!tt'mthllls ill ahsmpliull alltl d isposition 011 hull y k-vel-ttun-
n -lationshlps; ami Ihe methods used to assess plmrn \;t(:okindil' paramet e rs fmlll p lasma
undurinary (Llta foll()\\in~ e xt rava scula r udnuulstrat ion.
The term IJ;{I(I lA'lilaIJllity is l'CJlIllllollly appliloO to IX)jh rate ,lilt! exh-ut u f t!0l ~ inp ut int o
tilt' sys te rmc em ulation. 11mm glJollt thi s book the term will ht· Iilllih'(l to tilt' extent of
drug input and can 1M.' conslden-d as the Fraction, ur pcrwnt . of tht, aduuntsn-nd dust-,
abso rh{'(1 int act .

KINITICS Of ABSORPTION
1111' oral ahso rp tion of dm~s ufit 'li approxiruutr-s first-o nlt 'r kiru-ucs . {'spt"li;llly when Wn 'lI
in solution. Th e sam e holds true for the absorption of dmw; from llIany other extravascular
sill'S i nd \l(li ll~ subcuta neous tiss ue and 1Il1lS(·II'. Unde r these ci rcumstances. uhsorptiou is
d l<lI"llli{·ri;t.('(1 by an ahso rp tiull mtl' constant . ka. alltl a w rn'slx lIId i ll~ ha lf-lift,. 111t' half·
Hw.'S fill" tln-absorption uf drugs atiministen'(l orally in solution or in a ra pitlly di sillh~mtill ~
dl lSilgt' form us llall>' rdllR{' fmm 15 min til 1 lrr. OI"l"il-si<lllall>'. tilt')" an ·lflllgt'r .
OWTE ~ 4

Souu-tinu-s, 11 dmg; is ahso rll("(l al t"s<;t'n lially a constant rail', 111(' absorption kinet ics an'
tiu-u ('<llll'li u'm onler. D iO'N t'!Il,\'S 11('lwl"t' 1l <'.t'rn-on.lt'r am i first-on ll' r kim-tics an' fl lus,
tmtt"(l ill Fi ~ . 4-1. For a -ro-order absorpt km. a plol of amount rt'mai n i n~ 10 beuhsorla-d
ag;ainst tilllt' ~id ds it st r.li~llt lillt·, tln- sloll(' of wlitch is tilt' m il' of ubsorptlou ( Fi~. 4--1A),
HI"(."dll Imm C hap. 3 Ihal tht· fml'liona l run- of ded ine is constant for a first-order pRk't'SS;
tIlt' alllolint dl'C:liTlt's IiI1l'arl~' "ilh tum- when plotted st' lIl ilo~~aritl IlJlkal ly, III cont rast. for
a zero-on k-r abso rp tion pml'l' ss, t he fr.K'tioll al rail:' tucreases wit h n uu-, be c a use the run-
is constant hut tilt" amou nt rt"'lIlain i ll ~ de-creases . 111is is n ·8('(1("(1 in an l·s"t'r - illl· rt'il~ill)!;
g;rmlil'nt "it h tinu- in a S('1l1 ilng;arit lunk 1'101 of till' umount rt' maini llg tn II(' abso rll("(l ( Fi ~.
4- 1B), A ~mph it"llml't1\(1( 1 of l'xamining dIe kinetics of absorption fR)IIl plasm a data fol-
los\i ll ~ t"tr.wa'K'u!;lf lld ministm tion is ~wn in Appl·mlix (-C,
For til(' n-mamdcr o f th is chapte r. and for much of the hook absorp nou is assumed to
II(' first onh-r. If ahs(lllltion is zeroorder. then the equations developed in C ha p . 6 (Con-
stant- Halt' HI'¢ ult'ns) llpply.

A. Regular Plot B. 8emilogarithmic Plot

u 100 u 100
~ ~

..."
0
~
D 80 "...
0
~
D
50
Zero Order
~ ~

'"s 60 '"s
0
~
Zero Order 0
~
10 FirstOrder
·E ·E
.~ 40 First Order .~

E E 5
~ ~
o:
'" 20
""
~

~
c,
"Il
~

II:
0
Time Time
t"lII:, "-I. ., " "" I'-In" ", .. f " ,",...",Io'r and li"t-<""Io'r al"" 'l l(inn I'I'"l......" .". n.,.1<-.1an', ..\ . Il,~nlar .u,,1 H.
,, 'mik'l{>Ili thmk I,k~ ...f II.., 1" 'rn'Tll n '",,,i,,i"lI: In h.. ..1......."..1 ~ ',.I tllTll".

BODY lIYIl·TlMI RIlATIONSHIPS

Comparison With an Intravenous Dose

Absorpt iull t1, 'lilY~ ilnd ll'(lul."·" tllO' "1lIJ:,/Iit l/ dl ' eif Ow Il1.'ak {'OIIlIl;Irt"(1 to tha t s('("1I follel\\ill~
all t'(lua l i.v. bol us dost·. TIlt'S(' 1·0'1'(15 are portrayed for aspiri n in Fig. 4-2, 111l' rise awl
fall of till' dOl~ couceutrutiou in plusma art' be s t understood by n'lIlt'III I I('ri n~ (C hap. 2,
Ell. 2, p . 16) that at any ti me

dA <lAo
I·A
d' d'
Rate of Rate of Role of
change of o b$Orption elimination
drug in
body
 CHAPIfI! 4

when- A" is 11M' amoun t of dm~ ,II rln- ah~)'11ti ull ~ il l' n.' lIl ili n i n~ III Ill.' absorbed. \ \ 1lt'1l
absorption IIl'CU O h~' a first-onk-r p R ll't' S" ,
tilt' rate of abso rp tion i.. ~n'n hy kn-Au.
Initially, wi th al l dm~ al the ahS()'11Iioll silt' and nOll(' in Iln- hOlly, rate of ah~)'11tiul\ is
mamual an d rail' o f elim ina tiuu i.. zem, The-n-efter. ;l" d Ol~ is ahsorht'll. ito; r an- of ah<,uq l-
linn dt'1·n'il<'(~ , ",1Iert'a<, its ra te o f r-luntuatfon tncrc.ea-s. CUII''l'( plt'lIl l~'. tilt' di ITl'rt'IIl'(, Ilt.,·
IWI'l'n lilt' I\\'U nm-s diminid lt's. If nwt'\"('r, u-.. ltlll~ il" tht' rate of OI!JSC IIVlitJIl C,\ ('t'l'(L.. thut of
t'li millatioll lht' plasma concentr atkm cont inues to nw. E\"('l1tually. a tum- I ....... is rt'adll'll
wllt"n tilt' mt(' o f t'lim inalioll matcht'li tilt' ran - of ah..u rplioll; ti lt' ("l)1l('t'ntmliou is theu .11
a maximum, C....... Suhst.'qu e ntly, lhe mil' of elhntnatton e:\('t'1'1I.. thl' rats- u f ubsor ptfon and
tl u- p lil..lua conceutra uon dl,t:lim's.
111t' pe-ak pla...ma concent runon i.. always ICI\\'t'r folle l\\i n ~ ('\tm\"il"!11Iar ad ministral io ll
than lilt' initial value fn lln\\i ll~ all ('lillal is. holus (lelSt'. In Iht' Iomu-r (' ''-'it' . at Ihe Ilt.'ak
lilllP ~ ltllt' d m~ n-m.uus at lilt' nhso rp tion silt' alltl <,(llllt' lms been t'l im illalt'l l. whilt' ti lt'
entin- c!US( ' i.. ill ti lt" hudy illllllt'1lialt,ly fol\(l\\i lll' rlu- Lv. di N' . Ht, u llcl lhe ()I'ak tune, tilt'
pLt..ma ronce-ntration t'X('t't'lls that f(JII( J\\i ll~ L\". ;ulm illisi ml iull uf till' sallll' do...' hl ,('<IlIW
o f tln- m nlinlla ll'ntl)' of d m~ iutn tilt' boc.!y.
Fn-queutly. till' ris i ll~ portioll of lilt' pl'l..ma ('tm('(·lllratimH irnt' ( 'U '" I · is culIt'tl tln- (II,.
'U''7,tim l ,'}IIt\·t' and the dl'('l i n i u ~ portkm, Ihe t,/i mi llllt iml l ,l ltl-w. As \\i ll hI.' see-n . litis dt ··
scription ma~' be mislt'ad ing, Also, if biclil\-.tilahility is IfM', lilt' c1mg concvntr ation llIay
remain IClwI'r thau tltal Uh M·"' l.'ll aftt-r i.v. udnuuistration al all ttuu -s.
l A {:. time, 111l' dday hl'lwl't'u drug administ ration alltl lt.l' Ix.' ¢nnin,g of absorption. lIIay
III.' llitrtk111arly important Wt.t'li a mpid o ust'! of t·lTt'(,1 is des ln-d. The b ,g tilllt, ran III.'
auywln-n- From a fl"w minutes 10 many hours. Lu n,g la,g tunes have 111.'1.'11 nIN'n'!.,,1 follc I\\ill~
in~I.,; l ic lll (If t't\It' n c-(.'t)alt,,1 tabh-rs. 111t· (.'t lilli n~ is resistaut to till:" ~'l\l ril' envm uuueut , IllIls
p rtJlt '(1iug an ;Ki tl-Iahi ll' d n 'g or pn:"' l.·ll till ~ ~a.\tri(' Irri tntiuu hy a dnl~. Fal"tor<, n lllirihuting
10 11ll' lag lilll<' an:' lhl' ddil~' ill ('mpt)ing Ihe product from the sto mac: h am i tllt' lillll' taken
for IIU' pmlt '(1ivt' ("llilt i ll~ to e1issu!..'!.' o r to swc,lI and n:·tl"l~· lilt" ililw r ('tmh-nls into tilt'
inlt'sthml llu ick Olll't' ah<,()f]ltinll III.1,rjns. h (J\\ '( '\'{'f, it may III.' .l.. r.lpitl il" \\i I1l UIl("Ilillt'tl
lahlds. CI('arly. ('IlIt' ri('-{'tlitlt'1l pmdllt1 5..hnllid not Ill.' 11<;('(1 wllt'll a p n )lllpt alld p n 'tlid 'lhlt,
rt'sllI.JIls(' is desirl'll. A Ilw lhlll.l fur esli lllali n~ tl~ tit lll' is c1iS<.1 Is<'( 'l1 in Appt'nclh I....C .
Blo(l w iltJlJilit y aud (In '(1 an.' al<,() illllll.Jrtanl f.tt10N , As (liS(.'usSI'tllllon' fully in Chaps. j
ancl9, lilt, l"l)lIlplt'h'IIt~ .. of ab<,()'1Jtio n is of primary im po rtan('t' in t1lt'mpt'lIli(· ..iluations.

~ 10
0

~ 8
"
~
~
0 -
6
';;~
.;:; E
.5. -
4
.::>
~
E 2
~

'"
0.
0
0 20 40 60 80 100 120
Minutes
t"iJl:.4-2. '-\' I" rin (6.''10 "'It) w.... ,.Imini'kn'ti ll.' all ;nl r..... 1.. ",. I M~ Il. ,.1 . ,,,1a' all ur,.] ... ""ti"" (OJ" n .. " ..."1..
•• 'Ol . i" .... til II.., ... ml' in.ln" I,,..). " ' '''' '''11111 >11ca,,_ '" ,,,.l.t~ . lUlIl .. \c... .-rilti/: {If II""I",·ak l". Il, ·nlr..tio mII rnlo1I. ..
.5,.5 j.I~ l l . ( ~ I , ..lifin l frum ,I... tLI... of Re... L,,"!. ~I " 1\;."·I,,,all. S., I I..m •. 1', .-\.. ;.... 1s l...Il"lT. S I)., ...I""'1>1io"
l i,....Il... <i "-'1lirtn In nl<U' f"llc... ,,,!:
ur..! all",jni.lr~k," " f ;lfJ "'I"" "" \lIlll(iU II. J 11w m. S<.i.• ,,:\ 17U-.-v..'). 1\1j2 ,
A,Lq>tI'tI..1t1, p"' n n i" it ll l ,i ,h., ("I~~J I '....' ItT )
 EXTiAVASCl.J.AR OOSE
"
TIl(' h iua\Oiilahilil)', F, is proportional to the-t otal urea lImlt'r the plasma couceut ratiou-time
curve (r\ Ce ) irn'sl)("(1in' of its shape. T lns must la- so . Heeall From C hap . 3 th at :

T0101 a mount eliminaled .. Clearance ' AUC 2

hul tl.t' lul,ll a mollnl t·!illlinatt'ti is tilt' <\111011111 ah so r])('(I, F . Dust" tllt' rt'fo1l':

F . Dose - Clearance ' AUC 3

Amount Total amounl
absorbed elimina ted

Thus. liIl n\\ill~ tlo,,-', ch-arance. and un-a. hioa\1lilahi 1i I~' llIa~' l lt, den-mum-d.

Changing Dose
Unless ah"-''llt ion half·lift' or h io<l\'ailahility is altered, i ll(:n·a.sin~ tilt' dost· produce-s a p ro-
po rtional ill(:n:',l"-' in phlsllla coucemrauon ut all tunes . TIll" value of ' "",. n 'maim unchau-
gcd. hilt C"",. increases p roportionally with dust·,

Changing Absorption Kinetks

A!tt' ml iolls in t' illlt' r 'lhS()'lllion or di spositioll produce changes in 111l' ti me profiles of tl u-
amou nl ill IllI' h(ltly am i tilt' pl.l-sma co nce ntration, Thi s poinl is iUmt rolh"tI I,:,' tilt' tlm 't'
situations dl'pi(1("t) in tilt' o;( 'lJlilo~~arit l\lll il- plots of Fig:, 4--3 tnvolvtug only a dlal\~t' in tilt'

Case A CaseS CaseC

'00

300
100 Absorption

Elimination

o , 8 '2 o , 8 '2 o , 8 '2 16

Hours
t "i l(. ~1. A .1'''''''1:: (fn nn \o.'ftt" ri" ht l ..f ,lmlt Jo.·di,... at til<' a1"""llCi"" .il.. (It""..., !t"".apI" l ,I..~., I...· ;ollllin n"'n l
" 'MI ,1. ~ TO 'a...... tI ", " "' l(Tli'n, lr"or tI,,· I..;ok l'u"TllI dro it l~"'I<Tfl, h"n (I,'f' """"" )' In C 'l _ A "",I K (hoUom I...,
~aj>l" I , ;o1o"" l'liou (IoLoo.·1< lmd io .. f.., II'r pnll~,," tI..." ('hmll Ii,," (cul..,..IIi.... ). In CoIL'" C (Ihin l ",>r..pl, on
lilli""" I, al....''1" ioll' II,Loo.·1< li'''' l r.." , h",i l' ..h", i"" lio." "" 1"" 1, I.·di 'l<· Il( .In ti( in pt..,,,,,, " .fI."t1$ a1""orpt"." r..tl,•-r
,I,w, ,·Ii," inat io •., ; l. ~"",, , tla-n- i. a ''' '! ,' h", inati.... nf dniK (!llrinlt tht' ,Wi,,,, pt..u... t...• r"l(' o( d imi,...lioll is
,h"",t ~· j..'n"oat,'r t ]..... 11 K" r..It' .. f ;o1""'1" i..." In all II,,,.., (.......-s. hitl\(·n liLJ.ilily i$ 1,0 ;0,><1 (.I.';or",,,"t" ~. ll!1l·h"n!:,,,!.
c.''' '' ~ I"."n l l~-. tl,,' ;on'" , ,,,,,1.' 1' 11"' 1,1.," ";0 (~.""' '' Indit m · li nlt' ('\/1'\'0', k.. m~r- "Mli r>l( li",,,,r 1'10" o( II... I''f' 11m..'
~pl" ) an ' itl.'nli, ,.1 n M "..H ·C. Ilr tI.., Ii'''';or pit" . or tI,,· n" I.. d..t,, ;oll' 1lI.. , "'-1"llIl .."t'au't' II inl' V .,] or th.. ....1('
of ah" ''1" '''lIl, ;0""""" ,,1....,..+....1. '''I'''''' II,,· inh V ,,] o( I...· ra,....f r h",inatio", """..",t ..Ii"'i, I•..I.
3. fKlRAVASCUAR 005£ CHAPTER 4

ah sorptio n half.llfe. All other fat1nr.; (hio' l\1Iil<lhilit)', d t ' llnU J('( ' , and voluun- of distribution
anti lu-uce elimination half-Iifd remain co nstan t.
In C,L'tL' A, 11.(· most ccnunou sltuat km, absorpnou half· lift· is much shorter than r-lhn-
illation half·lift,. In this (""<1.\(' , hy the !iIIit' the pt·ak is reached. ruc st of tilt' d m ~ hil~ leeu
ahsu rbt'( ) am l litt lC· )la.s 111:" '11 eltnuuan-d. T he n-after. dt"l..hm- of d nl~ in tllC' hotly h den-r-
milwd primarily by tilt' t1isl)()Sitioll uf til(" drug. that is, (II.~JJo~itlon b 11ll' m tl'·/imitill1!. .\ tt7',
T Ilt' half-lift' es timated from tht' dechue phase- is, thercfun-, til(' elnnmanou half-life.
In Ca<;t' B, ahsurp tiull llalf.lift· is 10l 1~t"r than i ll Ca.<;t, A hut still shortr-r than t'li lllillalioll
half-lift" TIll' Ix·a!.. IK'(1.mi later ht'<.'atlM· it takes IOIl ~l"r for til!" amount iu tlu- hudy to reach
the value at wluch rate-of clumuatloumatche s rate of absorption. till" C is IllWN 1)("(,:tIIM'
les s dm~ has lx-eu ahsorlx"i.l by that time, Even so. «leorptjon is stillt·s.-' 'lIlially complon-
befo re t1 lt~ majo rity of d m ~ has IIt'("n ehminated . OmM'fIIll'nlly, d isjx)Silion remains till'
rate...lilil itill ~ stt'P, and lilt· tcrmtnalhalf-life remains till' elimi nation half-life ,

Altsorpliol Rat,.Umited Uiminatio"

Occasionally. ab sorpuon h:M-lift· is 11111<:1. IO Il ~(,( th an elim inalion half-lift·, and Cl<;t' C
prevails ( Fi ~. 4-3). TIlt' pe ak occ urs lan-r and is lo"', N than in till' two p n '\1ous l'lN·S. T ilt·
half-l ift, of dechnc o f d nlg ill tilt' hotly lIOW corre s ponds to tilt' ahMlrptioll half-lift'. 1> 1I ri ll ~
tht· rtw 10 llll" peek. lilt, ra te o f eliruiuation increases ami t'\'t'n lllall~', al tht· peak. e-quals
lilt' rate of abso rption. Ilnwt,\"(·r. in con trast In tilt' pn.'\10 IlS situations, ubsorpttou is so slow
that much of 111(" d m~ remains to lx- ahM,rflt'(l well Ix-yond tlu- peak tune. T Ill' d m~ is
either al till' abso rption site o r has be en 1·!imin:I!<'(!; htt le is in rlu- I)(KI)'. In f.ll"t, d ll ri ll~ the
decline pbaw, tt.l· d m p; is e limi na ted a'i fast ,LS it is ahsurllt'(1. ,VJ,\'OfJJtiorl ~~ fllJU: tlw rate-
limit/'l l! slt?J. Under t111'SC circumstances. since the rate of elnninatiou ('sM'lItiall)' matches
Ihe rate of absorpnou . tilt' f(JIl(J\\1 n~ approximancu (... ) ( "lUI 1)(' written

I·A - ia ' Aa
Role of Role of
eliminotion a bsorpl ion

thai is.

A
. body - (I)
mount a . .
-I . remaining
A~" '
10 5
In be absorbed

A(1.,(lnling::ly, amount in till' Iltltly (am i p lasma ('()m'('lltmlifln ) du rinp; tln- dr-cltm- phase
is <Iirt"{1ly proportional to tilt' amount remaiuin~ I" lx' ahsorbed. For ('xamplt', wln-n
amount wmaining to lx' ahsorl a-d falls hy cue- half MJ docs amount in IXKly. Il o",t.'\ "(·r. the
!iIIit' fur this to occu r is the absc rp tkm half-Iifl'.
Absorp tion Influe nces lhl' kinl'ties uf <In lg in the IKKly: hu t what of the A(/C? BI"l'aIlM'
bioilvailabilil)' and clea rance ....e re hdd constant. it f" lInw,; from ECI. 3 tha t Iht, A VC must
1)(' the same fur Cases A. B. am i C ,

Distinguishing Absorption From Disposition Rate-Limited Elimination

.\ 11 1.0 111-:1. d ispm il io ll 1-:1'lIt'mlly is m lt · · li lllit i ll~. tht' pr('('I"tlilll-: d i<;(.'u.\siun Sll~t"lil s tl llIl e d. ll-
lilill II lay Ilc,('f l h i lit, c'sl'rd '\t'(1in ill!l"llrdi ng tilt, II lt 'a ni ll ~ of Ilalf-lill· del('mlillt't ! fmlll the
t11·diIW pha",' fo llowi ll~ t'\tr.i\'a\('lllar adminh lralion . ( :o llfu\ inn is a\~lidt'tl if lhe d n lg is
CHAP1H A ,.
al~l ~\"en intnl\"{'llollsly. III pml1k'-'.IIIl\\·I·\"{·r, i.v. dusa~c' forms of Illany <Inl~ do IIOt exi st
fur eliuical IISl' . Distin"..nishi nF; ht'l Wl'C'1\ ah sorptioll ami d isposition rate -limitation s is
aeh il'wtl by altt'rillF; the ab sorption kiuet fcs of lilt' t1nl ~. This is most n'adily accoruphdn-d
hy ~h i ll ~ the t1mJ{ t'itlll'T in diffen'llt do sa!?:t' fo rm s or hy d iITen'nt mutt's. To i11l1stmte thi s
po int , l'ulisitiN data fur t1wuphylline ami pC'nidllill (; .
FIMMI nnd wate-r inHuc'nl't' tilt ' oral ah"': lIv tion kinetics of thc'tlp hyllinl' hut nul t "c~ ha lf-
life elf tht, dc't.'lilll' pl.llw (Fi~. 4-4 ). li e n ' then, dispnsitioJl rute-linuts theophylline elimi-
nauon. In contrust, fur penicilhn. \\ith a \"('l)' sho rt d iminalinnllillf,life , Intrur nuscular (LIII.)
ahsOIVlioll eanlk,(11lllt' mk·limitin j!; hy fonllllialion of a sparingl)' solnhle salt (F ig. -1 ~5 ) .

<IKIngiag Dispodtiol KiM'ks

\ \1Iat happe ns to tilt' pl.lsma concentration-time profile of a d rug when till' ah "':Jlvtiul\
kim'tit... n-main constan t. hut Il1IMlifil'iltinns ill d islx",ilion 11l1.1Ir? \ \1 lt'1l d e arallC'(-' is re-
IIlIl1.'(I, but bi{lil\1Iilahil ity n -mnins constan t, tilt' I\ve must illl·Wit.st'; Sf) mu st IXlth tilt' tirue
itntl magllitll<ll' of tlu- lwak coucentranou. 11\{'w events an' depicted in Fig. 4-6. \\'ilh a

10 1-"11/,. +-4. T" ., lal.l<1'. .-;00;-1, c<M'I.unin]( 1.111 "'I:

8 t h'. 'l>l l~ m,",.'''' 1'1' ,..k.... I,> 6 1"...Jlh;o-,. ,jun" ~· n "11 '
~
tiN , .. rio.. " .",.. Iilin'" _ i\ IKC oq>tlo n .,f 1I"''1>1,., lIi,,.·
6 " ,. . .1 r~>i, 1 .. ~ ..·n tI... ,,,h it.., "" ' 1'1 ' di. ...>1""11 ill
,,"';llO

§. 51111 ",I. " f ",...k r . 'MI ,..k-n on lU I " ln l>l~' _t" m,.d ,
c 4 (0), T akin1/: tiM' ,..ltJ.'!, "'; 111 2lJ mL of .....w. ' "' ""
.~ " "'Ilty ,1" tI ", (0) ~ull ...1 in "'.... ·r ..h""'l'h,,"
e tha" t.,k",!: tI ", "ith Itw Il&mt' " >1"" ,,. <If ",.. I,·, i",·
~
u ",...Iia"·~· li>llo...i nll: .. .tantLordiD..1 hill:h {1lrhnhy-
c
0
2 , I',d. - tlM·..l (el. D' ''' 1'il '' rlifT.. 1'f'fK'M In roll", nf a!>-
U ...,rl'li"l1. I.."",·....r. th., It'n niruoJ h;Jf·lif,· w~ II..,
~
s ..."... 1".3 h.."n) ."ttI.
tl...n-f", e . il l. tI..· .-li miu "li,, "
or
1....lf·lif.· lh''''l,h yili"t- ( I mWl • .5.5 f.l\l l. ( " ,..d .
'"
~
~
0
~
~
1". ..1 (nUll \\'..Il l1l~ P.G .• l.yo
an,l Trudo!a. G .A , l" fI"
I_I ~ , enliJt. \\".A .
of.1ire a,Ml IIniel un
~ hi"""".;I,,1>11;1,- of 111......,11) 111ne . C h n. I'h" rUl;U'11.
~ 0.5 nM'r " ; ,475--4'jll. I~~.)
E
~
.ss
c,
0.3
0 4 8 12
Hours

5 HI!:, t--S . "' '' li<:illin c: (3 1fW\l() ......, ... Iminio·

c h,,,,..1 intTII.mmn,Larl" to I 'u iI" lni<llIaI un
0

~ P·I.M.
dltT.· n t " I '( oi" n. ... li n " " "III ti,," (1..' 1.1
e 1 "nIl I'n ...oai, 1.. -niM llin in oil (P· I.M.l ...nd in " il
8c "'ith .I n'''''''''n ""'IOCKt<'anll.. ( AP, " ' ! ,). Tho· .Iif·
0 _ f"ri"" or or
rod... {It·di n., tl p1 rna t'f"lO'ntr.. h.",
';; ~ "T"i.." r-.tl.·_hllllt....
~E
uf 1"'"i..,lIill G 1,,_"1 to an
Ii.... ...i...., tltio .." hlliutic b Kt'-TT1 .... I'..,
1"''''' ''''' '
"
u-
.~
c,
0.1 I.M. t:----.. "",II rn oil. J)iotint1k. , ' '"''. .... n Tll.t .. . 1illlit...1 ..I...
"''1>1;'''' "fIo, 1 raI e- Ii "';t~ th'l"lSilk'" f,~"",,1111: i,,-
tnun " .....' wr ...Iml"i.t ratif", trl tI......1'.......... "" Iio-It,
E
J t'ltIl '''lly t... m...It· by K*'i"!t l""..iMllin (; intr. ' .. -
~

J! """.Iy. ( I mWI. - 3 .0 "M ). ( Mod ili,·,1 f ru m

0.Q1 M"",,,. I> F .: o"tli"" ..f Fu lld..,..... 'I"" 11"mll......1-
18 24 ' ~'. e h" n... C. Th..rn...... SprinKfir1t1. II ~ 19.-') 1.)
0 6 12
Hours
 n n AVASCULAl1 rose CHAPTH <l

~
0
10
",,,I.., tl,,' I,l"",;/' .. ",n'nl.a, ~
Fill:_4-fi. .\ ,,,,, (,,I.l " ~ I ' M1 " " , in (,I.-Mall'" j" .
tl..· .on-..
'"
•.0: ... ......
~
,..,"-,''',,, 1,. .."....11"..·. 1,,1' Io:r"1',/, ),... . .("lel, ••", · u 5
~ -
p.......II" ,1,.,1 ,,( tl..· .. ml n~ 11>I...1Ii",-) ..f" ·r ..
" "l:I, · .·\lr..' ....."1..1 .1. \ \ ';111 ''', d ~Ul~" ill "I>.
8-a,
""!,h",, Li'", tin 1... " 11 ",, , ah"''l'Ii'' '' r.lt,-
=E
0 _

!' rnhl.· wit l, lo",,· ) (, .. "' l li,..·. I. ,tt u lIl l::r..I'IoI. 0" 2
~
110." ".It<- .. f ,·I""i".di" ,, < 1 Ii'..-. I..,n"", E
1:'''1,11 \ l" I..· 1<",,-• .,t Ii". 1"'1 ,,,
j, ,~ .... ·... , .. I
~

I...... " ..· C.. ·.,I<-, Ih.... tI,."

"f tI,,· .. 'IIln,I II,I...1 ~
1",,·. I.. ~ Ic " " 1:'-"1",1, .., II..· Mo' " ","I.., II..· nor-
" "'1" ,,,.1"'1:: h,..·". p"."..
f ' I"....· ....10· (.,n ,... """. 1000
h." '''1".,1 I" tl,,· .10 · (" F;( . "~1 1. 11..· ,10··
,·rt·.....· in "!.-,...",,, " , 11.., I'O"', L '''' '''' ll l r~ ·
'M'" ,,, I.· I:"'~r,'r ,,,..I'n ' ..... r ,,' " 1;'10" h UH" 500
h ,,,l~ , hl:h' l ~ ,MT" n'''! h,·",). 11..• I" ·,,l li UH" '1( ' .
" ' ''' " I..·" ,I.., r'l" '''( , 'loU"'~'!" """'I,,~l. ' h, ' r.." , - Absorption
.,f " I"" ,!' I " '" 11" '11" 11I l:'''l'h l. T Il<' 1,' rn,;" ..1 200
, I" ..• n·II...1- 11..· ;,,,·n·..,.. I,·I""",,<lI<.,, 1",1(·101;'.
~
§. 100
~

'"'" 50 / ' / Elimination

20

10
0 4 8 12
Hours

n"t lm ·lio u ill dl'ilf;llln' und. IWIll, '. ('!illlinal ilm run- coustaut , a g n-a h' r a mo u nt of t1 nlg
IIHlst hi' a h\ll rlll "ti. am i lI lt' ptl\lIIa l'lIll" lIl ra tillll 1I1mt Ill' gn'alt' r pri o r 10 till' li lllt' wheu
th,' rutr- of dilllillalioll ("tillais 11.(· rate o f ah\l)'l)liuli .
As SI.(I\\11 ill Fig. ·1-'j , tl.,' t,\('nls a n' d in-I'n 'nl wln-n an illl' I'(',I-\( 'l! volunu- (If di st rihulilm
b n 'sl'NlI\sihl(' fur a IUllg(' r (,Iilllinalioll l.a1f·li f(,. Um ll' r 11ll'\(' r-i rcumv tances tilt ' t\ UC is til l'
s.uue if h iu;l\"ailahilily and ('(1'011'.1111" a n ' 11II(·ha ngl,,(1. 1111' peak IJ('('11rs late-r ancl i~ 10w('I',
htlwt '\I 'r , \\'itl. u b r):t,1' \'UIIlTlIt' tlf distnbutton. 11I0 1'(' d m~ IIIU\I IN;' ahsorlN;"t1 (,('fo n ' 11.('
p l.l-s lIM{,(lIIl"('lll ra tioll n-acin-s a vulue al which Iht , rate- o f eli nunution ((.'1. ' C ) (,,( plills tlu-
mit' u f all ,mplio n: the- ubsorption run- is 10\\ 1'1' tlu-u ilTltI so is ti lt, plaouu 1'lllll" lIlralioll .
PreetKting Changes in Peak
Qll alil"lin- d l a l\~(,s ill C".... am l t...... •rn - diffu-ult 10 pn-du-t whr-n ab sorpnon or d ispositioll
is nhr-n-d. T o f..l'i litalt' t h is pn'll idiulI , u IIII'mlll)' aid h,l-s hl"t'li foun d to IN;' 1I<;('fl1l . Til('
h..stc prtnciplr- o f IIJ(' lIw tl uMI ( Fi~, ,,--Ii) is silllpl("; 1l11\(11"])tion iUl'rt' ;L",-'S <111I1 dilllimition
" ('('n ',l-\('<; li lt' amount uf t1 m~ in lilt" 1'N'Nly. Tlt l' f;lslt' r III(' ahSl:I'l)liu lJ p n ll' '<;s (ant';Lsllrt"t1
hy ah "'ll'lltion ran- ("(lIIsIOlIlI), tilt ' g rt';ah-r is till' slop" of till' ah\ll'l)tin u lim' , ;\1J(1 111t' rou -
ve-rw-. 1111' fasn-r tln- ('!illl ill;llioll P",I'l'SS ((,Iim iualillu ra n- 1"(lmt.lI1 t), tIll' sh"('I)«'1' is till'
t1.'('!im ' uf tilt' ('Iillli llalioll lim '.
If a h\lI'l)lioll raft- constant is illl·n·.lSt't1,Ihl' 111'\\' poi nt of inlt' N'('tiflu iml it'a!t's t hat Iw ak
anmuut is illl·n "lSl,,1 und thut it lll'('ur; at ,111 carln-r lillit' . If t'l illlill<ll ion rat(' coustaut is

T Ilt' gr<lph is dl'si~IJ('t1 for pn"( lit1 il\~ d l<tl l ~I'S in t_.
iUIT( ',l\l '(1. tilt' IlI'W IMlinl uf illh'rsl '(i ioll (J('l'u r; at all earln-r t ime-, h ut a t a Illw('r a mount.
and IJot';Ik a mount in 1111' bo, Jy. It
appli,'s as wt-ll 10 C ....., \\ i lb 11 1I' ('\u 'ptioll of \\"111'11 \ul llllll' o f di st ribution is aln-n-d. An
CMAP 1E ~ A .,
I-l K. " _7. .\ f\>.,,(,,1cI i'K.,.,·.....· III ,I.., ">I"",,.
tlf
,1I'l ril..,h.." (."'" ........ ,,,,,fuM ;'Il1'1·.....· ill tlo.-
,·!im j" ..ti .. " I...I(·l i(. - ;on<1 ,I••l",~ . tl". Ii "", .. I
"foid, tI..· 1" 'oIL pI..,,,... ""..H ,lr.dio", tI(U,I'
... 01<,0.11".... "'I' j(ml>l,\ .... "1..." ..1til 11... (. ,u·
I n ,l , 01",,' n d lil m ",Lt.{ li".. l ;tll.'r .. ,i"I:'" ,'\I r..·
"IM,J,....·. With "" d,.."\,,,· ill ,-I.·at,nM. ....n'"
,;t...

' ,ullk" I",. ' ar Il.·"tr"'Ii.. "·fj"... 1,10.. 1 ;. " " .

'~'''''I:', l .m.t p l nllK""tr.. li""
i, 11,, ·n·I ~· n-.
,I"n'd ISo ....,,"'· "I" .. " ...." , , ·.,lr.ll ...I1. •" t.'
"f o-li,,,i,,.oIic,,, i, i ",tial~' . 1. ,..1 (I,.I.,n..1 [illl ' ,
I....' ..m I(r"I", >. I",1,i,,,, -,I..· .." ...." '1 ,·]i"';II"I., 1
1000 ;, II..· ...." III ,,· ,L",·I. ,.1,·
" f •.fi"'I".lIiI.......·,,·
,,,..I~ i. " " •., II."" ,I.", "f ,I..· ',lI.l,,>I lill.. ,l
500 IUN', h"tt"", 1(,,,,,11 1.

_ Absorption
200
~
S- 100
~ / / Elimination
a: 50

20
r
10
0 4 8 12
Hours

. '11:. 4-8. Me mu ry aid to ;u... u du. np:l'l in pt'a k

Iim.. . nd prak a moun l in the body. ftl'rnlraval-
B,' MIla r ad m lni l tnatlon o f ;0 IrinKJe ,) n . b.
m rpt lo n or di~i1iun " . It..red. n... tiYr
pt'u 11m.. anU Ih<- I't'l.o.tiw' ["'a le amount art' tn-
, dicalNl by lhoe Inlerwctlon of the ahwrp hon and
,
, ..limlnaU,m lin... (A) with .Iopo-. n-p....... nlinp:the
, a h....pbon a nd ..lImi l1.lllio n rale conttanll.~'
, A
, ,.
11\~ly. n...
p....Jic.1lo nJ (OT a n IIKTt'aord a hso rp-
, l ion ral e:' co nsta nt (colored dashed line and poi nt

,, C Bl and an Incn-.ur<! ebmi..-ion rat",unlU'lan ' (col·

, c red dolted lille'. nd point C) . .... shown. ( Modi·
, fl...d rrnm 0 1... S. • nd Tour, T,N .: A m..mory aiJ
, 10 a. Sf'lt duo nKM In pralc ti me and pt'aIc COlKTn-
lra lion wi th aheratlo n in druJl: .hoorpuon or duo
Time pm iUo n. Am. J. Pharm . ea.. 46:154-155, 1~2. )
!IIe l'l'il'" i ll vnlunu- o f distrihut ion v..111M'S a d('('n ' ;l<;(' in pea k concentration , and the cnu-
us e-xplained under Ch'UlWI\~ Dhpusitinl\ Kinet ics . Spt"<.ifil· rt'l aliu llst.ips for t'sti-
\"(' I"!\(' ,

Il l<lti ll~ tln- ' -'llut's of C....... ,111(1t _ . wle-u absorptio ll am i dispos uson are fin t·o rtlN an' wn -n
in :\ ppt'lltli\ )..-C.
ASSESSMENT Of PHARMACOKINETIC PARAMETERS
lI ow sonu- paralllt"h-r vuhu-s art · t'stimalt'tl follo",i ll~ t'xtm\ll-"l."olilr ad ministra tion ran lit,
a pprt'('iatt'(l hy {"Iln si dt' ri ll~ ho tll tllt' pl.t\ lIIa conceutratkm -tun e (·U ....es in Fi~. 4--9, ohtaillt'(l
42 CHAPTER.4

2.0
Fl~ . ~9 . \ 51"'" "" , ~ ...... i. 1/;i"'" ;,,' r"""'''-~ II...I~·
,e- ., "'K IIIr.J I~ (0- . ·0) h. tI..· '<a"'" .u h;'"<1 .M,
"-",,m'h' , ;,,,... 11,,· t1nlj( i. It·•• loi.w..."il..IoI.· 01",1 1.0
" ..1", ,.1 1 ",,, n ' .1<""1:-
fn ,m .1..· ",,,,-' l,,,i nh.. ti ,,..l
In.d , A l'.mJ Io·1 ,10...·li'.... 1.."" "H"r, inopll<" lilA ,Ii.-
, ,,," il ;' ''' i. ' oI!t". ]im ih " l: ill ""d, i n,f..lln '• . 0.5 00 0
0
0
0
0
0
0.2

0.1
0 2 4 6
Hours
y.w 1. D.ttI 0Ith newl... &tI.I.I........... SOO _ . . . . . . . . . hi
hlvll It)' Dlfte_,,' .
l'\A.'.M.Il. o,.o..l'" ~(),t.I"
!'WJ~( Cl,Wl.U..1N( AAlOJll

eon """
'....A>
,-,
DECAT PI-t.o.Sl: E lC tn1DLNC ~O
l""!ll

InIlO.-enou~ 76 190 152

Intromuscular 74 185 147
0 01 35 193 70

r(lllm\in~ i.m . and u ra l adm inist rat ions ,,( SOl) mv; of a dnl ~. and tln- mld itin ll"l tnformatton
in Tahh- -I- I.

P10sma Data AIon.

Hinn n.i1l1h ilit,... Sup plt'lIlt'ntal dill•• [mtn L\'. ad lllilli"tmtioll allow ('a l('u lal iclll nf hiu;wail-
ah ility. f . n il" tol ot! Ace fullo\,;nv; extravascular adminis tration is d i\itlt'1l by ti lt' are a
fnlllJ\\ill~ <Il l l.v. holliS. ap pmprialt'ly tllrrt ·<:ti n~ for t1o<;('. 111(' h'l\ is fur tlais cal culat ion.
whk-h ass tlllWS that d n lnlllCf' rrm atnx olllMtm t , is .l\ fullows :

In tr.t\"(·l\ou s (i.\,,) (10<;('

Do~, , ~ . = Clearance ' A UCj ~ , 6

E,l m\·'l\t'u la r (I'.'·.) ill, S('

F. ~ _ . Dose. ~ .. Clearance ' AUC. ~ 7

Fo r ('xa rnpll', app m priatt'iy SlJ ltstit ut i ll~ till' an-a 1II(',l' urt'lIlt'n b ill Tahl(· -1-- 1 illto ECJ . S
intl it-,Ilt's tha t the- bioavaila hility of tilt' LIlI . doso is 97'l . Virt ually all dm ~ illjP<.1I"{1 into
11111Sd t, is abs orbed s~~tt' lIlitM.tIly. III contrast. only -16% is btoavailable w hen drug ts ~'1.'1l
ondlv in so ilitioll,
A'II alll'nlalin ' method of ('stilllatill~ bioavailabthty. w htch ~vt's the- same answer, is to
subs titute tilt' vahu- fo r clearance di l1."(1:ly into Ell. 7, Clearance can lx- es tunan-d fmm
bloo..1 (or pb,sllla ) data foll()\';I1~ euher an i.v. bolus dose or a constant-rate is . infus ion
(C hap . 6 1.
Rl'1ut it t, hitl(lt"fli!"I,il ity is dl'l enllille..l w hen the re art' 110 i.v. (lila. Cost, slahility, solu.
hility limitations. am i polt'lltial hazards art' major n-asons for the leek of an i.v. p rep aration.
Hdati\"l' hi();1' 1tilah ility is det emuued hy ccmp an ng different dosage fon ns . difh-reut routes
of admillistrati oll. o r tliffl'n'llt condutons (e .g.. diet. di ~·a...e state ]. As with th e calcula tfou
of hi();l\"ailahility. d t'am lll'(' is ;\.ssUIIll'd to I)f.' constant.
T hus . I ;lkill ~ the ~1'1U' rall'l'it· :

F" . Dose" = Clearance ' AUC" 9

Amou nl Totolo mounl
absorbed ellmlnoted

Fe ' Dose e s Clecrcoce . AUCe 10

Relotive _ fA • (AUC6XDoseB) 11
bioovoilobility Fe AUCB Dose6

TIll' n ·f('n 'II('l' d nsap;l' fnn n d lO'i('lI is uSllall>' th e om' with the highest hioavai lahil it>·, th ai
is, tilt' on..' h<l\i llp; till' hiV;lll'st un-a-t o-dose reno. In 111l' exampleoonsklc red , th is is the i.m .
dose ; th... n-latlve hio;lmilabilit>· o f till' oral doS(' is the n -16%. If on l)" two oral doses had
I ~ '(' II ('fllllpart... 1. Ihey nmy havebe... ·11 e-qually, ullx-it poorl y, hio;l\'ail ah lc·. It should I)f.' 1I0h'i.!
that all th e p rt'l'l,<l i ll~ n-lanonshtps hold, irres pec t ive of mule of admuust ruhon, rat e of
ah sorpt jon. u r slla p(' of rlu- cu rve. COIISla ll(")' n f clearance is tilt' only req uire ment.
F r acti o n Eli m ina ted . Ba.<;(,<1 CIlI till' n· lati ollsbip hl·tW{"'l·n an -a and amou nt dimill;lh "{!
pn 'S!.·nt c"{l in C ha p . 3, ..\ UC lip In a given tune, for e xample. t n.... , n ·f1t'l1:s th ... amoun t
l'1iminah 'i.l up to that time- ( ~"(' FiR. 4-10). TIlt' area Iw)'oud ' n_ rt' f1 I'l1: S the amounl
n '1l1ainillV; til I ~ · t'1illlinah'i.l. Th e latter an-a n'p rt'M'lIls dmg ill the hlld y if ab s orpno n is
filst compared to r-liminution, because absorption is essentially fin ished . Converse-ly. it ap-
proxtman-s amo unt n 'mailling 10 be uhso rbe d if absorption is rdh'-Iimit i n~.
Otht'r Pllllnllll('Okint'lic Pa ramt'l e n . Gh 1.·11 only extravascular da ta. it is sOllll' tiTnes
diffi('ult to C'stimah' pl mrn ml"lJl.i lll·til- pamnll' tt'r!i. Indeed , 110 phannal'flkillt1ic parameter
l" 1Il J~ ' dl'l e n ninc...1 ("lmfid c'ntly from ohse-'rvatiolls follcJ\\inv; only a stngle oral dose, Con-
sick-r: Art'a can be (1Ik'lIlah'll without kn(J\\; Il ~ hioa\1Iilahil ity. but cleara nce ca nnot. Simi-
larly. alt holl ~h a Ilalf·lift· cau be ;\.s<'ri l )f."'lI to 11)(' c1t'l~dY phase, \\;llIoul kll(J\\;nv; whe-ther
uhsorptiou or d isposition is nue-ltnunng. the vahn- ca nnot J)f.' assfgncd to t'i tllt' r aleorp non
o r ehuunation. \ \'ithou l kIlO\\ ;ng allY of Ihe fon.-goi n~ pa ramete rs. tln- \"0111111(' o f distri-
bution dt'M I" ca nnot I ~ · calculated.
 CHAPTH 4

Fort unat e ly. tl u-n- is a su ffid l"lll hod y o f dat a to determuu- a t Il'lLst till' I'limi na tio ll half-
lift· of most drugs. Failure o f food. dosa~t" form , and. in till' I' \iullplt, in Fi~. 4-7. route of
ad minist ra tio n to arTt'(.1: Iht· lNlIlillil1hillf-lift' indicatethut th is must ht ' tilt' r-lhmnation half-
lift". Also . a d nl~ is "ftt'l\ fully bin,lva il,lh l!' (1" = I ) From i.lII. or sllll(.'uta nt't ills silt'S, Ih·m"{·.
t'!t·a r.lllt"{· can II(.' (:ak11Iah 'tl k lJ(,,\i ll~ an-a (Efl. 3 ). am lt lw vulunn- o f d ist rih ution t";1II lx'
t"sli malt'tl tlIwt,t ht' t·limina tioll Illllf·l ift' is known. Consider. fo r t.xalllp lt-. just tilt' i.lII. dat a
in Tahlt, -I-I. C k -arane-, uhlaillt"{l hy t1i,i din~ dost, ( 501l 1ll ~) hy Aue (7.... 1Il ~- hr/L) . is 1.1
Lznun. Di \ldi ll~ dt'amll<."{' by tht, el im inat io n mit ' cous taut ( U. 69.1I 1 ~,) min ) ~\'t 'S tlu- \111-
1IIIlt' of dhi rih utitlll. in t his t' LSI' :JOll L.
Pn...i ons!y. a r.lIlKt· o f likt'!)"ahso rp tioll llillf-livt's W,LS II\lokt l. TI lt' v,llm's wt' n ' t'Sl imalt'l l
imlin'(.1:I)· fn nn ptLSlllll t'tlllt'(·nt mtio ll·tilllt' data. Dtn -ct I1lt',LSUn 'llIt'lits uf llhso rp liOlI kt-
rwt tcs an' illlpos sihlt, ll(.'l.H dllst' p!,Lsma is l ilt· sitt' (If n u-asun-rueut fo r both ilhst lT))tioli a nd
di spos itio ll. To calculate til(' kim-tics of absorpnon. a nu-thodmust tllt'n 'fn n ' 1M' dt...i st'(! to
Sl'!l;Ir.lh' t hr-se two p n l(.'('sst's. T \\11 n ,lal in ·I>' sim plt, IIlt'tll1Mls for ad lit'\l nK this Sl·llilr.lliflll
an' dtscusscd ill Appl,IItIi.\ I-G

Urine Dot. AIoM

G in'lI o nl)" uri ne data, m-i tln-r ch-umnce nor \Ullllll(' of drstnbunon l '1lI1 1M' calc ulated. If
n-unl c k-anmrx- of t1mK is constant , mi t' u f d m K l'xc n 'titJII is I' ml'urt ion a l 10 its pt L\ llla
concentration, ami IIndt' r Ihl 'st' circum stances . thco n-tunllv. excn-tiou mit' dat a can II(.'
rrea ted in 1I IlIl11111t'r sim ilar III Iha! fOT pl.uuur dat a. In l' r.tl1:'k t " dllnll~ l ilt' firs t t'tl llt'l 1: io ll
o f urme-, usllally I or 2 hr a ftN drug administratinn, ahst lT)ll ioll o f lll,lIIy \\"t'II-a llsm IJt"t1
t1 n lJ.,'S is \irtllillly fiuislll,(1. A shurter t'()IlI'l.1:inn Inn-nul is Ilt't't lt'l] 10 d larat1:e ri v:e- ah st lrp tioll
kiuelit."!i hil l is tmpracnca l bl'l.";I1ISt· uf ill('O lllplt'tt, (' lIl pt~i ll ~ o f tilt' hladd t' r and a ll inahility
o f it sllhjl'l.i: til p mdll('t' a uriru- s ampk- 1111 <It'IIl,mll st l fn 'tlllt 'llt ly. Uriuurv t'wn'!ioll ra te
data an' the-n ofh-n of lillI e USt' ill t'sl ima l illl-: a hStlll'lio n kim· lit'S.
Cumulative uri ne- <lita ( <III hl' Ilst'(l to r-stima te- hiom 1lila hililY. The lIlt'I IIIM I n -qum-s Iha t
the- vulur- o f fr remains constan t. RI'(.11I fm lll C ha p . 3 Ihat fr is lilt, mho of lilt' Intal amount
t'X{·n·!t'(I Ill\('ha ngt'll ('\1',,) to tilt' totul ;alllo uul a IlMITIJt"t!.

1-, ,,. ....10. 11,,· ,\ ["C "p 'n t.."" . II..•

B
tim.· "I" ",:t~lm ·Il,-,· ..f tl ..· I 'i~ ""'1 .." ..., ." .
Ir..li< .." c....... n 'Wi", h . ,I,,· 'nl..! .,\ t·C / C_
" 1"""""" tl..· .."...."' t .·li ",in...h, 1at I ......
n·I••t,,", h' II,,· l<Jlal .." " ..,,,t ult i",.d.·~,
6
,·l""inat,,1("''t' t' il:. ......1 ).
c
.~
;;;
E 4
~
u
c
0

"
2

o
o 3 6 9 12
Hours
CHAJ'T£ ~ 4 os

Fe _ Aex
12
F · Dose

T1lt'II, Ilsing: lilt' SUhSt'ripts :\ and B to d('noll' IWII treatments, il follows thai

F... • Dose... = Ae,,-•.Jfe 13

Fe ' Doses = A• •.elf• 14

Amount Ictcl amount
absorbed elimina ted

t, g (A•..A) . (~) 15
Fs Ae"" s Dose,.,

1111' ",tioof till' dO<;(·-lIonnalir.("I1('u mulatin' mnouut (,:lOl'n '!l"ll um:lmuK("I1is 111t'n·fnn· tilt'
ralio uf tilt' hio<l\'ailahiIHil's. \\1w TI Dose 8 is ~\"t' ll int ravenously, Iht· rat io is rlu- hioavuil-
ahility of , lit· d nl K' 0 ,11(''''; <;(' till' mHo ~W!i tln- n-lative biu;l\1ulahilily . For example, fm m
thl ' ('l1 l1 lllb lin' urinm) r-rcrr-tion (Lata in Tablt· 4-1 . it is ;IPlmn 'nl that til(' t.m. dos(' is
almost l''UlIlp l(·ft'ly hioa\~lilahlt· : til(' mm'Sp0ll(lill~ value for the ora l dU M' is only 4fill ((70
mwl ,52 l ll~ ) X IOU], :\o!it" that . ,t~ l'Xpt't11"l1ifJe is con stant, thi s \ -al i li' is th(' S<Ullt' ,t.. that
l'sti nmlt"ll From pl.l\lIl<l dala.
Urun- dala alom- can 1)(' IMrtit'lIlarly useful for t'sti lll at i n~ hill.availahility wllt'll thl' {rae-
lion t'\ (·n·!t'1,llludl'Ul!!t'l l appm;,dll's I. Undt 'r this condition. changes in n-nal d('amll t"
(aml llt'lI(, ' total d l'a roUll"l') alTt'l1 :\ t·C, hut lIot the- amount (·u ·n '!t"ll. whit·h is a dtrect
m(';l\ Un' of am ount ah..m ht"ll. 111t' majo r proble-u ln-n- is in ('lISllri U ~ l,(lmpldt' urme
colh-cnon until \irtually all tlu- ah..o rlx-d drug h;L~ lx-en excn-tcd.

f'tasma and Urine Dota

T Ill' n 'nal dt·;lr.II1(,(· u f a d m g: r-an 1)(· es tilllit!("(1 when bolh plasma an d urine da ta exist.
TIlt' app" );\l'h is idt 'nti l";lllo thai taken fur an i.v. dose- (C hap , 3 ). Sinn.' no kllowlt"lI~(· nf
hi();,\"ailability is n-qui n-d. til(' ('stimatl' of n 'nal ch-arunce From combhu-d pl.l~lI1a and umn-
dala fol1()\\; ug: t·:l.lm\·;L"l'ular udmitu strunon is us accu rateas that obla illl,(! fnll(}\\; n~ i.v. dmg:
;u Inunivt rollion.

BIOIQUIVAIINCI
1..IWS lIl,mda!! ' th at nt 'W tlnlg: product s ht· Slife and (·IT('l.'lin', If a IlI'W pmt.lul1 of;l t.In1g:
h;l~ lilt' Sl IIl1\ ' Illolar tlo....• and is of sim ilar fonllulat ion to mn- aln-adv sIJO\\1l to 1)(' S<lf(' and
('lTt'l'liH', SHeil laws allow n1;\rkd ill~ of till' new pmtlm1 if it shows hioequb'ulence, i,(·.•
similar ('ffieat)' am i safdy. 111(' majo r ronceru is .\·IL·/tclw bilitlj . tilt' ahi l it~' of a p"li( 'nl 10
(·\t·1l;1Ilg:1· UILI' p mtlu l·t fo r tilt' other. Two p mtlul'lS an- 1,1llSiclt' n'll 10 Ill.' hh)('fillh a l('nt if
till' l, m{"l'ntr" tion-lillll' pmrilt's an' so similar that t1ll'y an ' llnlikt'ly to pmtlul,(' dinim lly
n-h...'au t t1ilT('n 'IlI" s ill l'itll('r tllt'mp('util' or ad w·rst· (·IT(''l.'ls. The common 1I\(',Lsun's used
to ,lSSl'SS dilll'n'n(,'s in ab\U111lion art' AVe , C....... alld t.......
.. C HAPTU 4

In p ml"liet·, C...... um l I ...." a rt" ('slimill("(l [mm till' I li~lu 'sl ('UlIt'\'utm!iull measured and
rlu- linn' uf its occurrence . As till' plasma coucontratiou-time curve is fluitt· flat near the-
pt·ak a ll tl h t"(';lUW uf assay variability. til(> vahn- of t...... dlll'O(' 1I 1ll;1~' nul lx- a ~ull(l "·(In··
v-nta tiou of II\(" act ual value. Furt hermore , thl' iK't.' lr.ll·~" o f tln- t""'. ('s lima!t· is Iilllih.J hy
silln plt·s II(' i ll~ o hla illt"tl o nly at d iM-'n'h- times.
nillt '(llI j val (,Il('t 'I ('still ~ usually urtses when a pa l(' l\! (Ill an Innovator's dnlJ' ex pi re-s. O ther
manuflu-tun-rs lIlay tlu-u wis h to ma rket tln- sam!' formulanou of tilt ' dnl ~. Formulations
thut are hio('(llIi\'a lt'1I1 wuh that of ti lt" innovator a nd ht'ari ll~ till' 1!( 'II t' rit' name o f till' ( I nI~
an' ( -;1111'( 1 ~l'/lI'ric products. Bil)l"(iuiva lt'll t'(, tl"slin~ is also r"..
rfomu-d dllrill~ the t'(IIIN' of
d t"\t'!"pIlIt'1l1 n f new drugs. wh en a foruurlation is d mll~t'1 l. or wln-n tilt· sitt- n r I1 wlllOtl of
tuaunfact un- is a lk n't!.

STUDT PRDllfMS

(Answers to Study Prob lems ore in Appe ndix II .)

I. I dt 'lI ti ~v t'"el. of Iht' stateme nts below tl mt an' corn-et (see- Fi~. 4--.')). For Iht, one. n r
mere, that is lint t'OITt't1, st,,!c' wb y it is no l or su pp ly a llualifit'a!inll,
a . All utllt'r paramdt,rs n ' ma ini llg tllw hallgt't l. li lt' s!IJ\\'l'r tlu- ahsorpl iull p n l(' '''''s , lilt'
h i ~l 1t' r is lilt' peak pl. l.s ma concentration afk r a s i n~lt· oral d n....-.
b. :\ fiN a siug!t' oral close. 1II 1 illt'n 'lLS(' in hin; lvlliiahilily t'tlltst'" the pe ak ti me In sllOrtt'll.
e. Fur a ~\l' 1I dnl~ in a sllbjt"t'I, ..\ UC is p m)'nrt itllla l to tilt' amount of t1 n l~ abso rbed.
d . If kll < < lc , 111t'1I the- terminal slo pt, of tilt' p!;LSIIl'1t'llllt"lltralinll \l 'rsliS tum- t11rVt'
n-th-cts «leorpnou . lil lt cluntnatlon.
2. (:ralTlIl'r d al. (( ; m lTllt' r, c., Juhnsso ll. ( ; ., a nti Sji~n' n , J.: I'ha r m;l('l,kill t'l i("S (If pro-
t"1till;llIlitlt' lut ravr-uonslv am i omllv as conventional a nd slow- n-h-asetable-ts. e lin. Phar-
macol. 11 1t'r. , / ;'":-114-12.3 . 19 • .'» ), in l'\ltlua ling tlifTt' n 'lI1 dosagt' forms n f p n ){'ltinm nid t',
uhla iTlt'11 the fnlt()\\; lIg ,.\ l:C and ('u lIlu lat i\'{' u rine {'u'n..tion {la ta Hste-d in Tahlt' -1- 2 .

T.~"4-2.

cos -o: IWOJ'{I t .«:t HlO

eccn 10-48 "'I to-gl
.- '"
500
("'9"'/1)

13 1 332
0 0'
FOIm,,101>Otl 1 1000 200 586
f Ol m,,10110'l '2 1000 10 0 554

u. E ~ l i llmh' " olh hioi.t\1tilahility a m i rt,lali\"(' hioa ntilability of Iomudatton 2 Irom hnth
ptl\lII<t <llId urim- data. \\11,,1 a rt' tilt' assumptions lIIat!" ill ) u u r t."1tl(11Ia linlls?
h . T Ill' half,l ift, of prtxunuunide- fouml in lh is siudy wa'~ 2.7 1tr, \\"l(.~ till' uri ne- (1IlIt"t1I'11
o\'('r a Inug {'lICmgh tinu- urn-rcul to ubt aiu u ~Otl( l {'stima h' of tilt" t."1l1 l1 ula lin"amount
t' wn·lt'd at in fillilt' ti llll' ?
c. D o(,s n-nal dt'amnt'(' (If p n ll.." ain am itl,· va l')' much ;UIIIlUg III(' tltn.'t' trt'atlllt'nls ?
:1. I )" pil1''t1 in Fi~ . -I-I I a n ' ('unt's of plasrua t'llllt'(' niraliou ami 01111011111 ill f ill" hl " ly \\i t h
li llll' flJlIU\\ill~ till' oml ill~t'sli{) 1\ of a si ll~l t' tlOst· of a d nl~, F irsl d mw fi\"(" pairs o f
1'lln,'S i(lt'l1lil 'al ln 1110S(' ill Fi ~. -I-II . 11 1t' li. tlmw mll ltlll'r ('un·t' (Ill (';l('h p;lir nf tht'S('
e lln,"s tha I show.. till' (·!T('(.1 of t·ad l n f Il.t ' fnll()\\; I1~ ;tlh'ml io llS in phann;tl ' lkind i('
!l,;lf;IIItt"lt"rs. III 1';!l'11 lW>t', tilt' t!uS!' "t!mi nislt'n'tl ;Int! a ll n tllt'r IMmll ll'h ' n; ( a"ll lll~ f",
ktl , \ ', ami C /. ) n ' ma in \l llel.a l\~t"l. l .
 .7

Time Time

a. F dl'('n ',l'>("(l
h. h, Incn-ased
c. CI. mcn-av-d. k Increav - dhy ~1I 1l(' (idor
d . C l. ck-cn-ased. k d t'('T!,it'>t't ! hv same Iactor
r-. v i1wrt'a.'>t'd , k <!l,( 'H' ,l'it 'i! hv ~l1l1t' factor
-I. Kumpf d al. stm li("(1 till' ph ,;rm;,ll1Ikillt'ti<-'S o f reeombinaut human (·1')1h m plli{'l in . a
j,(lyl'()sylatt,<1protein ( ~ I.W . = 34 .000 Wlllold used tn lncreaw n -d blo od {'('II Ionnation.
in pa tit'llh \\1111 ('nd -staj,(l' n -nal d i ~·il'it· after s i ll~lt· i.v. an d subcutaneous (s.c.) ad min -
istration s of -10 Illl il!>/l; j.( nil st'Il;lrah' O('(;:L"io ns . Tahl(· 4--.1 lists lilt' saltent fi lld in~ o f
t ht"w studn-s. Tlu- nu-an wt"ighl uf ti ll:' pa tie uts wa... 60 kg:.

T.It•• 4-3. M_.. AU~ Maxi• • • PI. . . . CeIK _ ••1HI ' ....1...1H.If·I'" ef
Iryth p.I I S el DI _ _ 'onowl I.•• olld •.c. A
a..... I..I .

~S!~"TO-'
_.",
«c "'"""'"
COt<EN1lA10'1
.....",
" "
"""""
CO'-.a NTV.!lON
(> ' '''''''
..,
"",a,

I"'!ravenous 3010 4 17 5 mm b 67
Scbcccrecos 1372 40 ,5 17. 16,1
'--...::I _ ~ 0 f~ ( U • ><'* H C ~ "'" C , t~ 8 . .,... 5ctooooalo . M _ ....... col _~ '--
~"""""""I'QhfI<O>"'"~nglo _ ~~ <><h. . - NoP-. 0 1 )QJ-)Q8 1991
., _ ...... I,." I>oc<j ~wa> "' ''''

a. Dd l'0I 1ine tilt' d l'arann ' am i vclunu- o f distribntjon of this d r ug.

h . Calt-ulaft· tilt' hill;l\'ailOlhility of ('l)1 hropclic'li n aflN s.c. atl minisl mli o ll in tl.t'....· pa-
tk-uts. lI ow lIl i ~hl }UU exphdu }ullr answer?
C', Tln- muxin... rn ( 'o ll l '(' ni m tillll o h.st' r\"t"(! wus uun-h Iuw('r after tlw s.c. do...-. II nw dn
)',," l" plaill lhis " h >;l: 'I"\'alioll?
.5. Clnunn-r uud Holx-rts ( W ~51 stud ic'(l lllt' t'fft '1. 't of del ayt't) (osoplmgt·al trans it O il tlu-
absor pt iou of ;\c'{·!,"nil lllplwlJ. Ead. o f 20 pati ents ;1\\1Li ti ll~ (~.lR.li 'K· I·llt l.dt·ri7..at iou swal-
loWt..t1 a single' tahld ('(m ia illilll?: acetaminopla-n ( 5()(). m~) and bari um sulfan-. T Ilt" fin-t
J I sllhjt'(:b swa l1ow(... J tll(' lahlt,t while I)i ll ~ t1l 1\\11: in III of these subjects. t ra nsit IIf
lilt' ta bid W ,l S d t,la) l,(1. ; l S \i.slIaIi7J'(1 hy lluorosco py. In th e ot he r 9 sllbje<.1: s who swul-
lowt't1 tht' lahlt'! wh ilt' sta lld i n~, it ent er ed the stomach imllll'(liatdy. III both ~rnll p~
tilt' ta bid was ta ken with a snffid t'llt \~ )l tl llw o f wa ter to past" swalltl\\i ll ~. Table 4-1
Ih ts Ih t, a\"t'r.lJ.(t' ph sllla ao-cuutncphen dat a obtatncd ove r 6 lrr a ftl' r s, m lluwi llJ.( tilt"
tahlt'!.
•• CHAPTU 4

T."I.~ .·

o o o
10 2.1 01
20 50 03
30 58 I 1
40 03 19
50 47 28
00 4.1 32
Q() 3.5 39
120 28 31
150 22 29
180 17 18
210 18 17
240 15 15
300 075 07
"-..c_ _ o-- ~ ~ _ ~-.. CJC f-'d~~ _ .,..,..-_""'--""""" n.. ~ n- .l7n_
10. 10 85
"l:>.. "'9Jl .. 0 (I .....

a . \ \ "hat d Tt'(.1: do('~ dd ay('(I l's()pl. a~t·al t ransit havl' 0 11 the slx"{'(1 a nd extent ( If ah-
sorptiou of <lct·ta m illoplwll?
h . \ \ 1M! pn ll,('ss, a hscl'lltioll til" di sposi tion , rate-limits tlu- dt '1.-line ill pb.sma dnl~ ('1 11\ -
l't'nl ralion?
c. Al't·tam illoplwlI is !I st'(l for tilt" n-ltef uf p ain. Do tilt" fimliuj..,rs o f thi s sludy affect
th r- n-comna-ndatton for rlu- li S(> of this d m~?
fl. Bt·sllyah d ul. ( Bt'shya h. S.A., Anyanku . V.• S ilhthya lliUllhiln. n., Sharp , P.• and Joh n.
ston . D .( ;.: 111l" d Tt'(:t o f SlIht'ula lU'()IJS injec t ion sitt' o n ah smp tio ll of hu man ~rn\\1 h
hormone: Abdomen \,(' fSUS t hi~lJ . Clin. Endocnnol.• J .5:40H- H 2, H~Jl ) examined the
l' lTt"(:1 of s.e. illjl"<.1in!l site Oil III(' absOIvtioli of lm mun ~n)\'1 h hormone. T ah le 4-5
lists till' meun seru m rmrcentrutlons ill I I subjects ohserved dunug the first 12 h r a fle r
thr- adnnmstration of ", IU (illte m alio llal u llits ) of bios~l lt ht't i t' hu man ~n)\'1 h hormone.
T Ill' t1 nl~ wa.s inj' 't.1t'(I, 011 Sl,'!l<U'dte IK'<.~d...ton s. into 11 Iifted fnld of skin Oil tilt' an terior
t " i~I I am i a Il)\n 'r lluadr.ml of Ihe alxlonn-n.

,.It'.4-5. M_. h __ e.- _

•• c. 1.lectI_ .. 4 IV I. .... AIHI._ o-wth M_ _ " , 12 .., ,.11.wI..,
1111...

-
1w.E il'-1 0 1 J 4 ~ 6 J 8 Q 10 II 11
"'C!lCNSllf SoIR\.w. CONCf"ITlA l1ONl""""""";

34 92 84 75 74 24 20 12 8
n "9 h
<2
<2 10
55
27 27 37 28 28 "
23
31
20 19 14 12 10

a. Is there informat ion ill l"t'Sl,' data, ~lt'am"(l From graphical llllalysis. 10 SUAAt's l
wln-thr-r ab sorpnon or d ispositio n of gn )\\1h ho m lollt' rute-linuts tilt' terminal de.
d im'? Brit·lI), d iM-·nss.
II. \l allYp n ueiu... Kin 'lI sllIK'uliUlI'llllslynr intramuscula rly a n ' partially d{'g mdt 'tl wi thin
Illt· lylIlp ha lit· syste lll bcfon- ft'ad lillg tilt' S~1i h' lll i<: ctreulu tion. C a lt11la te tilt' n-lanvt'
hioavu i1ilbility of lilt' dmg aftt'r Sot' . inject ion inlo lilt' Illigli (ft,latiw to ahd olllt"n ).
c. T"t' dearmlt't' o f gnJ\\1h honnouc hits been rt1x lr1t'tl in the literatun- 10 a\"{'m~('
about .5 I Jh r. Houghly es tima te tilt' hioil\1ub hility o f tln- dmg fnlll)\\i llg alxlominal
s.c. illjt"(1io ll.
CHAPTH 4 4'
;, I'l ll 'Il~ I t'lhyllll alllll id(' ( I' F. ~ I A ) is Ont' of til(' majo r me-tabolite-s of t ln- anlit'p ilt'plk (In l!!:
prtnudom-. As part o f il p r ogr am to ,lSSl'SS the potential use of PEM:\. as an autk-pileptic
tim!!: ilst'lL its phannacokine-ncs wert ' stud ied foll(l\\i n~ L\'. and oral adnunistrut lon of
:Jon Ill)'!;. Table 4-6 b"l ow lists till' resultan t plasma concentration s in om' suhjt"(1. Also .
" I'l- o f till' i.v. doSt" wa.s recovered i llllri1lt' u n ('h'Ul~t,(1.

eo..c I 0-1 a".I. I.trwtt•• at

III' at HMA
T.It•• 4-4. PI••_
to .. s.ltl~
tI••• f.II_I., 500

TWf(lY] on 0$ 007 1$ 1 4 6 10 16 24 J2 48

F'Iom'la conc enlrahon , ~ 14 7 12 6 11,0 QO 82 7 Q 66 6 2 46 32 23 1 2

(mg/ll o c! 24 3.8 4 2 4 6 8 1 5 8 5. 1 4 I 3 0 2 3 1,3
·~""""P'><I".,f O"d ~<""" ... ~.......,.<J~tp[ lMIa1w<:o'Qlatd-.our.cn-_ C"" Pto-
"""'010 .... 8 272,276 IQ83

a , From a sl'lIIilogarillullk plol of 111l' p lasma concentrations. estimate till' ehmtnanon

hal f-lift· of I' E~ l:\ in lilt· subje-ct .
II. Cal{'nlah' tilt' total Av e f()lIo\\ill ~ i.v. and oral administration,
c. F ro m tlu- i.v. datu, ('st imalt' Ilu- dt'amm'(' and VO ! U Il l(' o f di slrihutioll of P E ~ I A ,
d . Cak'ulah ' till' ora l hit);l\"ailahility o f lIlt' dm)?;.
e. Cak-ulatt' tlu- n-ual dt'ar.lIll,(' .
,"i. Umdam l ("/ til. (Howbud . ~ I .. Epstein. \ \ '.. and R i {'~t'lman , S.: Ahsorption kinetics o f
).!;rist'o ful\i n in man . J. Phu rm. Sci...57:WH-9S9. 1968 ) ga\'t· grtscofulvtu om lly, 0.5 g: o f
a mk'rtllliz("l.1 d mg: fo rmulation and . on anotln-r occ asion intr.t\'('nously. ]lX) 1Il~, III
volunte-ers. T I](' ph..ma concentra tkm-tlnu- data ohtaim-d in mn - sllhjt"(1 art' W\'('l1 in
T able -t-; lx-low,

T.ltl.4-7.
eon rm 11'01 0 , , , ,
OQ8 000 0 80
r • "
,.
0 . 8 035 OJ'
" 0"" " ..
""'""
G<,~""~
Conce<l"'O'"""
0
" " 0 "

o 0 4 OQS 000 I OS 090 0 85 080 050

Img/tt 00'
'" '" 'OJ
" "
Frmn appmpriatt' plots and cak'ulations, what can lit, {,mdlltlt"l.l [n un tl ll' St,' data with
n 'slx'{1 10 :
a, Halt· tlf ahslIIvl ioll of griSt"llfuhin with tiuu- 011 orul administrutiou ill this ind hidllal?
II, ( ;olllplt,!t·!lt,SS of ahStlrptio n?
9 . l\usl l'llhalldt 'r r-t al. ( 19• .'5) measured plasma phcnytom coucentruttous ufh-r tilt, ad -
lIl illi ~t ration of St lllium pl J('I\~1 n in inl r.UlluSt.·lIlarly (5(XI 111~) and inlmn 'llollsly (2.'50 lll ~) .
Tln- :1\'(·r.I)?;t' data obtahu-d ill 12 Sllhjl'<.1S. each o f \,1IOm rt"('('i\'('{llxJth trcat nn-uts. art'
lislt'(l ill Tahl" -t...s'

,.ltl.4-a.-
1MI"1
"'"" 0
o
, • e •
3.
" " ,
n .. . ce
08
""
oa
,. s"a " " " "" 0"88 oa
Pb"""~",,,~ 1~IrO"'lI1(:uIo- JO 3J 38
Conce<>MO'oOf'l
Img/lf
" ......
I~M~ JQ

""'W«to<l,""", ,~ He ~ H ."Io:G:o.<"',JP F~.l~.Pooo- ... DG 1liod"-,l"' M >u,.. we . O"d . ..... ~w

oo.'.,O"d~~oIo"""",.<J~~ n... 0.. F'Ion-o<cI IB u~'>O. 1075
'0--0"'\l/l e ~ 0 ...' "
 a. Estimale tl.t' hiflil\"aila bilil)"o f plll'll )'to in From till' i.lII. site h;l<;t'(1u n an-a compart -
~T1 S .

h . From an apprupriah' plot of till' data, couuueut 0 11 lilt' pml''S.~ Iilll itin ~ Ilu- dechue
of Iht' p l ;l~lIIa pllt'II~1oill l'()lIl'('lItmt ion fol lo\\i ll~ i.m, udnuuisfr ation.
c. T Ilt' authors analyt.l.'ll tilt' p lasma conccntranon-tunc dat a and found that. folJ( "'i ll~
LIIl . administratkur, 2.1% of till' do St, was ahsur l....'(1wi thin tln- first hour . und rln-n -.
after absor ption wa.~ much slmn-r. Tln- curuulatm- absorpnou dat a an' shown in
T ahle -1-9 . Arte r th e rapid ahsorptioll in tilt' first hour , is Iht' j,lIIN't IIlt'nl absorption
1....-tter charact e rized by a zcro-onk-r or a first-order pn K:t'ss?

,.ltle 4-9.

P.,..cenl <:J bioa.o,loble dfug c bscebed

"
h-oml.m, ~,'" 23 40 80 Q()
 Section II

THERAPEUTIC REG I MENS

 I'
L
5

THERAPEUTIC RESPONSE AND TOX ICITY

OBJl(TIVIS
The reode WIll be able k) :
1. Explain why elfecr [desired Of roxie) 01 a drug is often bettef cceeoed with plo~ con-
cenh'allOf'l thon with dose.
2. Define the terms: graded response, all-or-none response, rhetopeulK: ccoceoncnce range,
Ulilily CUM!, and tolerance .

3. list !he 10 nge of plasma cceceoscucos ossocc'ed with lheroJ:')' fa cny ollhe drugs given
in Tobie 5-2
4 Deccss bliefly situations in which poor plasma drug ccoceoececo-resccese relatioru.h,ps
ore likely to occur
5. hplain bfiefly why modality of odmini.wo rion of a given doily dose con affect therapeutIC
outcome.

TI l(> rational d(osign of SOI[ I' a nd (·flkliLiolis d O'i<tg l ' nW"It'IIS is 1I0W examtned. In this section ,
fuudauu-ntal aSI)('(.1S o f dusll~l' rt.1.ri llll' 1IS art' nln'n,1 pri marily from the {Xlint of view of
tR 'nti ng a path-nt population \\; tl. II gi\"(' 1\ d l'\(',I-'\(', It is realrzed. IIf (',( J11I'M.' . that iml i\; tlu als
\'a l)' in thei r n-spm lst·s 10 drugs . ami subst'( )III·ntly. ill St'(1 ioll Four. flx'us is turned tow ard
th e l'st ahlish lllt"nt o f dOS;.Igl" n"¢llwns in illtlisiduall),;'tit'n ls ,
A t1w mpt 'lIlil' dnsagl' n -wnwn is I)';ls imlly de riw d Irorn tilt" kind s of information shown
in Tahk- .'>- 1. One co nsiderano n includes t!lCIS(' fadon; thai fd att' to both dlil'at" , and
s...'lft't)' of the dmg. that is. its phannal'Utlplamks and tU\k(llo~~)', Anotlll't l'u llsit!e t'a tion is
1111\\' th e hody act s Ull the drug and its dOs,;I~t' fo nu . Ihe essence of pharmacckmcncs . A
thinl n )lJsit!emt inn is that o f tilt' clin ical state o f th e !),;t1 it'lll and his or her tnl al tllt' mpt'u tit'
rt~ lllt'n . A fourth eatt~of)' includes all otlu-r Factors sllt'h us gt'lwtk differences . tolerance .
and d nlg tutcn«..1:itllls. All of tilt'S(' dt'll' n ninanh an' , uf course. lnn-rrelan-d alltl in terde-
pt-'nl!t·lI1.
1l<:1.... lgl· n~ lIlt'llS an ' ( !t'S i ~ l t-d to produe- a therapeutic object ive . TIlls objt'cti\'{' 1I 1i1)'
lit., ad li('\'t"t! by S1lriOUS modaltnes of d mv;admi ni stmti o n, t'xtl' mling fro m a sinWt' occa-..iullal
dose 10 co ntinuous and constant inp ut. An exampl e o f tilt' for mer is the list" o f a...p irin 10
In'al uu 11l'(.-a.siu llal lwmLld ll'; til(' conunuous is , infus ion of le-pann to maintain a tIl'siR't1
dt ogn't' o f a nt i t't "'I~ ll at ion is all ('x3mp lt, o f tilt' latter . ~I o n' commonly, dru gs an' admtn-
isleR'll rt'IIt.'ah'tll)' ill dlscn-te doses . Tlw fR't"II'III'y am i duration Sll ry with the- l'tllld ilio n
Ilt.'ing treated. Sonw d n 'hry;. 1II't'. admintste-n-d R']ati\,t.'Iy infR'tl'lt'utl)" prtX lll<.in~ larv;t.' IIlIl'-
Illations ill Ihl' plasma conccntranon. !tt ' il'it.lIlS fur thi s approach incl ude tilt' dt,\"(.']uPIIlt.·"1
of tolerance to th t.' d ntJ!: an ti llit' 1U't't1 to produce hi~h concentratio ns fO f sho rt pe-riods of
nme. ,1-\ OI"(' U fS in some lllllillint ic am i anticance r cln-ruotberapu-s. In ot her situations, mai n-
54 THERAPWTIC RE5PONSE AND TOX!C1fV

tenance of a "-·b lively constaut concent rution of dmg is 1ll"('1lt"(1. In all cases , attempts an'
111,1(1., to minimize uudesirable and toxic effect s am i pn-veut ine fTt"t:tin " therapy.
Evuh-nce- t'xisls tim! n 'sptllls(' is often la-tter co m-lau-dwith plasma concentranou than
\\; 111 d uS(' 'I(Jm iuis ll'rt'tl. A(:(:(J nlill ~ly. it would S('{' 1Il to he must appmpriah' III apr l>' phar -
macokim-ti c principles to the desi).,lJI of dosa gt· regtmeus. 11111s. ~i\'t' n ph annat1lkirwt ic da ta
f(JlI O\\in~ a si ll~l t' d"o;(', tlu- plusma conceutrunon O f amount of drug i ll tilt' hod): fllll()\\ill~
any dmill ~ sd ll' lI11' can IH.' estimated. Ultillllltdy. however. lilt" value of a d()~g(' rt '~IIl('n
ruu st 1)(· ,l-ss('s"'t't:) hy tln- therapeutic and to xic n 'slxlIN'S p"-)(III('('(I. Plumnucokiue-tlcs fa-
dlila h-s til t' achievemeut of an appropriate dos,:l~t, rt" lIlt'll and _'it'I"\'('S as a useful !lIt'1II1S
of (,vllluat i ll ~ t'xbti ll~ t!USilJ.:C n.-WIllI'IiS.
III Illis ehapn-r. \1uiOIlS r-k-ment s of tilt' l"tlll<."t'lIlrution- rt'spOll'it' rt·laliullShip an- ('X-
plcn-d. Prilld pll's fur att ai ning and lIlilinl ainin~ a therapeutic It,\"(,1of dmg in tilt' bodv un-
d ist.'usst't l ill lilt" subsequent h-\u chapters of Ihis seceton.

RESPONSE AND CONCENTRATION

Ih 'sp..lIlM' Illay ht, as n lWlt' ax a g"'lwml fl't'hug of Imp r ove-uu-nt or 'L~ p rt"'t.'iM' 'L~ a l"I\\"t' ring
of tln- di ,Lsto lie h luod p ress urt' hy 30 IIUIl I lg.
lnfo n uunon rdalin~ conceutrunou 10 rt'Slltlll'it' is oht ,ullt"'t l at Ihn-e h-vels: 1'1 r;ll m ex-
perinwnts, nntmal st ndu-s . and ill\"t's tig:atiolls in hiuuun volun teers and pal it'nls. TIl(' last
\('\-...1 is II.... !lIml releva nt to human dmg: Ilw mp>- but. unfortunatr-lv. onl>' Iimilt "f.1 lnfor.
mali! III is 01'11'11 uh la inah lt, !lt' n ' a"ulil Ih.., nature of the dmJ.:- rt·(-'l 'ptor tntemcncn. /II l:itm
cxp -rtnu-n ts. wh id l indmk' studn-s o f the act ion of dmgs Oil ('Il7.pll(·S, receptors. mien..
nrgallisllls. ami isolat r-d tiseues ami organs, st' l"\"(' this purpose Ix-st . lI oWt'\"(" , in iM,I.ding
tht' va riah ]"s , lIlany of lilt" comple-x Inte-rn-lationships that ('xisl in 1:1..,., are t1t'st n ~l 'tl. An-
imal Silltli('s hritlJ.:(' much of tjn- J.:ap h..'I\\'("'t'1I in t:it m t'\pt'rillwlltation and hu man tnves -
tiJ.:alioll. Studies ill animals introduce bot h lilt' variahh- ti me, with all that it connotes. and

Thercpecnc WIndow Ab>o<""",

Di~lIlburlQ/'l
Sod. ""'"
To,,,,Jy MeIoOOIism
Coeceeeceoo-se scoese ,elohon!>h t~ EJ«:rehon

Dosage
Regimen

Sl A't QI PArtNl O IH( ~ l...clorS

Age. weoghl Nv"h,pIe d"J9 lhe<opy Rou1te 01 odm iniSIIOf.on

Cood "l()ll be,,'9 lleoted ~~e 01 reg'men Dosage fo.-m
h,~tenee 01 orner d.seose $JOIe~ Compliance 01 potoenl Toe-crce-deperoeoce
I't>ormocogeneliu-odl<)$Y"C'osy
[)-ug Inlefoct>on~
COO'
OWTH 5 55

till' elements of abscrpuou a mi tlispos ition ;1..s \\'1·11 ;L<; till' fl"t'1.II"lt·k t.'olltm l li)'litt'IIIS tllilt
operate- tn mai ntain homeo stasis. Animal st udi es a n ' nfh 'n most IISt'fu l for l."\1J uatin~ tilt"
p lmnll"nlln¢ c lipt '1.1nllll o f adhi ty of u pOb'nti,,1 tlu -rapcutie a~l'lIt a nd for dt'tl'rlll ini ll~
;L\I'It'1.1S of its to '\;il'il)" pmfill'. IrT(·spt 't1i\1.· of tilt' It,\·d of information, I.tJ\\·I.-,\1.'r, th e conclu-
ston is the sante: A rt-latkmship, allholl ~h sometimes complex. e xists 1I<-'f',\1.'<"11 the t'UlI(.'t'II-
trutiou of ;It1h1.' a~l'llt ut tilt, sitt' of III(',l<;un'lll t'nl and tilt" n 'S!'ltlllSt',
TIlt" 1ll'ljOril)' o f d n lgs list'll c1inlt,;J I)' ad n '\T rsihly ill t ha t tilt' e lTe(1 ts u '\"t'TSt'l 1 UpO Il
n'lludll~ conceut rattou ill tilt' silt· o f m.1iu n. ~1;1II)' n'S!)flllSl'S produced arc j!,mdr d , S( ) called
ht '1.'illls(' the Illagn itud t, of tilt' n 'spelJl''l' ran 1'It· <;(';llt1: 1Of gradt"ll. An examph- of a ).,rnlllt'( l
n.'s po llo;e, St.fM11 ill Fi~. 5- 1. is tln- illlpnJ\'('lIlt'nl of pulmonary fun l1itJII produced hy tlu-
hnmdll'lllibiur IN h ufalilw . aftt'r its s.c . admi nislratioll . TIl(' inll' n\ily of t he n '!ipo llse varies
with tilt' tl m ~ cmu-ent rution ill pbsma. Ma TI)" otllt' f phannacolog tc and to xic rcs peJlls('s tin
1I0t occur O il a cont in uous I"l'iis; theS(' au' knowu us ({u(w lnl Of nll..o r- ,ulIIt' fCSPOII"iCS. A ll
O" \;OIlS bill extre me l·x.a mp lt, i ~ death. :\lIol lw r h till' supp u 'ssio ll of all arrh)1 111I1ia. TIlt'
arrt.)1111Iliil either ts or is nnt sUp p u 's"l'(I. SOllwtilllt"S, a limil ts St·t nil a gm dl'1l rt' SpOIiSl'
ht'l o w which an t·lTl'(1 is said not 10 OlXIII" dini mlly. For exam ple. a poh'nliaIl)' toxic (·llt'1.1
of alltihHlt·rknsi\ 't.. therapy is an t',l('t'ssin' It J\\'t' rin ~ n f hltlllli pTt'S.'iIlTt·. 111t' I (M·t'ri n ~ of
h ltll'lll pn·sSllrt· pnxlul,('l l h) ' th l' antih)] 'It,rtt'lIsh"t' a~t' ll t s is it ~radt '(l response, hili h)]x .-
te nsfve Imidt)" is said to Ott 11f u nl)' if l ilt' hh'lll pU'ssu rt' falls In IIlll ItM' a \1J IIl'. Hen- the
chmcal I'ntllx)int is all-or-uone, bill ti lt' phafm 'tl'tllo¢l' n 'sl)fIllS(' is ~Tildt'll.
Ht't llnl illg 10 tt·rlmtali nt'. F ig. ;>-) is a plot o f tlu- fof( 't."ll expi r atory volume in I Sl't.,(lIltl.
a me-asure o f pIlIIllOIl;II.,: function. a~itj llsl pia.s ma concent rutiou. 111(' plot is dmmt'!t'ristk
of most graded ft'Jij'ltlllSl' curv e-s. A ucu rly lillt'''f n ·l;ttionsh ip 1'It'I\\,('1'1I t ht~ intt' lI:'iity of rr-.
SpOilS(' ami tilt' concentration al ItJ\~' coucent r attons and " It'ml t'ltl')' to n';~ h a lu .L\inml
n'sl'ltllls(' ;t! high concent rations 'In" a ppan'IlL
Unlike a gr aded n·spoIlSl~ . the- co m-lattonlx-tween a flualltill n 'sl'ltlllSt' and enncentru tion
is t·.\p lo n'll h)' I'xam i nill ~ t he fn'q'lI'P1oJ of tlu- event with conceut r anon. 111i:'i is iIlust Tilh "ll
in F ig. 5-2 "y II p lot of fn"(llU'"l'''' of ti lt' supp n-ssion of ventricular errhyt hmias us II Function
o f the plasma comvntrauon o f till' untiarrhyt hmie il~t'll l pn:lt'~ti n;u ll i d(·, III IIltr.;1 palit'lI1s

3.5 . '1 11:. 5-1. n il'" n..-_ f"'.....1 •.~pi .

•
• • 011"1)' .... >1""... in I .....'('n.1 (H':l' l)
j n (· r,·a~ .. t wnh Ih .. on.. an pla u"a
~
E 3.25 • • • lUl l<..·nlr 11 1, ..;1 tin l<.. in
10 p.tl it-"b I(i'~n O, ~ "'II: of ft·rhu.
=_ l..Ji,..· "ull<~,"'.r"" " I'Iy. n ..· i"'I"''''''
0
>:. • nwnl in pulm" nary {uIIl·ti un In-
". ~
_o c0 (." ....... ,,; 110 pl. ,m a ('t.nt"· ulraU,,..
.~ :rl 3 h"l "l't........ I" "'1'1 _ ... a 1i",;Ii..Jo(
' ·aluI". l ll ...l nown r on ( ),,,I.. rt,,,i• .
'"-''
.:l • B.• 6 ......1. I' .. K< C .M,J., ", ..I V....
~c
~ .- 6"''''1. C.).: t1 rm ...""indi<'-p" "r.

"
of 2.75 m....... lynami<· " It4i"1t or 1.-""'1".
ln..· h.." ..d .... lilal i.. . . llo ma. elm.
PI,.. rm . c,,1. Tl w r .• -IfJ A6 !1- 4';'S .
• 1\1116.)

2.5
0 2 4 6 B 10 12
Plasma Terbutaline
Concentration (JJ.QIl)
56 THE PA!'E UTIC PE5I'()NSf AND TOKIC ITY

100 37
" l.it. ~2 . n ..· (1"K~'n l r;i1i"l\ " f pnJl·;uII,,"'il lt· ' 101 79 r-
' ld n mj'.....1 in "",r :11 0 1 "I..... n......1111'1... ulo'ail 1
807 ~
fn " n zYl ["'Ii/- nh n '(,...i' ; Il l( rhi' ,In'lt fu r lh. - ! " ,,,I ·
llIo''' 1 ,J ...m li...· ..rrt,~dlrn i.L. , n ..· rn"I' ,, · rK~·. t'l-
80 r
1'"- 1"' " p,-n , ·nl .. f 110" n 'llnl ~'r flf 1'L..",,;o \.;1m· 1 ~6
I,lt~ ilh ",,-I' il-l, .. ...·n" " n ·"I ....' ..'" (' >m ,L.I. ..
....it l, .·IT....i i\<· ' '',·rolJ.~'. illl...• "'illo (';><-h inl'-"',;I,t
"f iTIlTl·..' illl{,,,,,,,,,,·utr.lli,," n ..· 'Oil",· ..I..".. '-;0(·1,
60
I , ,, ·(.-n t" ,h., "",,,1,, ,( " f "''''1'1.... "ith;" ,10, ' n',
' 1 1" ... ,uI.. ...'1I1 lIu " r.II1l:<' {I "'II: (1",,,,111 . - 4,3
11 M ). (Frn", " ,.\\.,.... 1'. J.: '" r1...n".... .I.'l:,' ..,..I 40
tI..· Furun ': Pr..I.k-m. in n ,,·r... ~-. Edih..1 by <:T.
Ol d.. ;1,..1(;,11 . ..\"............ ":"JJ't·r. &.....1. IY7.1 \", ~ _
.1· 1'11_ ~U
20
~

o In
<2 4~ 11-10 12-16
2-4 6-8 10-12 > 16
Plasma Prccainamide Concentration
(mgIL)

rlu- a rrll) 11 I1n iR~ art ' .~ Il pp rt's<;( 't l at {'OIl{'t'lltrtlliflll\ of 2 III '" mJiL. Il uwt'\'('r, tllis ht'lies tilt'
entin- pk-tu n -.

THERAPEUTIC PLASMA CONCENTRATION RANGE

Fi~lIn' .')....,'] shuws tilt, pt 'n.'t'nt u f IhclS('()<ltit'IlIS who did nol respond to pm ca inalll idt" 1110<;('
who responded. t!lllS(' who cxlubin-dminor sidt , t'fTt't.1S, aml lllllS(' whu t'\hihilt'tl S('riollS
toxici tv. Sidt, (·fTe<1 s wen- {1Jllsidl'rt'tlll1inor wlu-n ('('ss<llioll o f lilt' d m~ WR~ 1I 1Illt'1."t'SS<II)·
aml serious wln-u disturl xmces of cardiovascnlur [unction o r othe r al!\,('rst' (·fT('1.1s nr-ces-
silalt't l d ist.·onlinualion of II\(' lim" . It sllould he uolt-I! ill part icular Ihat S('riUIiS Imidt)"
h(1Qlls to a pl"t"ar ah(I\"(·.s m!-i L and occu rs \\i lll i n{'n'ilsi ll~ fn'llnt 'llcy al h i ~l lt' r e uuvutrn-
lions . AI)( l\"(' l f 1Il!-i 1.. the toxlc t·lTt't.1s lIlay pm\'(' fatal. Fmm lill'S(' d ata. it can 1)(, con-
eluded Ihal the m ll)!;e o f p la.sm a concentr ations of pnJ{-d.inalllide ilssl J{; alt'tl with ('lTt't.1i\"('
Ihemp)' and \\; tho lll llnd llt' Imidt)· is -l to ,Ii mg/ L. This r.lll ~(' is (1)llllllo llly known as the
tllf'rfll H1' tiC n mcn d ro tloll m 'll!.r of tln- dm ~.
Cl t'a rly, no l all patients n't1'i\i ll ~ pnJ{'ilill'llllidt, for tilt' treatment of ven tri cular errhyt h-
nuas 1It't't1 ptlSIII;1 coueentranous 1)('1:'\\"('('1\ -l ami ,Ii lllJiI.. In a few , tilt' arr hythmills ar e
supp ressed al concem ratlons 1)(,IIl\\' -I, mw'L; ill otln-rs. toxid ty 1J{'('Urs I)(·fofl.' t,m (, ll" , alld
fur 11\('111 pnx'aiuanude is ('('rtailily lint lilt' drugof d llli{"l'. Thus. II therapeutie eoncent r atiou
is most appr opriatelydefined in terms of an imlhi du al l)<ltit'nt's n-quin-nu-ut . U Sllall~', Illis
in formation is unknown. and Oil i ll i liali n~ tln-rapy, tilt' tht'mpt'lltit· coucvu tr ation must I""
r-stunan-d Imm co nskk-rutlon o f tilt' prtlhahility o f tbcrapeutic S\l{'('( ' SS wi thin tln- Iyp i{'lll
patient pop ulat io n.
Also shown ill ri ~ . .')....,'] is a curvethat rt'pn'St'lIls th l' frt'tIIIt'II{'y o f tllt' mpt'ul i<' l' fTt't.1 in '.
nes s. i.e .. tilt' ffl.'IIIll'Ill, -of t'fTl'(,tin ' tlt('rapy min us tltl" fn 'llu {'lll')" of all toxic t,lT('(1s. This
lIlay IJ{' a n illilpp rtlp riatt' meuus o f ('s li ll1 ali n~ tilt' concentmnou at which therapeutic sue-
l"t'SS is 1II0si probable. Pe-r haps tilt' minor toxi{' t,fTt't.1 s shoukl not 1)(' wd~il tt't l {'llually
ag:lulISl lh l' dt'Sifl.'t1 n 'S!XlllSt.' . Oh\iollsly, tilt' major toxtc t'fTt't.1s should ht, ~Wll 1II0 fl.'
wt'ig:hl. TIlt'S(' art' ('o nsidt' ralious rt'l luirin)!; j tltl~U lt' lI l .
CHAPTU 5 57

Therapeutk Window
Let us expand philllsllphil'i.lly 0 11 thts l'()n('t'pt of \\l-'i~htin~ dt"1.'!opt'1l for p r ocainamide
u sin~ lilt' iuforr uat um in F i~. 5-.'3. "d di ll~ Itn 'Jl.'rsc.'J\sithi t)' and a.ssign ing values 10 tilt' re-
SPOHst'S al'(.1mli ng 10 OIlT 1'Jl.'st judglllt'lll . Figurt' 5--1 sho,"\" lilt' prnhabilili('s of til(' re-
SI'Jl.J!lSt's. p lus that of I I~l)( ' rwll s i l hi ly, each wt'i~h ted b)· a j U<lgnw lllal factor WfSUS lilt'
logarithm of Illl' plasma conceut ranou. TIlt' facto r is nttatiw for untlt'simhlt' dTt '1."ts am i
positin ' for desir,,"lt, t'fft'1.·ts. 011 ;.lgt' hm il~d.l1y addi llg tilt' weighh'1l pmll<th ilitit,s. a utility
n,,1."~' is ohtahn-d that simp l)' SII(J\\'S tln- chance of t1wrolpt.'utic 5\1(:(1'S5 u.s a fun ct ion o f tl.t'
pla.sma c uux-ntr attcu. Bo th low alltl h igh conccntrunons have a lII~alivt' utilil)'; l.e. at
IIlt'sl' roucentr attous . tilt' d mg is 1)(lft'lIlially mort" har mful than ln-lpfol. There is an opt imal
umt1'IlIraiion (S mW). ) at which t!wral'Jl.'lIlk success is most ltkely. and then- is a rangt' of
ccncvnu utlons (abo ut .. 10 10 mwLl within which till' chances of successful the rapy an'
high , Thi s is lilt' tJlI'mp('lI t ic Id ud ott' or tlwm peut ic a mCl'lI ' ra t ion mn{!.e. Prec iselimits. of
l1JUN', an- not dd inahll', particularly umsidt' rillg tilt' Sllhjl'1."ti\1.' nature of till' utility CIII'\'e .
Each dmg pr oduce s Its 0\\11 pecu liar reslxmst.'s, and tilt' wt'i~ l ti ng a\s i~llt.<J to these re-
SPO l1S~'S t1ifTN, hul !lot h tilt' ill(.'idl'lIl1:' of till' d lllg l"lT,"(."ts and tht, rdalhl.-' importance of
each dTt'l"! mu st he evaluated to determine till' t!l{'m pl'u lic conce ntration r,Ul~e .
Then- an' probh-ms assodated with tlte acquisition o f tilt! incidence o f til(' va rious fl'-
SP O IlS(·S . For exam ple tlu- procatnanude data WNe obl aint'11 in p atients \\110 we-re some
t fuws titrated wil h till' dlll,g. That is. Ille dosage was adjus ted wlu-n till' patit'nt llad nut
adt 'tillatl'ly n 'spo ntlt'(! or when Inxid ty was present. 111,,'1." 1..' 1', pat ient s even Oil till' usual

20

o
o 4 B 10
Plasma ProcainamideConcentration (mgll)
H K. .5-.1. Sd"'n~ttil' n ·l'n ....·nl ~ti.. n uf Ihl' fn "l" l"K.)· of 1rM,ITI'dr. 'l"IIM·IllJl:'·. ..IT.'l'lr.,· Ih" r"P:", m in... , itlt· ,·IT...1...
" 'n'M" I,,\I.,I~· . • ",1 - IIM'ro' !,,''' Ii<' ~·IT''l1r.1·11n.' · i t" rl....
lIl<l (. IIK.'l'"lnllic", of I'nK.'>lill.lIui<lt· in I>;o.l it-nt. n'l1-Mu l/:
lI.i, .! m~ ror or..
II..• In 'al l1" '1I1 rrl l~dll"i ",-•. n ,,·r ,lk toIT''l1i....''•.,.. iJ .1,Alr.....I ..rl lil r..,; I~, .... " M' .!iIT,·n..,,:.. In lh.,
(n "I"'·' K) · I.' ·""1'Il .. ff''l'l I", tl" 'rdl':" "'K!I.."Ic~,ff,'l'l'; II... t ht' r.pt.' ufK't·fft'l1r. ...1WU(C'o l" f('lJ lillt' ) .. f pm.:>lin..mid. ,
...·;1(·1..... ~ l,,·,,~ .. t 'I mWI. (I "' ~ . - -I,311- \ I J. (/" I.' I'« 'l1 fn >ll l ll.., ,I." .. of K,K.1,·W....·r . J.: I.. 111<l"',.'l * ~· ,,,KI
tilt' FIIIII" " l' n ol ,I" m_ ill n ..'r"py . F'.<lih111,:"' C.T ()~il a ;UK! c. n. An.-IK"'Ifl. KI I)I:.. I. IM.d. 1\173. \',01. 3. PI'
~') . )
 " CHAl'TEIl 5

t1l'\a~t · ~ 1 1l'w " witl,' r.t ll~(· u f l'C Ill("·lI t ral i(lIl.~. I('ad i ll~ rme- 10 ques nou if sdt'l1it lll uf Il<tlit'uts
S "U"ill~ tll\ id ly lIIi ~ht han' (Jl:'l,IITt"tI. To avotd this h i;l'\_ l'a<:h of tilt' patit'lItJi sl,ollid Ilt'
l il r.l It "t l ll m lll ~1. all tilt" n ·spt"N,'Ji. n tis is, o f ("(IIIN', t·t lJ kall~· un acceptabb- Our infunna-
linn 0 11 Itl\idt} mus t come fnnn th e- patit-nl wh o . for OIl(" rt'a\llll u r al1othN .. ('xh ihih lo\icit)-·
hll'l"dU"t· Ih t· (InlR ('IJll'("l' n l rd tlo fl is (,\I't'SSI\'t' or \\110 !la' an u n usual " "!ipon....• a l a 11M'
t'l IIl('l 'lit m h! In .

Desired Effect
+1

n Ullioty Curve

Serious Minor Toxicity

Toxicity

- 1
0.1 03 1.0 3 10 30 100
Plasma Drug Concentration (mgll)
. '111:- 5-f. 5.-1.......1 da.althm of Ihr ,",lp;hlnl pmb.bilib... of rnpon '" Wnul dw.o paa..... ~ n1 rabon o f •
•I~ n...prnhooh il,t1 from Fill: 5-J (plut . h)T'Ol:ktnl h)l'"V 'lIIttvity ... amnn) . ... ~t...J by ,.... loll<-.
in lt L..1" "" ',...I ..ffrct. L hYl""""'ft.Qlivity. -5, minor lulU<'1ty. - t ...nou. tnUdty, - 5 . ~ a1K"bnoioc . um of
I.... --1,;"1 1 pmb.. hiht..,. ,. lhe utility CU~ (cdo~ line). ""CONIn'; 10 Ihi. K hellMl. I.... hl.v-.I ...."l'II(hIed.
I'n >h.chthty o r Ihrn[""ul k: , uaT" Ott"\In al II mw'L and c.'O T"KTnirationl ....l.- 2 mWL and .lxM. 12 mWL .....
pnlt'nl l:.llly mo rt'" harmful du " bt'nt'flcial

r Or til<' lll;ljOrit~' u f 1l;llit'llh , klluwl ("dgt· uf ;l dm ~' s IIlt' mpt 'ul il- p l'L\m" l'Ulll,'n fratiu n
filll ~1' aml p!J'lfl llat1, killt'ti('S ..hould h-ad to a ilion' rapid ('sIOlhlisllll lt'llt of a saft' and t'lli.
(',WiOll' c1", a),(t· rt·W"WIl. Il nwI"'''''r, ti lt' na rrrever Ihis r;IIII-:I', IIII' mon- difficult is li lt" m.uu-
n-namr- uf \"allU', wuhm it. 111(' p la.\ITl<l l"I1<.,'nl mtillll r.m),(I's ;L,..o d atl'tl wtt h s\ll'u. 's, flll
IllI'rapy o f ' I'll'('ifit, t'()lltl ilio lls a re ..111,.,, 11 ill T ahlp 5-2 for a 1lI11l111t'r of rt'pn'''<'lll ali\"t, d m ~s .
St·\"t'r;11 pni nt.. an' wort h 1l{)li ll~ alMlut li lt, dala in T ahlt, 5-2. Fil"'<il , fur lIlust o r tilt,,\(,
t1n1J.:" Ihl' Ihl'mllt'u lil- l'll!('t'lllmlioJl TitJl~1' is narmw; the lIppl'r aml llJ',\'('r lim its d ifTt'r by
a ': II'lor o f 1J1l 1~' 2 or :1. ()( eourse-. fllr many ot la-r d nl,L,~ , IIlis ('()Jl(" lll m lioll r.1ll~t· is 1Il1l(,I,
wkh-r. St1.'( '1lI1. "tllllt' dmg.. an' 1I" ..l lu In 'al " "'·t'ml t1i\t'a.'it's . and tilt" IIw"'c1pt'nl il- p la.s lII"
(1l11t1'lll mtiull ra,, ~1' lJl ;I~' d iffl"f " i tl , ti lt' d ise a,\t.' . Fur t' x.unp lt" a lu'Wt'r roncenr ranon uf
IIlt"uphylli llt, i\ Ilt't'tk'tl ln al ,u li..h ('pi\lMu's of n't,,"rrill~ " pm'" in pn'lIlahm' infants than ts
1Il 't't II't 1 In \ ul""l.mtially inlpfllH' pulmonary furw lioll in 1l;llit' lIts \\ itll dmmi(' ;li rwa~' d is-
,'a ,,' \ . ' ,'\1. IIII' " pl lt'r lim il of Ihe- p l...vtna rmnx-ntration may lit, r-uln-r. like no rtripl~'lillt'"
a n-sult of t li llli ll i \ I. i n~ ,·fft'(1h "III'S" .11 hi~llt'r ('UIl(.'('nl r;lti-t ms without IHltk" llhk' ..i~1lS of
im ·n,."i"t: I n\itil~ ur, lik,' l..:,t:I''''' ptl rillt·" a result uf ti lt· 1'M )<,sibilily of 1lt11hmlnudly . The
"pl'M'r lilllil m",)" al\t l 1M' dill' 10 Iilllil in~ dTt"t:'fh,·lIt's.. of lilt" d",~ . a.' "ill. Ilu- 1I\t' of \ll lk')'lit·
add In n ·lit"'l · Il.till. Finally , to\i(it)" ' "<1)"' lit, ,'illtt'r an t·,It·n\iull of III(" p"anll a(:1)Ic ~:k'
Pfll l'M ·rt~ ' of IIII' t1nJ ~ ur I(lt all~' di ~\lIIl·i<lh"l.l fnull its t1l1'rdllt'lIlil' "fT,,1 , TIlt" ll('lIlurrha~'
It'mlc'n,:,' 'I\"I(·I<III't1 \';11. an t·\ ('t.....h ,· p h~ m.ll't .. K't·III,..alinn of the- 0 ,..011 a uli('t),IJ:llI.UlI, war-
CHAPTH 5 THERAPEutIC RESPON5t: AND TOXICITY '9
furin. is all example of till' foruwr ; the- Olo lo"id ty l'iIllSt... 1h)' th e anlih iotk ~t' n t a lll i d n is iUl
example of lhl' latter .
DistiTld iOIl also Ill... -ds 10 ht· made hetweeu the Stl"t.·plll'SS o f a concentrutkm- re sponsc
t-urve andtln- width o f a tlu-mpeutic wt udow, Th is point is illustrate.. . ! SChl'llliltil'itlly in Fi~.
5-5. Fi ~lrl' ,5-.'5:\ shows a t1n l~ wi th 11 \,ide therapeutic \\im!fJ'w , 111l' \\idl' window OI"t.'tITS
tlesp ill' slt'(·p concx-ntranon- res ponse- 1'lIn '('5 for both efficacy and toxicity . li en ' toxid ly
OI"t.'IITS ,II lUIII'l·nt r.llio!lS wt'll uh"\"l· those TIt'("t.II...1 to achi eve maximum dl' sin...1d Iet:t , 'nit"
normal sl mh'~' wlmld Ill' III t'llsu n ' that all patients n-cefve a tluS<l.~l' n '¢llwn th<tt p n JtIUI"l. ·S
ple.. ma rouceutration s Ihat ae hil'\"l' maximal efficil' IlI'Y \\i thollt toxici ty. Fi!ttlrt' 5-.'5 B shows
a dm~ with a na rro w IIlt'm lwlIlic wi ndow. TIlt' narrow \\i ndow OI'('UTS tlt·sp ilt· shallow
couceutranou-n-sponse l'u n 'I'S for IMJlh efficacy and lo"idt>', 111is narTO\\1lI'SS ariM'S hI"
l'ilUSt' Iht' n 'spoll."t· t-urves IM'rlap wellbe low Illaxima l effiCill')'. so that it is d iflk 'u lt to find
pla.s lllill·om'(·"l r:ltiol s Ihat produo- t·ffil'ill'">, without SOllie tI~n"t" of limitill,glo"idly,
It is In ht· stn 'sst'l ! tlcu si,,~n i fiednl intt' rilltlisitl uill \"ariability Illil" oc cur in hot h rlu-
l.ffil'ill'y a lltl tm id ty n.·SptlllS(· curves . It'a<lin,g to difference s amo ll,g ind i\i d uals ill the 10-
l'illillll am l widt h of tln- tlu-rapeutie wf ndow. Tlus ~ lll JII ld be kept in m imi when 1,lIIsil!t'ring
111I' tlll'mpl'lIlk \\i mluw'i lislt'l l in Tahle ,5 -2. 111t' val ues an ' dcnwd from patieut popula-
uons n " /llirill/ot tilt' t1m~s and ap ply In tht' an·ra~t· patient wi thin thoS(' population s. Also .
h ...'l' in mlnd thut tlu- ultilllillt· ohjl"t.1i\"t· is I" trea t l'ildl illd hitillal piltil'llt il'i t·ffit'ill'ious ly
ami sa fdy ilS jMISsihle am i not 10 keep his or her ptLsma concentration s wi thin tilt' n 'c-

,.ltl. 5-2• • • ~ DnI,..... Thel.. PI...... c.__......_. U_.11y

~ __Iate4 WIth ""c 1n..-py

OOUG DISt-'So! / CQf\OIICN 1"")111 1. .'0'1

Acetozolom,de Oooccec 10-30 50-150

Am,l:ocin GtOf!'l'l'lll9Ol'.-e infOClOon 11-25"
Am,tnptyline Dep,,:!won 0!2-o25~ 0 43-0 QO
Ccrbceczeprre Epilepsy 4- 12 17-51
C~bspollne Organ tronspionlOhon o 15-04° o 13-034
Desiprom'ne DepteuOon 012<' 045
D'9'lox,n Codoc dysfuncbon 001-002 0013-0026
Digoxm Coooc dysfUOCf'on o <XXl6-O 002 0 ,<XX:la-0oo3
Elhow.. mode Epolepsy 25-75 lS0-540
GenlOmicm Gtom-negorl.-e mlecbon 4-12" 7-21
tdccc.oe Ventricular olfhythmios 2-<> 4-25
ltlh'um Noon,e ond recUfrenr depleMOOfl a 4-1 4~
Nortr,ptyline Endogenous dep<euiOn 005-015 02-06
flhenobolb<101 EpolepSy 10--30 40- 120
Pheny!oin Epilepsy 1~20 3G-60
Venrriculor OlfhythmlOS 1~20 3G-60
P'OCO'f'O:Jm,de Venrr iculo, OlfhyrhmlOS '-8 17-34
Propranolol
~~ 002-02 OOa-0S
Solocyloc Acid Ac sand pa,ns 20-100 150-750
~heu molQ;d onnllr,s 100--300 750-2200
Rheumo',e !eve< 250--400 1800-3<XX:l
Theophyll'ne Asr+.mo and ehrooie obsrruclo-,e &-,0 33-100
a,"""OY d.secses
5-10 28-55
Tobro'¥in
Wo.folin
"""'"
GrOm-negollVl? mfecrOOfl
Throm~boIic d, seo~s
4- 12"
1-4
35-120
3-13
Volproic Acid Epilepsy 40- 100 2S0--0QO
Voncomyc m Penic,II'll'fesiSlQnl jnfedOOfl 5-15' 3 3-10
" 1\-"'; .. ......., 0;;.,. a ')0..." ,.........",
• I\n<"O d>'vg ploA ~
' ~ ..,.,.; WNj-.

" ~ _>hoIcl< ~
<0"<:_
""""*""..
• ooq. ........... / ' -
o ~ """,......::l,..........,.., ... ~ a.:...
60 CHAPTfR5

ommendr-d the rapeutk- wim!o"v, Thi s "'iml"w doe s St ' I'\ "t' it S a IlSt,rlll ~\Iidl' . hOWt'\'(>f, par-
ticularly in the ahst'lIl'(' of mlditional Informa tion about til(' indi\i tlual.
n.".pe<llk Correlat..
So far. plasma couceutrattou has 1,(''('11 assumed to 1M.' a better com-late of " dnl ~'s thera -
pentie rt'sponSl' and toxicity, in a popu lation of patu-ms ll("t'(lill ~ 11 dnl ~. limn all)" utllt'r
measure . However, stnce doses art' ad ministl'rt"l,l. wll)' lIot UM' doS(' as a tht· mp.:uli<: cor-
n -lan-P Ct·rtain!y. in most ( '<1-<;('5 , rt'sP:lI\S(', plasma concentration, ami amount of dnl~ ill
the hody all Increase with dost" Still. plasma conccnrranou is (·xpt'<.1t'tl tn 1)(' a lx-ttcr

.111: ' ~' nit" " i ,IlI, " f .. t1...r.'l't·Ulk A

" ·imlco.... d"IWntb on the d"lI:ff"t' of 100
."'-rt.s' of the· ••ffir.....,..( 1)I;o<'~ lillt",) .",..1 ,/
!,niOl)' «'" I",n .J li"..s).uu." lr..i,,"-
"'''I'''''''' (..,....... A _ nIt· tl lt"T>I.!"" !i<-
" 'ir"IlJW b h""Il-d) ill wKIl· l ll"$(>il" shot1' 75
If I
('OIl (-. ' Il ! n. ! i o ll · r(" p<H1w (' II " ·.· . fo r
Id l. .. ffit"lll' - aI,,1 lU~Kit:v. ;to lh" n' i.
\i rt u••IJ:. 110 .." ...up 1..-t\oo.,'nI th.. "..,
"'''I''''''' ' (.......... B. Th' t1...r~'1'Ii<­
I
50
..i ... I<_ (st-I<.JI i. lI..m""· I..ot:>Ill..•.. f
.. h;¢. do"",... of ,,, .-lap h..ho...· 11 .. f.
ge,..., . .....1 l..:ridt)'
II", "''''1'''''''' (..,
.,." II"..,,",, 1",,1.
lUl' "...:Ill",,·. 25 I
o
) /
0.1 t 10 t OO reoo 10000
Plasma Drug Concentration
(LOll Scale)

B
100

~
~
75
~

- 8-
o
~a:
!l E
~
~
50
:.
Q.
~
E
.~

~
:E
25

o
0.1 1 10 100 1000 10000
Plasma Drug Concentration
(Log Scale)
 .,
corn-late than dosa)?;t" This II1ml 1)(' true follo\\in~ a single dose of d r ug. stnce with dose
alone 110 account is taken of tune. It may also he true for conttuuous dmg administra tion
hut for i t difTt'n '1I1 n-ason .
TI ll' objl"(1 i\"t' of most dmg tlw rap)' is to mai nt ain a stable t1lt'rdpt'u tic f{'spo nse . usu ally
by lIl ai n t:tin i ll~ all (·fT('(1in ' plasma concent ratio n. Figure 1--6 (Chap. I. p. 6) sho>\\'s tin'
relationship lx-two-n the steady-state plasma concentration and the rate of ad nnmstra tiou
of plu-nytom. ('xpn'ssed as the diUl)' dose pt' f ki l ~ram o f bod y we ight. "111Cn' an ' larg{'
inle rlndi' i d ual dl....-iations in till' plasma concentration at all)' dosing mil'; in till ' patiellt
cohort stud ied . tilt' plasma concent ration ran~('i l Imm JI('ar l)' () to .50 mWl. when the dosiJl ~
r ate is 6 lllWddy/k!!: o f hot ly wd!!:t.l. Had 110 correction bee n made for body weight. til!'
dt"\;a liolls wo uld han' h('('11 ("\'('11 ~n'ah'r . III contrast, plasma concentration ccrn-lan- s n -a-
sonablv well '\ilh effect . Thus. seiz ures art" usually effectively controlled at concent nations
hdw('('n 10 an ti 20 m!ifl.; sidt' t'lTt'li s O("(1 1r with inl're asing frt'tlue nl')' and severity as tilt'
pt Lsma coucentrunon exce-eds 20 mWl.. as sho....-n ill FiF;. 5--6. The fin l si?:JI o f toxici ty is
usually Ilysta~m ll.s . whkl. apr~.'ars above a concent r ation of approximately 20 mWl.; gait
ataxia usually ap pt'an wi t h a cencentratum app roach i ll~ 30 mw'l.. am i pRllonged drowst m-ss
am llt"i hargy lIIay bt' seen at con centrano ns in exce ss of 40 IllWL
For phe-nvt oln , plasma concentration is a be rter correlate than dose duri ng d m mk
ad ministration b{'l'au S(' ph arm al'tlkilll'tit.'S is til(' majo r source of va riubility ht,ty,'('t'1I dose
am i rt'Splllls('. Fo r other d m gs, s1I(·1I as umpictlhn. pbarmacoknu-ric V'd.riahilit)' within tht'
patit'llt population is n' lati\l'ly small, ami variahility in the concentranon-response cu rve
is la~l" In such cases. plasma concentration is no be tter a correlate ....tth rt's rxlllSC than
dose am i int!t'{'(l may 1)(' "UfS(' if. for exa mple. met abolite s con tribute to act ivity and toxicity
(S('t' be-low, Addi tional C.ollsidl' r.tlio ns).

ADDITIONAl CONSIDERATIONS
D('spilt, the appeal. meas urement of plasma concent ration is rt'latin·ly UIl ( 'O mJllO I\ in d in-
leal practice (St'( , Coucentruttou vtonnortng. C hap. 18). Tilt' major rcusou is the ....;dt·
margin of S<lfl't)-" o f many d m ~s \\ill1 dirt'l1 and Simple !lwam of a~o;es.sillg the therapeutic
anti toxic rt'S))(lIlS(·s. Another is thai plasma concentnation often co rrelates poorl)' wi th
1ll{·,t\urt'(l respollSl', SOllie examples of l)()(lr correlations "ill. explanatlous, when- kIlO\\TI,
folio...... T his subjec t is con sidered fu rther in C hap. 20, Phan nam! ogi<: Hes pcnse.

MenIal • •• •••••• nil:. 5-6. 11M, rit;.. ,,( tI.., "nl'..... rd ( ,If,,<-{.
Changes • of pI...n~-{"jn 1f)("R'1I.. ~ In p"'P',rtl"" I" iii (. .. ,.
<VTllr.lhn n in pla'ma ( I mWI- - 4,0 JIM ). ( M,,,I.
ifi<'(1 (nun Kurt , II ., \\l nt.. n , W ., KolMlj«", R.,
and Md )oy,.. ll, f .: 1 ),r'It'Il) II,~,""nl(>i n Illt ,t;a!>,,·
It.. " . I>h,,1 1o·....Is, ;11,,1 tnu(ity. An"', :-..."n....
....• ... 1l :6H----64,). 196-1 . Cop:o'rill:ht 196-1, Am..ric-lIll
M ...lIt..I A-."i",li.." . )

..:...:..
Nystagmus • ••••• •• •

o 20 40 60
Plateau Plasma Phenytoin Concentration (mgll)
.2 CH....PTU 5

Active Metabolites
VillI's>; ..eth l' Illt'talxllih' s an ' ,,1<;(1 rm-asun-d. poo r l"Om ·I'lt in ll:'l liMy ('xis!. For example,
Il;L\("() em its pl il\lIIil cnucentration, al p n-nolol Is mo re act ive as a P.hloc:kt·f wln-u J,;\'t' ll as
iI s ill~lc'lIral tlOSt· th a n wlwlI ad lllinisle fl't ! inl mn ·II()IIsly.l1lis t1 n1~ is h i~l.ly clean-d hy the'
lin-f. and ...., in terms IIf tilt' pa rent d r ug. till' om) do St, is pnorly luoavallable. 11IJ\\'t'\l.' r,
l a~I' a mou nts of Il1d ilho lilt·s, illdtltlill ~ an ad h '(' SI)('c:ic's, " - h}d rn~11Ipn:' Il(Jlol. a n ' fo nm't!
d ll rin ~ th e «leorptlon prnt't'ss, whlch exp lains ti lt' appan'nl dist·rejlillll")'. Th e fri<-)'l'lil' an-
li<!el'fl·M"'lIll i11l1il rip lylint· ofTer.> a s("(.111lt l esamph-. Its a lll id e p rl's!i.;lIll ;«.1 i\it)' co rre lates
poorl y \\i lh till" plasma concentration of p aren t drug. O nly' «tu-n tilt' cont n button of its
at1 i\'I' t1t·smt'tl.ylllll't lthol ilt· is alsu ('llllsid t'rl"{! can IIst·fnl co m-la tions Ix' estahhshed . OI)WT
t',,-am plt's IIf ,1t1in' Ilwt aholih's allt l III(> Implk-a tions \\;111 n 'slx'{1 10 the-ir p lmnllOico lngk
n·slx lIIst· a n ' d ist.·lIsst't l in C ha p . 2 1. ~l l'l al x )l i lt' Kill(>l il's .

Chirality
:\I x ml 41)q- uf dm ~~ contain run - o r mon- a.~Yl n ll Jt' l rk k h ira \) l"l.'n h'n> in tjn - lIIoll'{·IIII·. F ur
t'adl center, then- an- Iwo pos sihll' mirmr ilTla~l's o r enantionu-rs. the H· a nd Scfo rms .
whil'h o fh 'll tlifTl' r ill their pharmacokuu-nc a nd p l.'IOnal"lKlylla m ic properties . Bt >(-,UlSl' of
t1 iflil1lhy and cos t o f separation. Ihl ' majo rity of S' l ll hdil' clural dm ~s a n' lIlarlw h 'tl as
rucemlc IIlh !t ln's. FaHIITt· to list' a stereospe -ci f ic(:III'mil',,1 a......ay In II W,l~IIf(' tilt' Individual
t'wm iio lllt'rs can tln-n-fon- h-ad to probh-ms WIIl'II 11Itt'lllpting to co rn-late pl a.~lIla ('(111('('11 '
lralio ll wi l h n ·spo llst· full uwinj.!; ad mi nisl ratio n o f l ilt' r.ll"l·nmlt·, Even wlu-u a Sll'r't'oSllt't:ific
,l\Say is t·llIpln~ l'tl . il i\ not a lways 1 ',L~Y to kn nw !lIIW to ('(lIl1 hillt· the- I' na llt iollwr l"llll('('n-
t rat ion s to n -lan- III n ·spo llst· when IXltll t'n ,lIltiOTllt' TS coutrtlmte In ,1l1 i\il)', f o r exam ple,
altl loll,l.!;h B·\m rfa rin is II'ss potent than S.warfa rin . it can vtill pnKIIll"l' ful l an til"lli.IWlbtioli .
T h us. n ·spo nst· cannot Ix' n-lun-d sim ply In tln- SUIIJ of t he concentrations o f warfari n
enantionu-rs.

ToJeraMe and A(quired R.sistaM'

TIll' t'fTl't:l i\'('lw ss of a tln l,!.!; can di mi ni sh wnh contiuual u w. Al"lluin't l n-s tstance rk-uon-s
!11t' lIillli llisht'tl st' lIsith i l)' uf a pop ulation of ci -lls ( lIlil'n xlrga llislIls, 1I111pla.SIIlS) 10 a cla-.
lIlotlll'rapt'llHl' il~t' n t ; 10 It'f'dnl1' d l' no h 'S a d illlillishl 'ti pl mn mK"l llo~~ l' n'S lxlIIsh'{'lll'SS III II
d m ).:. TIll' t11'~n't· o f a("lillin't! n 'sisl;llI<1' \";trit'S; ilmay Ix· compk-te-, 11l1' n'''Y n' ll( k 'ri n~ till'
a~(' II I , l · . ~ .. a n an lih iol it.', iTll·fT('l1i\'(· a~aillsl ll lllienX I~llll i slTl , TIlt' d('~n '{' o f 101('fllll<1' a lso
vam-s 11II1 is Ilt'\l·f("lnnp!,·h', Fur exa mple-, within day.. or weeks o fits n-pe -ated use, suhjt '(1 s
run d t'\ 't'!o p a pr ofound toh-mncc but no t Inia l UIlTt'sIXJIIsi\'(' lll'SS 10 11ll' p llanna('lJlt~ C
l'fTt'(1s (r-uphoria, st't l!l io ll, n -spira tOl)" (It'p n'ssio ll ) of 1II0rphilll·. T ok-rance can d t'\ ·(·lo p
slow l\"; I'.).:., lolt· r.lII(1· In lilt' <1'lIlml lll' n nus S\"sh'1lI {'fTt'(1s nf 1'llI allol takt·s w'('t·k... ToIN-
lllll'l-."l"lUl al""l Ol'{'ur 'll'uld y (t 'll'lJ, p hyl l\ is ), TIllis. lull ' m ll(,{·. l·xpn·sst'tl l,,· a di m in ish t't l
(M.m lim ·'lw u b r Tt·sIXJllsi\'(,!It·\\, d l'\'( ·lup s \\ilh in lIIiUllk s follt r.\i ll,!.!; n 'lx 'l ili\'(' ad minislmlio ll
u f ma llY II ' pht 'l lt'thylil1l1iJ l t· . I~lx· S)lIJIXll llo lllilllt' lil's , Sill'l l ,l' i"" p rtlll' n 'lIo l, AI all~' mUlIll·nt .
a ('o r rd al ioll Illi!!:hl ht' found Ix·tw('t'll Ih(' inh' nsity o f n 'slx )llst· ami l ilt' pl'lsma l "l)lll't' n!m ·
tion (If lilt' dnl~, b u! till' n ·lalionship \";ln l'S \\i lh liuit' ,

Single-Dan 11teropy
0 111' do",,' o f ;l' pi ri ll l'~ lII l)ft l'lI n ·lil'\'l· a Iw,u!;u:,Ilt' . whil'1. d lx's 1101 rt'lu m l'\'('11 wlll' lI all ihe
ti m ,!.!; has IX1'/I d illlinalt'ti . Ollwr I·xalll pl(·s of t' fTl>(1i\'(' si n~I t' -( lost' IllI'ra p)' ind udt' l ilt' 11M'
of iso p m h ' rt'lIo l 10 rl·lil,\ 't· a n lK'ull' a,t!lIuOIt k ult aek. l"llleh ilillt· to In 'a l a ll a("ll h' ~l)lI ly
atf a('k, nil n lj..(lyl,1·ri n In n ,li('\'1' al11t!· t'p isodcs o f a ll!O na , a ll(l lIl0 T) !Iillt' lo Tt·lil'\'(· aClih ' pain .
A l! h oll ~h l ilt' slx't:i fk IIlt'(·!Iallism of al'lin n i.s " flt'lI Ix xlrly UIllII' rsl( xxl, till' (lS'(·mlll·fTl'{1 is
CHAPTH .5 THE RAPEUTIC ~ E SPONSE AND rooctv 63

km)\\ll: tlu- t1m~ returns .111 out-of.. balance- phys iolo~~k S)'SIt'1Il to wit hin nonnal ho un d s.
Then-after. fl"l'tlba l'k control s\'Sh 'lIls withiu the hod " mai ntain hom eostasis. Tilt" need for
dm~ has now t' ntlt'(l. I II tln-se- tnstanl't·s of sin~lt'-(!l)<;("lllt'mpy, 11 correlation hdwt't'n t·rTl'(·1
and peak phl.s ma roncentrution lIlay exis t, hut I X~~ lIld tilt' peak, :my such correlation is
uultkclv.

Duration Versus Intensity of Exposure

Sonu- cln-motln-rap-utic a,gl'nts . t' .~ .• nu-t hot n-xate. t'"hih il peculiar n -lanons lnps 1)('lwt't'n
n'spoll w am! tIm t'. TIlt' n'sl'NIllS(' ohst'r\"('tl n-lates rnon- dosdy 10 lilt' duration nf dosi n~
than 10 tilt" actual dosl' uv-d or coucentratious produced. Tl lis lx-havi or fur lIlt'tllol n' x.alt·
can ht' t·.\ plaillt't! hy its act ivity as an anlimdaholitt·, It tuhrbns dtbydrofolatc reduct ase.
Ihl'n'by prt'\"t'nli ll ~ lllauy 1I\I'tl lylai ioll react ions in the Ixxly. These reactfuns can Ix' Iuhjb-
Ited for sho rt periods of lillie. a ft'\\ ' tb~'S . \\i lho lll (~al l.s i n~ lrn...'t'rs ihll· tlalllil~{, . \\1lt'1i 111l'
l'SpOSllrt· is suffidl'T1lly prolonged. IlIJWt...vr, tilt' tll ma~t· is im...·t·rs;hlt· and po lt'utiillly
Id ha l.

TIme Delays
It o fte n takt·s sonu- tiuu- fnr ,I nu-asun-d re s!'N )I1St· to flllly rt'i lt'('f :1 ~ \'(' Il pla-SIll,1['(1I\('t'II"
trutton o f dm ~ . Unl il then. tln- ('ull linllomly dlall¢ ng I"t'spnnse makes allY cnrrelutinu
betwe e-n n'S!'MJIlSt' anti plusmn conccnrranon t·.drt'llIcly d iffit11lt 10 establis h. Ont· source o f
tln- t1l'1ay is till' tinu- n-quired for t'ljlli lihnllioll 10 Ot"l111' hl'''wt'li <l n l~ in pla..ma and that
al lilt' sitt' of act ion , usually ill a IiSSIIl' , Thi s tlday may ht· sho rt if III(' dm~ t'nh'rs III(' tisslle
r:lpid ly; Wht'lll'lTtdin', lidocanu- supprl'ssl's ventricular an-h)1hmi a.s wit hin a few minutes
of ¢\i n~ ;j IMII IIS <10M' ; thiopt'nlaI iudu('t·s am'stl lt'sia ewu mon'ljukkly, wh en till' ta rgl'l
organ r('sidt·s in a slow ly l'{lllilihf:lt in~ tissue, the dt'la~' Illay h(· Illan y hou rs. f or esampk-,
tilt' mudmum ca rdl,u- d Tt"l'fs o f t li~ox i n are 110t seen for ,III hou r o r more after adlllinish'rill ~
all Lv. bolus of lilt' d mg.
Anolllt'r soun-e of t1t'la~' I~1II urise when Ihe n 'spelllst' monito red is all imlin."l'f lIlt'aSlln '
of d m ~ t' rTt'l'I, A (h lll~t, in hllMM I pn'Ssun' is an im lin"l'f Illt·;l.s ure- of t' ilhN a dm n~,' in
lJt'rip llt'ml n-sistance-. in mnliae outpul . or ill both. Plasma uri c acid is anulht' r (·umplt·:
ln-n-, tilt' di rect t·fTt"l'f is all altN'dtion in uric :wid wnt hesis or elimination. Yl't another
r-xamph- of all uuhn-ct n.·SPOIlSt· is tln- dlan~t' ill tilt' 'St.'m lll protlmnulun t'(lllIp lt·x al'fh;ly
produced hy coumarin oral a lll ;(,(li.I~l l.lnl s . Tilt' mon- di rect t·fTt"l'!: of Ihl'S<' :lnlit'( );.l,glllani s
is 10 inl lihil s~ll t l lt's is of tlu- prothmmhin compk-x.
Tlu- dt ·lay ht'lwt't·u aUainmt'lll of" pLl..ma l'(IIlI't'lllnllion am llll'l\illlill im!;n "l'1 ...rTI't.'f
\·aril·s. Full rt'sponS(' in hlolKI pn.·sslln· to a ehall~t· ill lX'ripl wr:t1 n 'si stan('t' or in e .lrt liae
oulpnt IK'l'\lN \\i thin millllh 's, wllt'rt·a.'i lIl:txinml rt·.'ipeJIIS(· of thl' pmtllnllllbill l'tllllpll'x
al'li\;ly 10 \\~lrfari n ;s lIul S('t'll for J 10 2 t1a~'S aftN an o ml dOM' of Ihis an lil,(li1h"lllant
( Fig. S- 7).
Uril' ad d ;uld tilt' pmlllrtJlllhin ('()mplt ·" art' t' :Gullpll"s uf t'lldtJ!.:t·1I0llS m;ltt'ri"ls. Su ch
mat t'rials an ' t'tllliinnollsly ht'ing n ·1lt'\\l'(I. \\i th Iht· peM)1sin ' n'fl l"l'f in~ tilt' bal an t't' ht'''\l''('11
input ami loss. TI ll' impad of dlallgl'S in inpul and lus..s Oil tht' kind it's of t' "do~~1'1l0IlS
(,(lInpo unds and lilt' appruprialt· inlt' '1)rt'lillioll of sueh da ta .m' (,{)\l'f('tl ill ~n'at t'r tll'I ail
in Chap. 2.1 , Tumnw r COll('t' pts,

MODALITY OF ADMINISTRATION AND THERAPWTIC OUTCOME

As Illt'nlifJl lt'd at th l' I K ·h'; n n i ll~ of Illis dmpt l'f. lIlainh·n'lIIl't· o f a plot'iUla ('olll't' nt rat ion is
not alwa~'S a dt·sir:thll•IIll'rapt'uli t.. olljt"l'fi\'(', So mdill1('s, a ll ll d llali n~ {',(ll1t't' lltr:tticlll is mort.·
t1t·Sir:lhlt·. \I ud . t1q X'lld s 1m Ihl' plm nJlal'(KI)1l;U11i<.' fl'ahm's of t·ffiedt'y amllo:-.;idly. 111is
.. THEiAPE UOC RESPONSE AND TOXIC ITY CHAP1£R5

~
0
nfl:. S-7. 11... _J II~J, n "'I"""" in ""' 1'1;. .11...
~ ~
12 1,"111,,,.. nl " ,, n "" I'Io·\ ii< il)' I" inl,ilo,ti"" il> "r
~lll l ...' i' I,>' ...... rfarin
A''I1 ' I),.· i". lin 'l1 "..I" n ·
1l 10
~ ur,1.., "",;"_"ft·''' ''''1 ,<1 ,t.., <I" ..... . ·I" "i" alio..., "r
0_
B lI,i, (" "' 1"" \' F"r ,I..· liN 2 ( ~, af" 'r ";'l"~ a
~~ 6
.10 •
.Io ·ft·.."
lO r ".-arf,ui" . ,I..• "''''1'1..\ ..l1i\il~·
U" ri,,~ tI,,· 1i"'1 ,Lty. II",
'1"lM li ~
", -
~- lio..., "r
;: 4
rf;onn i_ . " ffi<.i<..,1 I" ;01".." 1 •.,,,,.
I"'... ·~ h" .·~ •• ""pl \~ " I I " .. i• . " . ..... arf..ri"
~
E ....... ....tr.dir..' r..II•. II ~1' 1 1 ...... r..I<' "r II...·

e ~
2
0 2 3 4 5
"""1'1.·, ir K"" ';"" " ..,..II,,· .f'll,r ' ''I" al. ,I r..I.·
"f .1.".."' lal..... "f II..• " ""pl.... 11,,·n·af!<" r tI,
II ..• \\1l11,,'<i . rah' .'U li"~ II,,· ral., " f ,Io-Wa-
.Ltlir;". II...'"'''' 1''''' 1i'il~ ri ,, ~ .....I.... ·" I "all~·.
" I..·" all II..· " ..rfan" I ~ .. I.., ·" .-li", i,~.h ..1. ,,__

E~ 100 I" m < I" II..• ""n"al I',,·...;'rf..nn ' I,·,..~'.'t"h·

Io..,.{ TI}(\ ILia p" ~nt$ ,01.,,· ,111' a....r..C' ~ f" l\u"'lIlt
..,""
ou
~ .s
~ ~
75 II... " ral ", 1",inl _Ira l io .., " f Lo5 '''10: . . .arf;<ri " ..
.Iimn I"" ~ I( l u~ "'''~ ' I in S ", ;01.. , ..I,mI ·"
~ E 50 (I ",vI. - .1 ,;) lI\ f l. (F n lU' .' all:"-_I,i,,, R.
"0
u~ ~
" (), H.·il ~ . H a'.. I I.... r- c., Ki,,"'ir... " f 1,1"" .
c_ 25 .·rr n..·
c1l~e m..., "' .!~k 1 < i" "u ,,: ;<nll<'o;<lI:" I." '1. '.
lio", " f ..... "rf"nll , e li". l 'Ir" ", ~I...I, n ..' r " 111:2 2-
" ~ 0 .1.'i. ltJ(>!J I
~E
~ 0" 0 2 3 4 5
z
Days

polnt ts well illustratr-d wit llllw alltimkmbial a,gl' nts, '1111' p urpO!i(' u f ;Ullill1 k m hial !Iwrap)'
is 1111' I'r.lt lie ,llillll u f an infl'(1 iu ll with minim a l tm;id f)', Figt lrl" ~ s!tows m aj or difTI' n 'll('t"s
in Ill!' t,(f1"l1 of t1ns in ,g fn'l IIlI' 1l1')" u n lIlt' ( ltit~· dOl"!' <If t ...·ft ,v.itl in l(· alld ,gt' lItami('in n-qutn-d
to produc...• 5( )Il of max imal ('!lit. l(')" in pueumnnia tim! is d ill' In 1\ldl,~ if'lla ,m"wum im' in
l1l'ul mpl·n it· mice. \ \ l l(' n'll-~ dl "l'n'll-~ i ll~ III(' frl 'l I' IC'''I')' o f adllli rti.~lmtioli . a ml lll'lIn' inc-reus-
in,g tilt' d t-gn'(' of !lm 'hmlioll in ph~ ma couce-ut r atiou. t1m\t it;:llly t1imi llisl,{"(I IItI' (·!lil·;I()"
of ,,·fla7.idilllt·, il had mi n im al {·(f{"l1 t il l ,g1·J1 ta rnidn. Tln- t'x p la natinll lies in tln- di (ft' n 'nf
phann,I('(Jt,I)u:uu it' p mfi l{·s of ti lt'S!' IWu d m ",rs.

.·ll(.~. n l{' infl , , · "f 1."'1011,. 1000

...,inl(tI..- ."><i"l: into· al..., tI.., .I.u~.
[".... r......I...I IQI' rt.Ir · .5It'l tl f ,n..., ·
i,rud .. ffic.'''''Y in ,,,';<tin li: 1",,-,wlC lt'u
(I<..' lu Kk-l..j,,-I14 I" ....","lnw ill 'It"",
' n 'P'·" i.: mil..· _.. riM " ill. Ill(' ",,,Ii ·
m iMt,hi al ~'t'1'I . \ \l,,·n >a.< ".. d1a IlI(.·
100
111 .l.oi l~· ,......" ..1 .. i llo ~'n l ...
,nI<1" (1.Lot ''I'''''). ,m...h Lt'W" r
<I f tTft.ozl< Ii",, · (m lo..-d...",..)
an- , 10...1 ...ho -r, ".1, ,,i ,,hl<-n, I Io.~,
r""I,,,..,d~·. <From 1" 10.'<1 1, J.E.. 10
t·..nli". a . t:I"·,,. s .c., T.II'uL.. K.,
\ '. ""4n",,•. It " ... ,,1 CroliR, W.t'.,
O " " I",r..tt ;Illtihiot k ." ....•.... 1 rr...
!'t·!:tl io.ltll-I!ip f lot'wral (I.n".i"~ i"lt·r.
,.,.j, in ",,,rin. · i' ",..",,,,,,ili' al..1
Ihij(l•.inr....1ion ,,1011.·1•. J. l" r'''-1,
1m .. 1....'1,2'l I-29'2. 1 9"~ , ) o 2 4 6 B 10 12
DosingInterval (Hours)
( HAFTH 5 .,
Ccftazidinn-, iii\(' other ~- lal'till n unt ibiorics . exhilnts onlv Illininml concenrmnon-de-
Ix'm lt'nl bactericidal l!l.'l hily. so Ihat bactcrtal ktlhug is more d,'pt'lllll'nl on time aho\'(' the
min imal hal"h 'ridlbl roncent rution than 0 11 the lII a~n i tude o f till' d n , ~ coucent ranou.
(;n 'atl'T Ix'nd it is tln-refon- adlit'n '(l with ilion' frequent ad minislra tion Ihat minimizes
tht, possibility of tlu- plasma concentrattou falling too low, All add itional reason for frequent
ad ministrat ion is thai 11ll' d uratio n of thr- pos ta ntihio til' d Tl't1- wh eI"('!Jy bacterial I-.trtJ\\1h
is supp n-ssed fo r s( 1Il lt' tune after Inte r mitte nt ('XIX1Surl' of b acten a to th e unn nuc r obml
agl' nl- is \('1) ' sho rt with rln- ~ · lal1 alll antibioti cs .
In cont ras t 10 l'l·ft,tzid illl(', ~t 'III;\l llid li alld ntl l('r alll i llu~IYl·o..idt'S pmd lll'l' a pmlml ~t'(l
postan tihiolie d Tt'l,t, T ll('y also exhibit marked couce ntranou-de-pe-ndent ki llill ~ O\"l'Ta \\idt,
TiUl}!;l' of cour-eutra tious \\i lll h i ~llt'r \~lh ll'S ha\i n ~ a mon ' pnmlJlllll...'(ll'fTt't.1 U II ti lt' raIt'
am i extent o f hal1t'rid tlal al1h i ty , :\l'l·o n.lingly.largt' lnfn-quent doSt'S of gen tauucm an ' ,lS
t·fTt't.1in' and po te ntially mrm- so than smalh-r mo re frequent O Ill· S.
A ltholl ~h data in pal it'lIls with infection s, of IIt'l't'Ssity . an' mnn- \11riahlt, th an those
ohta im'l l ill lilt' experinu-utal mouse modd. tht,), do tend to Ix'ar out tbe findings ill Fig,
,5-Ji. Mon-ovr-r. stud ies ind il"dtl' that rlu- lIl'ph m loxicily o f tlit, alll i n~IYl'lls; dl's can 1)(· re-
dlll'l'l) hy a onl'(·-daily n-w nll' n comp an -d to more fTl'llut'nt admi nistration. n lis ma~' explai n
tilt' It'm lt'lIl' ', ill ~l lll t· IIUitrtt'r.i. to 1l\ 1)\"l' From a Ihri ' ...·-tLtily 10 a olll'(·...laily ad mlnts trat ton
of ~t ·ll t alll ili ll .

ACHIEVING TNERAPEUTIC GOALS

Chapn-rs fi am i 'j pn'St'lI1 till' basic principles fo r l'stablishi n~ and t'\"dlna!inJ!; dosa~(' n~­
mens for th ost' d m gs thot! shu\\' n"I.-"'JIlahly valid com-Iatlous o f respo ns(, \\i lh dose an d
couceru ranon. C hapte r 6 t·xamint·s featu res of constant- rat e input , while C hap. 'j e xamines
tilt' prtncipk-s 1l 1l(1t' r1~i l1 ~ tilt, administration o f d rug ill disc rete du st' Sto attain andmaintain
tlw mpt'llt il' l'lllll'('niralions. SO Il l(' mltlitional l'lllllplt·xi!it.s of till' concentmnon- res ponse
rt'lalio nship an' addn-ssed in C hap. 20. P!laml al,(ll( ~(' He-spouse

STUDY PROBlEMS

lAnswers 10 Study Pro ble ms o re in Append ix II .)

I. Dt'fim ' till' It'TIIlS:
a . AII -or-nom ' n 'spollSt',
b. ( ; radt 'll n ·sl)(JIISt'.
c. Tln-rap -ntic \\illth,W.
d . Utilitv l'IIT\"("
e. Toh-runce.
2. Explain why t'1li.'l1 (de-sin-d lIT loxic ) is ofh-n 1M.'ltN co rn-luted with p laon« con centrn-
tin n than wit h dust"
3. U s! uud brit·lIy t1iSl1ISS four sit uati ons in whic h poo r plasm a d m g couceutrauon - rc-
sl)(lns(' n-latlonship s an ' likl'1y to occu r.
4. U s! the plasma concentration r.1Il~(·s l,(lllllll(JIlly a.'isociah 'll \\i lh tht'm lx'll tic n"SIXlllSl'S
uf cyclosporiru-. d i ~oxin " ~t 'lI l a mici n " lithium . plll'll Uharhital, pln-nctoin, and theoph-
, lIint·.
.'i 'Bril'lly discuss, with examples. 1\\11 situations for whidl f rt'l IIll'Il(." o f udmtutstratlou o f
lilt' sa l1lt' daily tinS(' alTt'l1s tilt' therapeutic out come.
 CONSTANT·RATE REGIMENS

OBJECTIVES
The reode will be able 10:
I. Define pIoleou and describe the factors conrrolling it.
2. Descube the relationship between hall~,fe of a drug and rime required 10 approach !he
pIoleau follow-ing a COI'lslOnHOIe inpur wim or Without a bolus dose,
3. hlimole the values of halHile. volume 01 dislribJ!ion, and clearance ofa drug from plcnmo
concentration dec obtained during end 1oI1ow-il'l9 ccoscoecie inpur.
4. Eslimole the values 01 holf·Me. elimination role COO$lOnl. and fJoetoon excrered unchanged
"om urine dolo obloined dlJl"ing and lolbwing COflslOnl-role input.
5. bllmole the valveof [enol clearance from combinedplasmaand urine dolo
6, Use phofl'l'lOCokineti<: poromelels10 pedct the pIoYTlO drug concentration and the amount
of drug in rile body wim lime during and following coosontroe input wilh or without a
bolus ccee.

.\ S i ll~II' do....· may rapidly procllll't· ;t t1" ,i n'~IIIll'rapt 'llt i l' «mcentrauon . hut this mode· of
administration is Il1lsuilahl. · wlu-n lIIaillh'II<lIl l't" of ph'IlI•• o r tiss\lt· conceutranons a m!
{·ITt'd i, t1 t·sin'tl. To lnailltail. ;I (~1l1slallt plasnM (~l l l n ' II I rat itIll. tim).:: must lIt' uchmuiste-red
;II ;l (111lsla llt rail'. Th is is lIIost rt·li"h ly a( ,(~ llll p lis llt'( 1 h~ in fllsill).:: dm).:: illtr-d\l-'lIously vi a
t'itl ll'Td rip o T:I pump. wln-n ~T('alt"T p rt'(>isi'l ll is dl·, in ·t!. :'1:0 ether mod(· (If administrutioll
pro\'itlt·s slldl prt '('iw ami w ac!i l.\· ( ~ lll t rolll ·d dm ~ atlllli llislralio u. It is. how('\'t'T, n-stricted
p rima rily to IU I' pital M ·lt ill ~' .
.\ \\id"r applieal ioll of (~ JlIs l a llt - T<lh' t ht'mp~' has 1 1t'(.~ 1II 1t" possihle- \\i th the development
.md 11'1 ' of t~ )u s l,llIt- rillt" rd(';lM' devkx-s, which can be ingesh"{l or placed at a \lIri t·ty of
IllMly sitl'Sand wllid l dl ,lht'T d nJ ~ for a 1)( 'ritMI of ti nlt' t·..d t.n d in).:: From hours to Yt'an. So nll"
l'\;lIl1pl.·s of II...sl' dl'\it1'S aud tlu-ir <Ipplit'iltiom an' g1\'(' 11 ill Tahlt, 6-1. Such <!(...-ices an'
adlll iniskrt ,t1I'\ tr;l\w« ·lllarly. " '11t'1l ~i\l '1l to pm(lu('t· a s~.,;It· lIl il' elTt"C.1, absorption is a
pn-n-quisih- to attain t'l1i'(·ti\l' ph,,"a ('ll1(~ 'lltralio...,. 11tJ\\'(·n ·T. for th e pnrpOst' of under-
't a tli l i ll~ tilt" p rindplt " ill this dl;lplt·T. dm).:: <1('lin'I)' frum tl lt'~· sys te llls is assunu-d to hI'
t'tllli\-alt'nt 10 a l~m ,I <l ll t - rah- i.v. infus io n.
TI lt' ' ;llil'lll ft'aturt's o f rln - ( '\( ' 11" lilll,...\illl..( a coustant -rute in fusion ure sho wn in Fi~.
fl I lilT ti sMIt' .I ~ pc ·l'la s lll illoJ.~c ·n at'li"lto T (1-1';\1 . a SUhS!;lIll'(' lISl"{1 to tn 'a ! myo(:anliul ill-
t;iTt"li' lllS. -111t' pl;ts n,a (~ lI t l"t- ll t r;l l il ll l riM 'Slc,warcl a constant valur- lUlll tln, )lSnlTilllllw1,l iatd, ·
"ftN the - infuc km u f IA lrIWlllill is stllPlwtl ,II hi) mill . Th t' half·lift· (If tilt' nmlj'M lllllti ill
th is pa til'll! b .'>'2 mill. '>0 IIU' dTH l..( is in fu"l"t l fOT al)(1II1 IS half· lin ·s.

DRUG LEVEl-TIME RElATIONSHIP S

., tim !!: is said 10 I.... · h<iSI'1l as ;( constant (ra h') infusiun when tilt' ink n! is to uuuntuiu a

..
sta hl. - p lasm;! t~ IlI{l 'II! r;lt im l lIT amou nt in tilt' lx)(ly_ In coutrast to tilt' short du ratioll IIf
CHAPI[ i! 6 67

infus ion o f a ho llis dost·, t ilt' duration o f ouotant infus illt l is IISIIa llv IIlI KIIIOII~t'r than tilt'
half-lift· of tlu- t1 m g:. T ilt' t·<,st·ul iu1 featun-s of rln- t'Wllts followin~· a constaut lnfusn m (':111
1M.' ap p rt"t: i:lh'il hy l'un sidl ' ri ll~ tln- ('W ills <!t·p il11'l.1 ill Jo'ig:. 6- 2.
The Pioleou Value
:\ t an y t imt· dll ri n~ an in fu sion. tilt" run- of d"lIl~t" in tlu- amount (If dru g in till' hot ly
(tI.Vtltl is tht" t1i1Tt"n·m'i·IM.·h\"t't '!1 tilt" rates of t l m~ tnfuston am ] elnulnanon.

dA
k· A
"' Cc euc nt role
o f inhJsiOll
Rote 01
el iminotioo

or t·\prt·....ill ~ tilt' equ.uton ill terms uf the concent r atton of d m ~ ill plasma.

Used lor i v. infll5ion

001 30.60. a QO mg/dov
odm,n'!>Iefed do,ty
f't>enyIproponolom'ne 25 rng rrreedoe ,eIeo~
and 3 4 rng/ht for 16
hr
Tmn$do><mol 00501 0 .1 rng/ doy
7, 14. and 2 1 rng/doy
(40 ltg/ em1/ hrl
ehonged doi/v
o I 100 6 mg/hf oYttr
1211,
o 5 rng CNef 3 days
Soma ~ a le pcrtIble.
o/he<s O' llt implanloblllt
Coburn ehannelblocker
l\Iond's,nltlg'Ol,ng S)'S1em is
designed 10 proede a
eonSlont 'Ole 01 -eecse lor
2411,
Appel'1e suppressont
System o,ms 10 prov;de a
(OI'\$lQn t a nd effecb...e
plasma ccecewcrce 01
pher¥prop:trOOm'ne for
16_
Treo lmen t 01 menopausal
syrnplOm$ and pl'l!'\I'llI'lt>Oll
01 O5IeOpOI"O$IS
AppIoedlO Inlrd:, 01 body.
inck.d"''oQ bullOck! a nd
abdomen. TWice ~ty
M b"0'''''''''''''' .
Pr~ a 'eoloOllObty conSlOnt
plosma concenllQ1lQtl 01
nicotine
Polch pIoced on front 01 bod
above 'NOIS! 01 on uppe<
outef pert 01 o'm
p.ophy4o.'s ogoinS! ollOCk 01
ong,na pectoris
Syslem a"T~ 10pl'ovide a
(OI'\$lQnl plasma
concenfTCll>Oll 01
nillC9!ycerin
Recommended oppliCOl>Oll S11e
's Ioleral cbes M;lW
U~ lor prevention 01 mellOn
"'.......
Applied 10 ho,f\es.s area
behindeo' o, leos/4 hr
beiee theonl~1( elfect
n deseed
. CONSIANT -iATE i EGlrW: NS CHAPTH 6

t'IJt. 6-1. n l l' 1>Ln",,, lUll" ' t • 1500

lil.., "r11,<"""I'hulll ti . ....··t)l I'I"....
l1 ,i''' 'ltl'1l * :1;,.,,101' (I· PAl rapi,Uy ..
1'"_·1 hmiti nl': ,....,... in .. patit >!lI
....h n n-c i...'. (UU Mt·j!,.. " n il "/ rnin
/ 1.-1 ruWlIlin ) ~' ('t'fl>tallt'TlIll ' in f,, - 1000
"'''' rur /:Ill ,n ino At th. ' " utl u( II...
infnsiun. IIo" I'I;o." n.. t· r A ('t" K't'nl ·
linn tin, .. r"l"'lI)' 1, ........1 1' ....' wilh
.. S.2-min half·llf... nN ' li".. i. til..
f"ndi" " C . 1320 ' (1 _ .. _ Q lnt)
l l" ri"~ tI.., i " (,,.itll ' .."tI C • 132l1 ' 500
.. - 0 .1. "',. .. lI...n''' (''-' ' TIlt- , ,.Ju., ,I
11,1.11. mill - I ('Orn "l"",t!, In ;a h"tf·
lift, uf 5.2 mill . (At4Jt 1 ("»11 K...•
10'1'. KW.•
Ka'f'l·r. t',.c......".
. \ lIn
A KI" rl. C .•
til., Williw, I'.A.•
"".1 W....tl...rJ,.·, R,C.: n... rJ...n nll ' o
l'o ~ i '1l'lk. of dcubl.. -charn ' · I' A
(d ",,~): en,,« or I,,>lu> injo"C:- o 40 80 120 160
lin" , in{" ..o.... a,.. I . I",I"I" ...41i"" I.,.· Minutes
....-i¢ ,t in p;dM'1,b "'itt. rn~' Il"olnlial
infa,,";" ". elin. l"hann;K", 1 n ......
5O:2fi7- 2"jj. l!:l!:l l. )

100
t
90 -, From infusion

75
~
~
~

~
<; 50
C~

"
~
a.
25
/ From bolus dose

0
0 2 3.3 4 6
Half-lives
.' 1/:.
6-2. Th· "I'I,.. _t.
In p1ah...u II n,,,tn>l k..1"n ~' I", t1,,· lt.df·lif,· o f II,,· , In' l: D'1"'-1,..1il a ,illlal;'", in ",,~, id,
a 1".Il1s .k...•(ll imm,..b.I"I:o· a1 lai"' ...1t! a n ""lanl i" f". Ior, tl..• af" ·T """inlai". ;o ,..""ta"l ," ,,,",,,1iu Ih.· "' ''~' .
A. th,' "",,"ml of l.... l" oIns ' k...· ft·mainillll: in II... I " >t~· falJ.. I ·.... i' ... ,"'rnplo·I1 "l ary ri,,' " ..,,!tUlle: 1'1'' '''' tI...
inf" Iit>!,. 8~' 3.3 It.df·li,'t"5. II..• a,,,,,,,,,1 In 11... I u.~ ...." ,,·;;." ..1 will. II..• i" f"';'111I n·;o<·I....1 YO'.'- of tl,,' I'LtIt·;ou
_,J,It'.
CHAPT£ ~ 6 CONSTANI-RAT£ ~£GWolNS ..
dC
V · 71 = Ro - CL · C 2

On s l a rt i n~ a constant in fusion. ti lt, amou nt in rln- bodv is zero, nndlu-ncc then- is no

el imilllitillll; thi-n..fort" amount ill tilt' hotly rises . TIlt' rise con nnues unt il ti ll' rate- o f d im-
lnat ion lllatdws tilt' rate of infllsion, Amount in th e hlxly am l plasma ccnceutratfon lin'
tl u-u said 10 ha\'(' n-achcd a '\'II'm l 'J sta te or "lalt'(I/1, wh k·h continues as I() n ~ us till' same
infusi o1l m h o is muintuiue-d. Silll't' till" rate of d lilll~t' of amount in the IMKly at plate-au is
zero. it follows tllat El ls. I am i 2 s i lTl pli ~\' to :

A. = Roll 3
AfTIOIJnt at Infusion rate
steady stale Elimination role constanl

c. • RoICL 4
Concentration Infusion role
at steady stote Clearance

Cll 'arly, lilt, only fadon ~o\'(' m i n !-! amount at plat eau an' tht ' rate of in fllSion and lilt'
eliuuuatiou mit - con stant. Similarly, on ly infusion ra ft' and dl'aroUll"t' cou tml the stt'ad y-
stall' ph~ l1la t"tll\('('ntmtiOll. SUppU<;I', for illllslmti\'t' purpost's, that a slt'atly-sla ll" phl-~ Tl1 a
Iheuphyllille l'tJ!lt't'nl ralioll of (,5 mg/l . is dcst n-d in till' pa lit'nt whoS(' i.v. hoius da la an-
sho w n ill Fi~, 3- 1. Sim'{' tilt· dt'arolll{'t' uf this d m ~ is" lAir (C hap . 3 ), tilt' n'lluirt"tl in fusion
r.11t' is 60 lllW'lr. As ti lt' t'limillation ratl' constant of Iht'C lpllyllilll" is 0 .14 hr - 1, till" {'(IITt·-
SIXllltlill,g amount o f tlm,gin till" IMItI)' at stt'ady stall' is 4V) III~. Altt'nmti\"d y, Ihl' amount
cun lit' (".lk·lIlah 'll hy lIl11[ lipl~; T1!!: tilt' plateau {'oll('t'n tm !ion ( 1.5 mWL ) by tilt' \"UIUllW of
d ist rihulion of tllt'llpllyllilit' ( ~) L).
To l·lIIp lal~~i:t.l.' tilt' fadon; tllat con trol the plateau. conskler til(' follU\\ illg statement: All
d m~s infllst'tl at tilt" . ..u ue r an- und hil\;ng Ihe sallie dl'amlll't' n-ach Iht, sarne platenu
com- entrution . This st,IIt'll1t' nt is tnu-. 111t' liver and kid neys ran d ear n l\I~' what is p rosenn-d
10 tllt'lII: tlu-v art' in<;l'milin' to di (ft·rt'Il{'t's in tisslll' distribution. TIlt· rate o f ehmimuion
t1q"M' lltl~ onl;' Ull dt'aml1t'{' and plas mu concentration. At plateau , mit' of di minatioll is
l'l lual to rate- of infusiull. Th e pl :~~ lIl a l'u nt'{'lllmlioll must then-fen- 1M' tl lt" sann- for all
dm,gs \\i tb tilt' "<lIlIt· dl"ar.U1('t' if atl millisl{' rt'tl at Ihe s ame ra te. I!O\H ,\·t'r, amount in lilt'
htltly \,ari('s wit h volume of distrihutiou. Onl y wnh drugs for which l'!Pilnllll't· and \lllulIlt'
of di slrihulio1l art ' ti lt' "'llllt' nn - bot h plasma concent runon mid amou nt ill tilt' IMltly OIl
plateau th e same when illfnst,tl al tln- sann- r ate. :'\nw l1ll\sitlt'r the next statement: \ \ l lt' n
infused at 111l' Slllllt' rate. tile ,tl 1IUIl Il I of t1mg in the b(ltl)' at plateau is the sauu- for all
(Im,gs \\i lll tilt' Slilm' half-lift" Thl: stllh'mt'nt is also true. I>m!?:s wtth the Sillllt· half-lift·
han ' lilt' sunu- elimi nation rate c uwt.uu . TIlt' di minatin n rate constant is tilt' [ructional mtt'
u f <lm ,g r-limmution. that is, Ill(' rate- of elimination dhi dl"tl II)' til(' amount of tim,!.!; in Ihe
1M Mly. :\ t plalt'au, rate of t'li llIitllllioli equals ran- of infusion, He nce amount in the lMMly at
plalt'ilU must 1M' ti lt' SiIllU' for all dm ~s witlJ tilt' Si.lIIW Imlf-Iifl', Alt holl~h tht' amoll nt in tilt'
IMMI)' is 11ll' sal1lt·, til(' {'t IITt'SPOlltli ll~ platt·a u l11Ilt'l'u tm tio!l \'Uril'S ill\'t,n;.t,ly \\;t h ti ll' t1mj!;'s
\"lllllllll' (If di st rihlltiOli.
!\Iluw lt,t!!-:l' nf tht· plah'all \"ahlt' at 0111' parlkular infusioll mit' alluws prt'tlidioll of tilt'
infusioll r;I!t' 1It't"tII't1 10 adlil'\"(' ollw r plll!I'iUl \'il!tWS. 111l1s, pm \idt·d that d l'a r.ul('e is
tUllslilllt, a dlilll~t' ill in fusioll ralt· p n Mlllt't·s a pOlporl ional dliut,!.!;t· ill plateau n llll't-'nimiion ,
Bdllming 10 lilt' tht"tlphyllillt' t·xamplt· . Ollt' t'xpt"t.1s Ihat a rode (If 40 mgt11r is Iwt"tlt'tl lo
7. CONSTANT RATf REGW,fNS CHAPTHO

p mdlll't· a plateaueoncent rutkru of 10 lllWl.. sinre an infusiull rah' (If fin m~~/" r results ill
it plateau couceutration of 15 1II !ifl ~

Mean ReslderK. Tune

Conceptually, a useful pardn wl N to (]t·scril lt., tho sojourn of t1 m~ in ti ll' (Mltl>' is mra n
n·.~idl'lln· t jllu' ( .\1 HT) , T o appn'<.i atl· its rt'1aliollSh ip In (1111t'r pllanJlal"okim ·t i{~ rxlnUllt'lt· rs .
consider tilt" Iufusam situation. Fur it ~\"t'1l constant run- of infusion. till' amount uf d m~
ill til(' hod)' at slt·ady ..tate- [ rat e- o f r-liuunathm "" roth ' f)f infusio n ) depends (Ill rlu- time all
a\"l' rd~t' 11101('(.' 11](' n-stdes ill tilt' Ix)(I)'. For ex a m ple. if 2 X 1U1I1 lllo ]et:u l("S are d i mill ah 't!
pe r hour ami ti ll" reside i ll the hlxl)' for 10 In , rlu-u only U1w-fl'nlh of tILL' molecules in
the hody a n' n -movcd IX'" hour. l111'n' must tlu-n-fcre lx- 20 x )(~ ' mul'~'II,·s i ll tilt' "ud~"
TIllis. .\fRY is related to , II.. infusion nil .. and th.. a IlMHIII! in tilt' h,lt l} I,}' l i lt, ""!.IIiUIISllip :

MRT = ~ 5

F rom Eq. 3, it is l'\ idt'lit th a t

1
MRT .. I 6

o r, as k "" 0.69.11'112

MRT ~ I .AA x ' 1/2 7

Furthen non-, a.. k "" CI./\'. it follny..s fmm l-~ I _ 6 tllat

MRT . VI et 8

For t11l"'C )ph yllilll' (\' "" Z9 1.. CI. "" .. L'hr iu t he' patient ('_x<l mpld . l hl' .\JUT is 7.2'5 hr. a
value- (,( lrrt'spollt l i ll ~ (E(I. 7) to a hal f-lift, of 5.0 IlL TI ll' II1t',lII n 'sidl'II("t, time (,(lIl("t'p t is
Iu rtlu-r di S('us ~'(1 ill Appcndu I- I>.

rune to Ream Plateau

A dday alwlI)'S e xists 1)(,t\\'t'(' 11 the sta rt of an infuskru an d till' t'stablisllllll'llt u f p lateau.
The sol(! Iacto r l"l llli mll i ll~ the approach to plateau is lht' hal f·l if(' of tilt' t l m~. To appn-ciate
this point. consider a sit uatio n in whid l a IMllus dosl' is ~\"(' n a t till' sta rt of a con stant
lufunon to illlJll('lliatt'ly a ttain th e amount adli('\ '('l l al plateau: clearly. tlu- si11' o f lIlt' hu lus
d ust" m ust 1)(' Au . Thereafter. the- a mou nt ill till' hody is maintained at IIIl' plate-au \1llm'
II)' constant infusion , ImaWlll' thut a w ay exists 10 moni tor separately dnl~ f(' llIai n in~ in lilt'
htM)" fm m tilt· bolus a nd th at al'l'1l l1l ll lat i ll ~ dill' to tln- Infu sjon. TIl(' events are d l'pid t't l
ill Fif{. 6- 1, I> m~ in tlu- hody ll"~l(..lated with eac h II11 Mlt, of ndmim strut ion is l'Iim illa!l't 1
ll~ tl l(Jll~h till' other were not p n-sent . TI.t' amount ll"S(M :iatt't l with til(' hulllS doS(' declmes
l"xpollt'nlially ami al any time,

Amount remoini...... in tne A e _..

'" l;I
body from bolus dose
•
..
•
9

However. as lon~ as tln- in fus ion is maintained. thi s rk-cluu- is <l lwa~'S eXill11y lIlaldll'tl by
 71

til(" ~ai l1 n '~lI lti n~ fm Hl lilt" infus ion. This mus t ' " " SCI siucc till' slim a l\\ll}'S t'(l"ills lilt'
amount at plateau. :lou ' It the refo re follm\'S that the amount in tile boJy a.~~.odall"d with iI
constan t infusion ("""nil is ill\\l l}'S tln- d ifTt'rt'lll "l' hd'w{'('11 tht· a mou nt a t pla teau (A ,.) lI lId
tilt' ;UllOIIIlI rt' lIlai l1i ll~ Frmn the holus dust", namely.

A ,,,1 _ A .. - A .. ' \9 - " 10

O r. hy d i\i tl i ll~ t hmll~" hy till' vnhmu- of d islrihlllioll.

.... ...;
C"" - C.Jl - . -', 11

Thus. hulll lilt' umouut in tilt' hotly illld IIII' plasma couce nt ranon (e ho/) rise a.")·lIlpt oli{~dl1y
to ward rt'spt"t1in ' p latea u values follc)\\ill)tconstant- rate d m~ infusio ll \\ilho ut a holm. dUM',
TIll' ;111I0 11111 of t1m,g in t 11(' l)lMIy. Of plas ma couceutrutjou , t"X pn.·ss.t't1as a ))(·rt",'1I1 of till'
plait-,llI vahu- at difh-n-ut limps after initiation of an infusion. is shuwn in Tabh- 6-2. In I
half-lift·, tilt" vuhn- in 11ll" htM.ly is .')0 '1 of tho plateau value. In 2 half-Ih '{ 's, it is . 5% o f tln-
plah';l11 value. Tln-oretically. a plate au is only n-acln-dwh en tIll' d nl ~ has 1M."l.·Jl infllSl"l.1 for
a ll infinite III11nlM.·r of hal f-lin 'S. Fo r pracncal PlI'l)( ISl'S, howt'\'{ ' r, tht· plan-au lIlay he con-
sitle ft'1l lu I M.~ rt·adlt"l.l in 3.3 ha lf-lin 's (90% of tilt' platea u ). 1111lS. the sho rter tilt' !lalf-life.
tilt' SCKll\(' r is tlu- platcuu n-achcd. Fo r example, I- I'A (haIf-lift· o f .S mill) n-aches II p b te au
within minute-s (3 .3 I.alf. lin ·s is 17 min ), wlwrt'il.s il tukes 2 to 3 \\'{'(· ks of cousta ut phenobar-
lutal admlrustration (ha lf-lift, of 100 Iir) 1M.'fo rt, tilt' plateau is n-ached (3 .3 hlllf-Ii\'t'S is 1-1
da ys ). 111l' important point to rememlx-r is that tilt' approach 10 pla teau depends .~ Hf'i!J o n
tilt' Imlf-Iift, n f tilt, dOl~. Fur t''(a mplt',!''''(-,lIlst'' the half-lift' o f t ht'1lphyllillt, in tilt' esamph-
patit' nt is 5 hr. il must I"" Infuv-d fo r 17 hr before plateau is n-acbedTlus is so whetln-r
flO mwllr is infust'1l to ma intai n a plateau conceutratiou of 15 mWJ. or t he infus ion run- is
hak t"l.! (30 mW'llr) to maintai n a plateau concent ralion of 7.5 mWl... In 1111' fo nllN case, tilt'
t h''11phyllilJ(' pllLslIla coucentrutfon at om- half-Iifl' is one-half th e co rresponding pl ate au
"ai m' of 1.'5 lllWI•. So. if O lll' want ed In lu:hit"\'t.' a p latea u concentration o f 7.5 IIlWL ill 2.5
hr. 0I 1t' woul d infuSl' a t a rate o f 611mwl lr fnr I half-life a nd then maintain this couceutration
hy I mhl l1 ~ tilt' lnfusum mho In 30 mWllr.

Postiafusion
Afh ' r S I(Jppi ll~ an infusion . tilt" amount fa lls hy one-half l"d(:h hal f-lift' . I lltlt't.'11. wn'n unly
till' <It'1:linillp; vahn-s of a drug. one cannot d "llfly deduce whether a bolus or a n iufunon
h.LS1"''t.' 11 Wn·lI. III Ihe '''tampl" of tllt'o pl l)'lIillt" H S 1Il ~ are in tilt' luJy at pla tea u follouln p;
an infus ion m h ooffi() mwl lr. Ap prm:imatd )' 17 !1r (3.3 1IaIf-lin ·s) after slo pp inp;the Infusio n.

,
c..
0-2. P.rc••• ef the ""..... Le....._he4 .. V-'_.
I.....I_ .. ~
tI_. f.U.wI. . .

"'"
1... 1.,Il...,j .....'"
PfKIMQf

05
2
I '"
50
75
3
,
33 "
90
Q'
5 Q7
6 Q'
7 QQ
72 CONSTANT -RAT'E iE ~ NS CHAPTH o

only llIw-tenth of the plateau vuhn-, O f 43 Ill~. n-mutus in ti lt' hody. 111t' SOUl II ' amu unt of
d n ,~ would he found in tlu- hndy Ii hr aftt-r an i.v. bolus dost, of .t2S III!{ of tht·ophyllilll"
Aftt' r rt:'1!l("inf; SO IllI' transdermul constant-rate rd t'iL'>(' dt... k t·s, dn l!-: {'o llti lilles to hi'
n ·lt'il,>(,(! (m ill h indillV; silt-s in sk ill fo r a p p reciabl e pe nolls o f tune. I n ,!JeSt' in sl' IlWt's. t he
plasm a dnl~ {'olll't' nimthm falls mo re slowly than afte r sluppinv; an i.v. Infus ion.

Chonging Infvsion Rates

The rate of infu sion of a d ntv: is somet imes d ,anV;t'tl du rin!-: 11lt'r.lpy ht '('llll'W of e Xl'( 'S Sh l'
lo'(kit)' (IT au illal!t'(luatt' therapeutic n 'spOIlSl', If ti ll' object of lin- dlilll!-:( ' is to d Ted . a
uew plat ea u. then Ihe tinlt' to ~l Irom ollt ' plnt euu to anoth e r, whel llt'f hiV;I11'TIl l' JOW I·f.
dt'lwm l~ .yo/e/y un till' half·lift· of the dm,g.
Conside r. for Illustrative purpO!;('s, a path-n t slahili:f.t'i.1 U II ;l 3H' IlIWh r infusiull run - of
t1woph yllilll'. which al'lunl ing In Fig. fi-3 should prod ul'(' a plateau conccnrr anon uf 7.5
m wl~ Suppose rlu- silu at io n now demands a plateau t"llllt"l' n trati u ll of 15 mw'l•. l 1tis 11(,,\\ '
plat eau value is achieved by doublin~ tht, lufuskm m ho tn fin mW'!tT. I lll a~rj l\t· thai inslt'ad

c 15
0

~
"
:c:l
u
0
10
~~ ................. " ..," . -
>' E
~
~
-
0
~
~
5
~
~

E
~
~
0:
0
0 4 8 12 16 20 24 28
Halt-lives

. ' IK. fi.-3. Sil""U.." III".lr.. li"" Ih.ol tI,,· ti".. , I.. ....;00:10 " ,.._ pL'I"" " . ",1H11...r I>i~lt' r " r lr"",r It,,,,, 11"' 1'''''irHI'
10.,....,.."
.-..],It· . • ''' 'I)' . ", tI... l....f.l;f.. uf" dm lit· A pl"I""" t"'I(~·" l rati..n .. f' oS m:o:t1 , i , "";00,1"..1 i " " pp m\imall'I)
3.3 tl"'f· lln~ .oft,' r ' I"rti"jt .. t"",.t ;u,1 i"f",i<H' uf 3fl mw1,r uf t11t~ 'I'I ,~ I1 Il"' . Ilt ",hh,,1it II... I"f" ,it ,,, r"t.. i' Io~.·
nW" hulIilllit :Jl1 mw1,r (tlo. ltlt..I I.w..·!tli'It·) ;llKl ' I"rtinlit ;ultlth" r t" ",lal,II " (,,,it,,, nf 3flllllit/l> r (m l"'l ..1,Lt.. I.."l lil" ·).
In "l'p nl\i """" '1)' 3 ,3 h.oIf·li' " . tI..· 11""'I'I,yl1 il... t~ ..It~·" I""lit .., ri... ... f">llI' .S "'Wi. I" IS "':o:t1. 11..t.; " Iit " n inf" >it,,,
....1.. " f fiO m~ r i, lUll'!t'l(t 1m I" ,1' W nlit tI,.. 0" 1'I,1t·""·" 1....,.· 30 llI~r inf... it,,1. 11..· I'Lo.. " ", t"' K~'n lr"I i<", nf
tI"~ 'rh~~lir ..· "P'l'n>••d ..-s ~ pI",•.•", " f 'i.s rnWl. in "1'I'" ,u m. "'I)· 3 ,3 h.:lf·Ii...\ ,
 CONSTANli ATI ~(;O.'tiNS 73

of i ll(.'n·a."in~ til(' in fusion rate. tilt' atlditional ,'30 mw'hr .....as adnnrustered at a d iffl' n 'nt site
and that a \my existt'11 of S('~lI'<l tdy moni toring tht"()ph~1I i nt' in the body From till' two
infusio ns. 111t' t'wnts illustmlt'(l ill ri ~. 6-3 shoe.... th at the theophylline coucent runon as-
sol'i;ltt'(l \\i lh the uew illfusion \\i ll r ise to 7.s mWL in l'ud ly tile sallie time ;L" in the fi rst
infusion: half the plateau conccutra ncn (3.75 mIQ'L) iu OUl' eli mination hal f·life (5 hI' ) ami
so O il . Adduton o f this rising conccntrunon to the prl'-t":dsting plateau couceutrattou shows
that till' half-lift, is tilt' .~"J(' dcn-munant of tln- tinu- n-qutn-d to go fmm 7.5 to 15 mIQ'L.
Xr-edh-ss to 'illY. •IIlYreadjustment Iu the Iufuston rate ill les s than 3.3 half-lives IIw a llS that
a 1It"\\' plate-au coucent rat jou wtlluot lit· t·stahlisht"(l.
111t' d t"(:!ill(' Imm a high plateau In a low om- is Iikl,\\; S(' n-lan-d to the half-lifl' , Cousuh-r.
for example. tilt' (-'\'t-'nts after stopping III(' suppleme ntary 3O-mW'lJr infusion mh odis(:usSl"(1
previously. l1 u' theo phylline concentratmu associated with this supp lementa ry infusion will
£111 tn half rln- exi.st i ll~ value in I half·l ifl-'. In 3.3 Imlf.liws, the tot al concen tration \\; 11 have
almost n-tumedto tilt' p n '-(-'.'(isting 7.5 1Ilw'L concentration. Also, it will take another 3.3
half-lives for most o f the tlwuphyllillt· to lit' removed from the body 0 1l1'C the oriWllal 30 .
mw'h r infusion is slopp('(1.
A lI (· ~lI l1pll.' of the dlaTl~e in plasma cnuce nt ration 011 dJaIlW II~ from on(' infusion mit'
10 anot he r is a~aill dt'lllonstrah '(l hy dat a on t-PA in Fi ~, 6 ...... 111l' half· life is thl' deter-
minan t of tilt' spt'('(1 of att;ti Tlill ~ tln- 1I1'W stl'ady state. C leardll(.'C de termines the stl'ady .
stah ' coucentrancn.

Bolus and Infusion

It takes app roximatdy 17 h r of coustaut infllSion of theophylline befon- till' p late-au con-
cvntranou is reached. An ('\'('11 1 (J11 ~(,( lim e is req uired for dm~ wi th hal f· livt's greater than
thai of theophylline. Situations sometimes dem and that the plateau he reachedmore mp-
i<U" . Figure 6-2 SU~l'Sl.s a solution, 111al is, at the start o f an infusion . WW a bolus doS('
equal to the amount d('sil'("(l in til(' hod y al plateau . Usually the bolus dose is a therapeutic
do ",,-', and the Infusio n rate is adj usted to maint ain thl.' the rape utic [eve]. \ \ 11cn till' bolus
du "t, and infusion mit' are (,.~ad ly matc hed , as in Fig. 6-2, tlu- am ounts of dmg ill the txxly

600 •• . '11(. 6-4, 11,,· r""'~'n.a ('O'l('(' nlr.ltiClllof

• • rllUrn i"'~"n ;O.:tin,lo , (I · PA) . I .. rl! ..I
..1""'1 .).'50 IUl m l. ( 1.2 J.IWm l.) ;0,,,1 ""I'"
::; •• pn-11t"S p!at....u ,,( S'iO IU/m l. ( J. ~ I'W
E • rnLl fotlt...i nl/: Iln 1.\'. 1" >1,,. of 10 "' II: a'KI
a t'OIulanl-r•.r.. infll, ion of 1,6 mWmin
~
c
400 fur 611 min Itl lUI irKIi\id ll..J ~1I1'jt,,<1 . Sui..
2- ' '''l ur nt l)', th r plum a ("<)nN' nln li " n

,.
c
.e dn'l" • • Ih.- dn. ~ inf" . it... i••10
III 0.3 mwmin , n... lim.. fn " n II finl
1

"
",•...J,. •Ialr 10 Ihr ..'<.'(_1 ,Io,,,·,ltl. " "
~
u 200 II,,' half·lif.. of lho.· d nL~ 6,6 min in t1,is
c ." hjl 't"l. ( Lpt..d fmm K".tt·r. It \\'..
0
'-' Collt'n f .. Klnft. C., Ka.<l"" r, F,J.• \-an
• .It-r \\,,,,,w , P,A_. Illltl \\'(';ll l...ri}·, B.c.:
• • ",.. p!uom"•.."tri'It'lx, of <It".h\to.duUn I ·
PA (dUb,..........): t:IT 1s ..f 1" >1" 0 injt-c.--
o lio n, in flloi"ns . and Imi ni.' ral inn 1,;.-
wri~'hl ill potllrnh wil h 1Il)-. ..... n lial In -
o 90 180 270 fan:1io.... Clin, Phannao:-nI, n...r.5O:26j -
Minutes 27i. 11191.)
 CONSTANT-AATf REGWlNS CHAPTER 6

a, sot'i ah'(l with th e two 1Il1)(It·Su f ad mimstranon an- (:u mpltollw nta ry : til(" ~ai ll of (JIl(" olTst"ts
t he loss of t he ntl lt"r.
Sow t'unsid N IWO sit untbms. TIlt' first . SllH" 11in Fi g:. fh'5. is 0 11(' in whkll di fTNeut bolus
dllS(°S a re' gin'n a t tlu- sla rt of a co nstant-rate in fus io n . In C,lo;(° A, tlmg is i ll fu~"li alom'
a nd till' amount ri ~'s . rt',lt'h i n~ a plan-au of 2CX) m~ in appmxim:lh ']y -I hal f·liv('s. In C:lo;('
H. tilt· bolus tlOM' o f 2lX) m ~ tmnu-dtatcly all ains. aud ti ll" infusion mi l" tllt"ft'altt'r maintains
the pla teilll amount . In Ca.'il" C . tilt' IMIllIs doS(' of .fUO IlIg is e xt't'ssh 't'; lx-causc till' rate of
loss is initially Wt-°alt'r th an the' r ate of infus io n. amount in t1 uolMMly falls. T his fall {,(lIIlilllltOS
until the sallie p latt'au ll' ill Case B is 1'('.\(:h('(1. It Sillmid ht· lIotit't"llthat till' tinit' to n-ach
tht· plateau d t·Jlt·ntls sol ely o n t he half-lift· o f the d rug. '1111ls. in CaSt· C at I half-life . Jun
1Il ~. t'tlllllltlS('(1 of zoo 111 ~ n ·lI1.uning fRIIIl tilt' IMllus ami ]OU mg Imm tlu- infu sion. lit·s
midwa y htOrn"("I'1I rhe bolus do w anti the pluteuu value. By 2 half-lives, ti lt' 2.5n lIlg ill lilt'
IM)(ly lie s 7.'5% (If tilt' \'~IY toward lilt' plateau. By app nn:ima holy ·1 hal f-Iiw s, Iilllt· of ti lt'
IMlllls dose remains a nd til(' plateau is reached . III C lSt' D. tilt· IMIllIs doS(' o f lUll 1I1 ~ is
below tht' plateau amount . B ( '('U llSl' ti lt' mit' o f lnfnslou !l OW t'xt't'('(ls the rlllt· of dOlI-:
e-limination, ti lt' amount in tlu- hotly {,(lIItinllollSly rises unti l till' S' U Il I' plateau us ill t!le

0; 400 Case A 0; 400 Case B

oS Infusion Alone oS 200-mg Bolus
~ ~
~
0 300 ~
0 300 Plus Infusion
'"
.5 '"
.S
0
0
~
200 0
0
~
200 "
",

0 0
"0 "0 ,,
»,
C 100 C 100 ,,
,,
..
0
0
E
0
0 2 3 4 5 6
.0
0
E
0
,

0 2 3
....

4 5 6
Half-lives Halt-lives

0; 400 CoseC 0; 400 Case 0

oS 400-rng Bolus oS l QO-rng Bolus
~

~ 300 Plus Infusion ~

0 300 Plus Infusion
'"
.S
-, '"
.S
-,

--' -- --- -
0 0
2 200 2 200
0 ", 0 ,
"0 ,,
,, ' .
"
"0 ,
c 100 c 100 ,,,
,, 0
'.
,'.
,,
0
0
E ,, 0
E '" ... .
-e ' " . ... -c 0
0
0 2 3 4 5 6 0 2 3 4 5 6
Halt-lives Hall-lives

. l lt_ 6-5. Silll",lk..u il1l1s1rMI ,,~ I",", tI..· pLot...." .lol .·'Kb "pun tI... iur" , kll' r.... · ""KI "ol "p. M' tI,.. il1lli41 lo"tll'
' ~ "'l'.\\110:-11..-r iI I.~,~~ .w....
lo leh ..n (c a. B. e . D) u, nllt «:...t. .-\)
al II , I",rt or II... inf",klt" 11K' ",,,,,,,,"1 of
c1",~ in tI... 1••1" "'I II..• r b " "UI il l h., mt· . ",.. ,"'.. .. "'1 uf tI... 11l ~ 1I' , n ·",..iniult in tlK' ,... 1)- ,.....];,,,..
t"Xf""wntial1~' (----) hill· tlK' lInKlI lIIl KilIl..d " illl i" fn,io:ll' in all , ri ,-,'mplutio::,,11) 1,,,,·,,,,1 plat...."
( . •d or ),;<> prnt "od I ~' c · .-\. I" e n.
11. e . a,.. 1 II..• .>1...·"',,1<~ K"~·lll r..I..'" (_ _ 1 I, tl..• ",'" <or
II.... "",,_\ \1Io:'n Il1ili.o.ll)- acl,i< l it I..k "'ppn.l1i,m'h·I)' 3.3 half·li
' Kit tu n ·.. pl"'I"a ll «(:as<" .\. C. I)). S ,It.·
a.I", in ea...... A. e. "'Mil> tlMI at I h41f·lif,· allK,,, ,,1 in tI... lu l)-II... mid ay I ~ ..·" illihal ;.11I1 pL... .",,, ,,,,1,,,-,
CHAPTH6 CQNSTA!'lH ATE ~EGWl NS 7S

pn -viouv ( ';N ' S is n-ached. O U( '{' again tilt' time to approach the plateau is controlh-d so lely
bv th e hulf-Hfe of the drug.
. Cav - IJ is dt'monstr;ltt'l) by t-I'A in Fig. 6----1 , TIll' holu s dust, o f 10 mg \I. -.LS insufficient
10 attain ti lt' stt'ady state achieved 0 11 infusing 1.6 IIlWmin. 111is result is expect ed fro m tilt'
6 .6 min half-life in this patit'u !. us lilt' " mount in till' hotly at plateau (ll./kl is 15 mg.
In tIlt' sec ond am i mo rt' comm on situa tion. t1epit1('l) ill Fig. 6-6, the sa me ho lm dost,
am ! infusion rate art' <Idm inish'R"t) to three patients, A, B. and C , with diffe rt'llt d t'araJwI>
am! 'l-sso(·ialt'l l half-lift, vnhu-s . TIlt' half-lin'S ill the se- patient s arc 3, 6, and 9 hr. R-Spt"t.'-
tiH'ly, AIl);llic'uts start \\; th tht, same amou nt o f t1nlg: ill the bod>'. In putieut B. this amount
is main tained be canw mtt' o f infusion is exactlv matched bv rat e of elimination . SilK"
I'lim inat ion is slowr- r. ti lt' amount ill patient C rises until rate (;f ehmlnatton ('(Ilials infusion
rat e. Th e finn- to reach this lugher plateau \'alm' is go\'e nl('(! St,ldy by the half-lift' of tilt'
d rug in this patit·lIt. Thus. hy I half-life (9 h r). tilt' amullnt of d m g ill p atteut C is midway
lx -twee-u tlu- bolus dost, anti th at at plateau . By the ti me the plateau is reached. all the
ho lus doS(' has be en ellmtnated. Also . it follows fm m E(I. 3 th ai for a gi\l'lI infusion rate,
amount at plateau is propo rtional to Ihe half-life . l1tis is see n in Fig. 6--6. wln-n- amount
in p<llit'nt C at plan-au is 50 1l lIigllt'r than that in patient B. Patien t A ellnunates the clm g
mo n - mpid ly th an tlOt'S patien t H. A("t' ln.lin~I)', the amount of drug in p<ltiell t A falls until
a new plateau value. ollt,-Iullf that of patient B. is reach ed. As alwa ys . tilt' approach to
plan-au is ~()\l' ml'tl so ldy hy tht, half-life, which ill pancut A is only 3 11r. TIllis. by 3 hr ( I
hal f.life J, lilt' " IIIit' !J1l-~ Ialk-u SOlI, of tilt' wa>' toward tilt' plateau. and by 10 hr plat eau is
n-acln-d.
111t, apprcl:leh to platt-;1I 1 t1l1 rin~ an infusion has been p resented so far in terms of tlw
time rt'llllin'(l (0 ~u from tht' initial cono -ntration (amount) to tilt' plateau. TIlt' lime to
n 'adl any vahu - on uppr oach to plateau can ht, dd e n ninetl by t''OlIIbining the pri nctpk-s
"I n.';ldy It'aOll,(1. Ht"t.·llllthat plasma cnucentrurion after an l.v. bolus clost., is C = C(O),- -l,.
TIl(" roucent runon n's u l ti n~ from a constant-rate infusion is gi W Il in Eq. I I , As each t'\l'nl
is imh-pe-nck-nt of tlw other. by Sll lll lll i ll ~ th eSt.' qeautmcs . one obtains co ncentration at any
tim e du ring an lnfuston. Th at is.

12

For e-xample. if tilt' initial vahn- is 500 J.Igft., t!le plateau va hu - is 100 J.Ig/L. and th e ( ' UII -
ccnt ranon to 1.(' n-acln-d is 110 J.IWL, then tilt' ttm e to reach this concentration ca n 1)(·
caleulah'( l a-s flllltJws, Ht'arran";ll g Eq, 12 and laking into account that ( 112)" = r - 1, (C hap.
3 . p. 23 ).

13

Suhs tituting for (; (0). C.. and C int n Efl' 13 yi elds (IIi = 0 .1l25. Snl\; ng for n, a eouce-u-
tration of 110 I1WL is n -achrd in 5 ,3 half-lin 's.

Pradicallssves
So far, tilf' appn l:leh to plateau has lx-en consfde n-d iu ahsolute terms. Pract ically. it is
lu-lpful to t'slahlish a tolc-runce, such ;L~ ± 10':1, for tln- final value. TIlt" HIllt" n:,(pliR't1 to
hl.' within this toh-rance "arit'S with tile sta rti ll~ and final \lIlut'S. 111is may lit, seen I,>'
application of Eq. 13. For e-sampk-. if onebegins at 80% of th t' final platl'all, th e Iillle to
rt'at'h tht' !fJ\\l'r limit o f tolemnl'(' (90%) is on l>' I half-lift' , III (, mtrast , if the st arti n~
t"llll('l.'n tration is ,50nC! of tilt' final \..tlue . it takes 5 .3 half-lis'('s to n:'aeh tilt' lIppt'r limit of
7. C0N51ANTv, rER[GlMENS CI-W'tH 6

300 Patient A
Halt-lite Shorter than Expected

200

100 ---
,,,.
·, -
,
o
Patient B
Half-life Equal to that Expected
~
'" 200
S
»: --
."2
o ·· ,,
,,
.,
° 100 ,,..
<5 , ', ,
,,
E
is
. . ...
!i 0 -I------.-:==~--~

Patient C
Half·life l onger than Expected
. ,,, -----
300
"

, , ,-
200 ,,,
,
·' J ,r
100 , ,,'..
,,,
,, '" ....
o
o 24 48 72
Hours
tl lC. 6-6. """.." .. ,,~ iU trMlIlK II.... IIw .moM,"! at ~ .. a" ... ".....t. ... ....Ir·lif.·. nit· ...,.,,,' I"J ut J._, , l
.. " ,\lMlI mf....... an- "" 'n [""'liMllo A.. K. .... I C . ",Ih l....:Jr. In." of J. 6, Afld II I.", ""1'"1'.... 1y \ h.....p;t. ." nl
"f t1NJt in II..• inotl<ll l.. ,j.~. i. II ....,. I2IMl "'It) In..n til,,", poot....'h m l in , .... h<.t,.. at , JOLot..au d.fTf"RIn
,Ln 'l1 !',.., ,,,,, I .. Ih."if n"'l 1J\~ (·1"'", !\ _
..ol oil.... 1. 01..0 do: 'UI>( (. • .) .. 'ilh hn ..,...,od> on
Ii incb. " t half-lif .1 tI ..· Iiil> .""lOInl in tbe- ho ..h '""' I ..'lh lhor n",",-,,! Inr ( I. Onlv
.. f , ,.... "I ~"" i. m"' Ia.oI.~ fNttt.rd ~ nt.. 01' inrll"'''' ~ d pa.t u in ' ..1:-· atlal 1 and ....d
(polO , HI, (1oI1..•.....,_ onl i n lho- t... ~ (- - -1 (iw>~. w,tiI..ftrr -rP",.j ~' 3.3 t..Ir·In.." plal ll k
..........I IJ"'4'....'h .' AlMI C).
CHAPTE ~O CONSTANl-AATl: ~NS 71

toh-rance. I){~ of the final \01l1 lt·. Al'('('plin~ a tolerance clea rly modifi es the statement:
TIlt' lime taken to rt'ad. plateau is ddt'nnillt'tl solely by the half-life of tlie dnlg, Now " ol li
!II(' initial and final values must also bt, l'llllsidNt'tl.
TIll' constan t-ra te n-leasc ~"li le mS marketed ma)' contain a Io.ltlin~ dOM' 10 facilitat e the
mon- ntp id ad .it'\"l'lIIt·nt of th("ntpt'utit' l'llllt't'nt rat io lls, Ad minislt'rt't! extravecularly. how-
ever. with Iln- addilional absorption stt·p, the att ainm ent of both the-rapeutic concentrations
and platea u wtll Ilu-refn re he 1001~t' r, alt hou~b perhaps mcouscquenttally, than that fellow-
i n~ all t'(llIi\'aleI11 L\' , regi lTit'll.

ASSESSMENT OF PHARMACOKINETIC PARAMETERS

Pharmucokhu-tlc parau ll'tt'l's are gen erally ddt'nnined just as rt'mlil~' from constant-rate
dat a as from L \ ', ho lm data. Ct'rtoullly, Ihis is so for an i.v. infusion . Foll{)\\in~ the IISC of
constant -rai l' rt·lt,it\(, dt'"tees ad nums tc red extravascu lar lv, uncertalutv exists about hi oavail-
ahilit)', whit,h the refon- requi res refe rence to t.v. data . S~lIt·tlll'll'ss, I;ow estimates of pilar-
lIlat'Ukillt'tit' jliir<Ullt'tt·rs an ' made is seen hy l't mside rin~ the p la.s ma com-entrattou data ill
Tabk - 6-1, obt aillt'tl dllrill ~ ami afh' r an is . infusion of a drug.

Plasma Data Alone

Co nside r, for rlu- 1Il01l1t'1l1. that measurements only dllrill ~ the infusion an.' amilahlt,. \\ 'hut
can 1)(' t'stiumli 'tl?
Finol. d hidill~ tilt' infusion rutc of 40 mw'hr by the plateau ro nc eutratiou of 9.5 mw'L
~ws ch-ara nce. in this (';.L<;(' .f ,2 LAIr. Indeed , thts is Ihe preferred met hod for t'St i mati n~
d earallt't-' Si lll't-· tht' plate-au concent ration can be de te rm ined with ~n.'at p reci sion byav-
t' r;\~n~ those l'tllll't·lIlr.ttiollS that dt·arly lit' al plateau.
Second, the Italf·li ft, is t'it\ i1y ascert ained. being the ttrne taken to reach half tilt' plateau
coucenrranou. !I()\\·t...v r. ill this example and ill most cases, no sempk- \\1l\ taken at tht s
tinu-. and s.() mu- mus t interpolate lx-tween the observed da ta. TIlt' half-lift'. estimated in
Ilus maum-r. ( Fi~. 6--7), is appr oximately 1.5 hr. A mort' acc urate met hod of t.'Stil1lalill~ tilt'
half· lift, li st' S all tilt' datil ohtaillt't l durtng rlu- infusion. O n n.'arT'dllgi ll~ Eq . 11, Ollt' ohtains

T.~" 0-3. Pi..... e.-............ ., .. ~I hrl.. , ..... After. c._...........1...

(40 M./hrl fer 12 hr

mA TMl'NT ()I 0.0.'.0.

C).mng mlu.sioo

,,
I 33 02
s.a
70 "0 '
i. 9
o
10
, 87
93
90
0'
- 0,1
95 00
",,
PCJ:S/,nlu$ion

"
,o "
0 .76
0 ,33
10 0 . 14
71 CCt-.lSTANl-iATf if(;W,fNS CHAPTH o

e.. - Cinf _ C.. · e - k, 14

which upon l aki ll~ niltll r.ll lo~~a ri! l lI lis yn-kls

In Ie.. - C;n.1 = In e.. - k· , 15

11l11S, tilt' tlt"'Clim' o blai llt"'ll 11)' p lultillg St'lll iluv;aritiullit~llly tilt' d ilTNt'lIn' hl'lWt'( '1l till'
plateau conceru r auon and that at l'ar lit>T tunes a}!;aillSt tilt' l'orrt'sp'llltling lill ll' should he it
str.Li}!;h t Jim' , TIlt' iIlI N l 't'pl a t till lt' zem is the- platt·au l'u lI("l' n l ra l iol\ (C.,> ami tlu- s1npl' is
- k. TIll'S(' differences in conccntrauou SIIl1\\1 1 by vertknlHnes in Fig. 1}...7. urr- presented
ill Ta blt' 6--3 ami haw la -cn p lutl l',t1 in Fi!-t. 6-8. Tln- dura illdi(.-a h' a Ilalr-Iife of 1.7 IlL It
sho uld 1)(· I\utt-d that t h.· ]01I}!;l·r tilt' infusion, tilt' c1ost'r the conc ent ration is to tilt' plateau
value a nd til(' ~rt'lIIN is til(' error i ll ti lt" diITt'rt'lIt, - nu-asun-ment . G.·III·mll)'. d ilT<"r\' Ul ,,{'
values calculated frum ceneeutra tions ht")Ul 1d gO'}. uf the plat euu haw l'\l'tossi\l ' error.
La st. tht' \,olt.lIlt' of distriliutfon is e,,,,k-ulah'tl kll0\\i T1!!: d ,>a"'IIIl't>and half.lift'; ill this
C'll"t' it is III L.
CUllsidt>r IInw tilt' concentration data at ami aflt'r tilt' end of Il.t' infusion. I'lolt i ll ~ t1 1t'st"
dat a 0 11 s(>lIl il( ~aritl l1nk- pape f also ~\'t'S a st r.u~l l t li l1e , (m ill which half·life l,<III I)1;' eh-te-r-
mined. since aflN stop ping till" infusiu n

ti lt. 6-7. F..Um"IiOl" OIf I".....na.-

l'Okh,...t it· ['4r" l1,...t('o f",,,, phu ," .. _ _ 40 mglh r - _
,L l;! , llI ri ,,~ .....1 "fh" a n .""a,, t in- 10
rU~iOlIl . The- \~-rtic".J 1ll11,..... "l'~'lIt
tI... ,bIT,·n" ,......... -tl> " l~" ..~·"t r;. · 8
li.." s ~ plot...-"u and ,oI ·" "I.I,,rill:(
tI... lufu.j.. n. 6
4
2
o
o 4 8 12 16 20
Hours

Flit . ~_ S.·"'il"\>tMitlllnic- pl..t (If tl,,· .IiIT,-n-n...- 10

I_I l,,-twt..... pL.t,~"lt c.lm :( ..." ..~..,.tr"h..n lU>t1 !Iw • (C.. - C) during infusion
" 1,....,,....1t1 nriult 11,(' inru,i"" """i n, t tim ... Als.. 5 o C postmtuston
pl"tt...I",... tl..- , It·dini,,~ \'...t, .... of pL..\lIllt dn'Klu .,
n'tll r" titltl (0) "'Pins! tiu.... "f,,·, " ' 'I'I"nK 11,,- infu.
, il,,1.
2

0.5

0.2 •
0.1
o 2 4 6 8 10 12
Hours
CHAPTH 0

C "C.. ' e - t , 16

\\11t'U t !le~' dilt<l un - so plnth'(I, tllt,y an - nh'i('''l,'tl tn sll(lt'rim(lO'i(' 0 11 til{' pn " iu lls di fTN -
datil l Fil-t, 6-'\ ), I II tl l{' l>ilrt il'ub r {·'t<lmpll· studn-d , tllt· llalf-liH's dt'lennillt't! from ti lt'
1'11('( '
rb i ll~ aud t1t'dillilll-t l'U"'t'San' t'(llml, (x1.'asioually t!ley difTt'r, Ihen-hy i llt l it,t1 i ll ~ thai dm~
d i spt ~ il ioll hils d l<lIl!-(I '( 1 UH' r tilt' I"lt.'rintl uf study.

Urine Data AJone

If (t'ual dl'aralll,(' is cons tant. tht' mit' of t'X1'n'tinn is proportionul to tilt' plasmu couccn-
tranou. Tlu-u excn-nou run- data can ht· tn'alt'tl in a manner anal ogollS 10 that of pla.slIlll
data, ami t'st im alt 's can 1M.' made (If d im ina tion Ilalf-lift, and fr action t'wn'!t'tlundmngt'(l
(f d . Au t'stimalt' offf' is ohl aiu t'(l at plalt'illl From

Fe _ 11:0le 01excretion 01pla reou

17
Rote of infusion

!»t'('iIlN' lilt' rolli' of infusiou is t' llial to Iln- rolle (If d imin;t1inll, Fur example. wllt'll tilt'
infusioll mtt' is -10 lIIWhr. tlu- ollM,,,,t'tl c scrcnon ran- at plateau for tilt' d nl g is 12 IllJ~/hr,
so fi' is 0 .;3,

Plasma and Urine Data

\\'i1lumt pLl.s lll'l data. values for volunn- o f t1istrihlltioll and c!t'ar,U1I"{' 1,lImnt II(' ('stim ;lt("(1.
\\ 'lu-u hnl" pl.lsm a and uriur- dala an-obtained, renal clearuncc mu ll(' estnnan-d in add itioll
to all 01 111'1' pharmat'okindit' 1>ilr.lll1t't t'rs . .\l on '(}\'(·r , a steady-slatt' experiment adlil" 't'(l
\\ith t'u ustanl infllSio ll is 1111' pn'fl'm'tl method for ('stimating renal clearance. At plateau.
al'(1lralt' ll\t"ilSU(('lI\t'nh ran II(' nmdl' nf Il(lth plol"ma coucentrauon and urine excretion
ratr-. In tlu- p n 't'('tlilll-t t'xamplt , n -ua l clearance. obnuned by t1i\idin~ excret ion rate al
plateau by C" , is 1.26 l Ai r.

STUDY PROBlEMS
IAnswers to Study Problems ore in Appendix II,}
I . Which 1 me or mon- of tilt' f(lllo\\ill~ statemen ts pt'rtaining to 1111lslant r ate infusion is
11Irrt1-1 :-'
a . TIl1' tilll(' to n-ach a p!;ltt'au concentration depend s U I)llII lIlt' rate of infusion .
h . :\ 11 dmgs I l a\i n~ tilt' Slllllt' ck-arano - reach tilt' SOUl I( ' platt'olll concentration when
~\'(' n at tilt' sanu- is , infusioll r ate.
I', Dm~s \\i tll tht, ....uu e clearance J!;t'lll'mlly reach tht· plateau con centration at th('
sa me tim e ,
d . TIl{' ' U lll lll ll l of dm~ in tln- 11Ixly ut p lateau cannot he Ihl' sauu- wlu-n drugs wit h
tlifTe n 'lll ck-umno- Valll('S an' infused itt the same rate .
I ' . :\11 of lilt' al li In' .
f. XOllt' of tilt' alllM',
2, For prt'lloll~t 'tl slI"";I,itl prt:lt1'lllln 'S, Slll'l.; nyld mlint· d llo ritll' is ~\'t'1I hy i.v. infusion for
xustaim-d mu scle n-laxation. A typ ical initial dow is 20 IllR fnUnw('(! b)' continuous
inru sion o f -I mWmiu. T Ilt' infusioll mllst II(' indi\itluali7.t'll lll'l.M dUSl.· or variatinu in thl'
killd il'S of Illt'laho lism o f slIl'(; m -!t-holim' . Esti mate tilt' r-hmtnatlun half-li\'('s of sue-
l'inyk-ho lint' in patu-nts rt'(luirilii lIAIllWlIlin alKI-I TlIWll1in, n 'sll('t1iwly', tn matutain
20 1Il ~ in tIlt' 11I1IIy,
.0 CON SIANT tATE ~E GW,f NS

3. In tilt" graphs on 11ll' fwd p<lgt' ( F ig. 6-9) art' '\\11 lIlutt ip l(. infusioll -mh' S<.'t·II arlos.
Sketch IllI" untk-ipated phl-Slll <l e uwentratton- unn- prufilt·, lin tilt" ~m p hs Oil t ilt" right
IIsing (1)lIl't'pls presenn-d in this chapter. Tilt' total (:ll'a ra rlt't' of ti lt' dOl g is ZOO m l /
min. Xu!,, that lilt' tillll' scale is expn -sscd in half-lift' uuits.
-I. D liriUl-t a n ill \·t"sti~ati ollal prt~mlll . till" calcium d lalllld hlud dng agell t Ilifl't )ip ilit· WllS
infuS("{! at a constant mit' ( 1.5 mW'lT) via a n -ot al OSIllOtiC pum p <It'vil't' for 2-1 h r. Tabh-
M lists till' plasma ll ifN lipi ll l ' coneeutrution du ring and after tilt' infusion , TI lt'S(' <b l a
imlil'l.l tt> Ihat a ll <lH''rage plalt'an l't)JJ{'t'ulmtioll o f 2 1 J.lWL " 'l.LS attaitlt'd . (;iH '!1 111<11 all
tlu- tnfus-d dm~ wa s absorbed and thainift'tlipilll' di sp()Sit i oll l~lIl 1)(· dlara<.1 l'ri i'~ ..:1 hy
a one-comp artmental modr-l.

, ..... 6-4. Nlfetllpl....I...... Dwrl....edel ......I. . . . Ite-Iy ..... With ...

Os."'. I)"S. . .•

o o
I 41
,1 14 5
110
6 130
75 108
10,5 no
I' 100
18 18 0
l' 110
15 180
16 110
17 71
18 , 1
·-.:l ~ ~,C H _ _ , I. do> ~, IGJ _ ~, P ond e.._,DD Niedop ... . _ .<l>"'<l ~.~
oect>I.........,.,.,-.ody,.,._an"""""",,,,,,- ()", ~ fho, ~3Q6-4 0 1 1\l 84

a. C ak ulatt' tln- ck-ara uce-, half-lift", volunn- o f d istri hutioll , and .\tHT of till" t1m~ .
h . Is lilt" app ru.u·h of tilt" conccntrauon til plalt"11I in 'l~n":'lIIt' n t wit h tilt' h.aIf-life o f
mfedtplnc observed on rt"lI1o,ill~ tilt' infusion pump?
c. If lilt" infu sioll rute- we n - 3.0 mW'1T inslt'ad llf 1.5 mgzhr. what would ht, till' expt'(1t..:1
concen trarious at I hr. 2 IJr, am i at plat eau?
d . If the tlt'sin ' is to achk-ve till' plan-auconeent ratkm 'l~st )(: iah'l l with tilt' 3.0 IllWh r
infusion rate instantly. what is thl' I ()adi ll ~ do<;t, rt'tlui rt'l l?
5. D ropertdol. a hlltyrnpllt'liont" dl' ri\"atin '. has 1.( '('11 IIM't1 for tln- preveunou and trea t-
mon t of U'Ub t'a aud \'1 )lJlit i ll~ ill po s tope rat ivt - pat it'llts anti in patients UlI\ lt'rgoi ll ~
dll'llIotlwmpy . Dropcndol is currently atlm iu i.~It'n"( 1 illtran'lIllllsly ami intramust:ubrly,
I)( ltt. iU\1L'ih , ' procedures . 111(' oral r oute crea tes a p r oblem fill' path-nt s who are- mur-
S('t11lS or \'(lIniti nJt. Gupta et n]. ( 1002 ) 1,,1illlalt'tl a 1'lllltilllluus-n ,lt';N ' n "(1al d nl )t.
dt'l in ' I)' ' }"itt"1Il as a means o f <ldlit" i IlJt tllt"mp:ofur;lll I"xtt'mlt'tl pt'ri(KI . Tablt, 6....') lists
tilt" mean plusma concent runon o f d mpt'ri dol obt aillt'd f(J IIO\,i ll~ li st ' of t!lis dl"\1<.'t>,
dt"lii~lt"(1 to dl'1iw'r d n')t at a constaut ratr- for IS Ill', iucompnrison \\1tll a 24 -111' coustant
r ate i.v. infus ion. rate 0. 125 mW'lr. Tln- n -ct al <It'\11'l' contahu-d a total of .1 11l~ dro-
ptr-ndol. Xo drug was fou nd in till" recovered dt'\1<.'t ,.
CHAPTUO CQNSTANlAATE ~EGWo.E N 5 II

, 1. 6-5. M_.. PI Dr.p.""" c._ • .,..tI

the U. . . . . . . . . .1h .. lc. I. I I.ht I."
II.wl I M

Tlf./f lh,) 0 0 .5 2 4 6 8 10 14 18 24 26 28 30
Plasma i.v. infmion 0 OW, 80 2 60 250 250 270 270 2W 310 1,40067036
ConcenlrOlion 1l!1( 10 1
Img/U dev;ce 0 0 0 49 OW 183 1,84 193 152 1,43 1.63 0,65 02Q 0 .10

a. From til(' pla.'illla t'Ullt'('nt rlltiu n dill" aftN slo ppi ng till' i.v. Infusion, t-,;ti lllalt' tilt'
r-linuuation half-lift, of <lnll)('ri<lol,
b. Ca leu l" h' the t'xpt'('tt'tI .\lHT flll1fl"'i lJ~ au i.v. hntus.
c. Esli ma h ' tilt' svstemtc h i()a\~lila"i1 i ty of II I(' dnl ~.
d. Calculate clcurauce .
e. \\1ml is tIlt' volurm- of dislrihulioll of d mpt'ridol?

2 5

1.6 4

1.2 3

0.8 2

0.4
"2 ~
E
·E 0 C- O
'"g 0 2 3 4 5
0
.~
0 2 3 4 5
~
0
2
"~
u
0
0
5
.~ <.>
~
~ E
~
1.6 /1. 4

1.2 3

0.8 2

0.4
I
0 0
0 1 2 3 4 5 0 2 3 4 5
Time (in halt-lives!
I-l lt· 6-9·
12 CHAPTU 6

fi . 1 1 "t1~m ft et ill. ('xp!n J"('(ltllt' r(·;...~ i h i li ty o f transc h-nnul t1e1i\'t' r) o f a new antidepressant
d m ~. rohpram . T allie fi....6 lists til(' meun l'J.l~ TT1a roltp nun <"ll llt 't' n l m t iu IIS ill six su bj ec ts
d u rilJ,i.:: and aftN a 24 -11 1' ap p!il'<ltiu ll of;l 25-t·m 2 !l<ltd l Illilt l t · of "ilit'o ll(' adlu-sive-, d m~,
alltl .5'l isn p m pyl m)"ristal t>Oil u po lym er "a(·ki l1 ~. 111t' p atches (5 <:111 X 5 e m), ap plit,<1
In forea rm skin an-as . '",n ' covr-n-d fnr 2.J h r. All his lillie , the Il<lld ws \ \1' 1'(' rt'l!Iu\"t't1
and til(' skill an'a cleam-d "ill. alcohol S>\1Ihs. TIl(' a\l.·rd~t· ck-arauce and IllIlf-lift· of
rohpr.uu an ' SA 1.11.1' and 3 h r. rt· sI)('(1i \l.·I~· .

, ...1. 6-6. M . . . . .11..-_ c..e.IIInrtI... Ihtn., ..... After 24.hr De.....1

Ap"nctlfl•• I. Six M.I. hltlects-

a. Cal('ub tt- tln- a\"( ·ra~t· mit" that robp ram is I lt' il1 ~ ahsnr llt"(l from the- patch la-tween
12 and 2-1 h r.
h. Dt'l t' n llilw lilt' total amount uf r ohpnuu lIhsorlx'tl d llri ll~ the 2-I·h r applicat ion of
IlIc' patch.
c. Doc·.. lilt' appmad l 10 sh 'ad)" slalt' follow tlu- t'xlx'(1alioll of !,otl ill I llilif-Iifl', 75%
ill 2: half-ljvr-s. am i so o n? If lint , hrid l)" d iS(1.lsS hnw the absorp t km-t ime - p r ofik-
<IilTc'no From that t'XIX't1c't! fClllm,i n~ con stant-ran- input.
I. Esttnran- tjn- volunu- of distribu tionelimination rate constant. half-life, and d t'ar.Ull'C
from tilt' da la iu Table fi- 7 ohlaillt'tl on i llfu s i fl ~ a clm g ;11 the r an- of 50 mw11r for
7 . ,~ hr.

,.1t•• 6-7.
T, ~ lhfl o 6 75 9 12 15
P1a!>fflO dfug coeceenctoe
Img/ll o 34 54 65 70 46 20 0 .9

1;, A dm /.: that d isplays one-compart ment ('t.aml1t'ri .slks was "d minislt'n'tl as a ll i.v. holus
o f 2.')0 1II)!; followl'tl illllllt'tliatd y b)" a ('()!Isla nl infusion of 10 mwtlr for li lt" durutton
nf a slud)", Estimate- the values o f \ 1 111ll11 t' of distribution. half· life . a nd clearance from
11ll' dut u in Tothl,· 6-1'),

t,me lhl) 03 50 50
Plosrc drug ccoce-ecnce
lmg/tl 98 76 40

~J . In tlu - n-xt on Illl)!;c' 75. tilt' pract ical view of the a p pnllid l to plateau \ \ Nd-S pn-scuted. If
tlu- tolerance at pla n-au Imd IX"(' 11 15%, instead of 10%. wha t wo uld lx, till' time . in
Iialf-lin ·s, m-c-dedto reach this tolerance wln-n lilt' iniliill concentration is:
a. S()~, of li lt' final (p lalt 'olll ) value
h. ,' j( )( Y.f of lilt' final (p laleau ) valm-.
 MULTIP LE -DOSE REGIMENS

OIJICTlVEI
The reodet win be able 10:
1 Pfeaid the lote and eoeot of dllJg occurnubrion lor a 9'vefl regimen of fixed dose and filled
interval.
2 Develop a dosage reg,men hom lnowledge of the phaflTlQc¢l.inera and therapeutic win-
dow of a drug
3. Evoluale the liroetlO of 0 drug givet'\ in 0 mulriple-dose regimen
IS EvalUOle the kinetic of a drug lo/b.ving 0 mvhlple-dos.e regImen 01 a conIToIIed-relea5oe
lormula!lon
5 Det-~ phormocolo ,netiC palOI'l"'letet'~ for 0 dn9 from pIcumo cooceMotion lor weel dolo
foIIov..,ng 0 rrulliple-dos.e regimen.

nit' p n iullsdiaptN llt ·;,lt "itl. (UIl,t,IIII -r.lh· TI"l,'iIlll'U\.. \ !It.' Mlgl. till ·.....· fi"l,tiltll'lI' Ill"'1'"
lIlany (It imhlt· ft..a tun-s. tht." an' II'" tiM" 111.,..1 (UlllIlHJIl nllt·... 1111' II M'n' ('tllllllMlIl "ppn",d l
In 11K' m aillh' llalK't" o f l"lm till lll MI'i 11 ... r.II~ h In ~\t. lIIuhipl,· t1i\C.Tt '!l- tlo·... .... 111;" r-] t, lpll'T
{"ll\l'~ 11M' p !M nn;K"Ilkindil' printiplt·' .1"'(I(; ;Ift"ll ,ti th "IM·II Imlltipl"-o:I'N' n'1.,r;"ll'II'.

DRUG ACCUMULATION
I> m~ a n ' mu"t ('l l lll lllnll l~' pn-scnlx-d to he l 'l~t ·1I 011 ;1 fiWt l d"w. fh."(llillw illll'nal ha~i~ :
" .~ .• Il KI III ~ Ihrt"(· finn-s a <by, In .,, ~oc:i a l i o n wi lh l h i ~ lind of 'u lrHillhlr.llioll . Ih. · pl.l\lIl'1
IUll('t·nl r.llicm and ,11110 ' 1111 ill Ih t· botk 1I11l1l1ah- <111.1. ~ illl i lar 10 all i llli l~ ifl ll . ri,,' lowartl a
plateau. .
Cou..id ,· r ti lt" sim p!"sl silna ticm o f a t1mag" rl'l.(inlt'lJ <"('II1IIO.)"l"( 1 o f " 'pla l b"l ll ~ dust·s
ad lll j ll i ~INt"(1 illlm\l'lIl1usly a t fht"(1 a nd " ' Illal li llw illll 'n a k C lln .· ..\ of Fil.(. • - 1 ~11l1\\~
III1\\' amount ill tilt' 110. IO. k ,"ilrit·.. \\i ll. Ii Ill! ' \\"111'11 l\,dl t111~1' i ~ gi\( '11 ~ll('t' 's ~ h r-lv twio - , '\I'n
I.al f·l if(" Under 111t'....• <~ lIIdi l illll \ t l nJ~ ..,':IlIllIlI.Ilt'S ~lIh~lalllia lh ..\ n : lIl1lllb li.:ll l ll,, ·tl,... III:'
(';J,1I'ot' dm ~ [rrnu pn'\inllS liu'lol"ll has nu l I.. x-u <'l ullpl"h ·ly rt ·Ill,~('( I .

MOlina ond MiaiJna 01 Accvm.lcrtiol lo tIM PlatfOtl

Tu dpprt...-iate tilt' p ht'unlllt"ltllII of ,t<,\·UllIllb lio ll. t'llll~i.I, ·r \\ 1••11 11ol1'lIO.·m wlu-n a IO()' III~
hoI", du!io(' i.. gin'lI in lrd\t" MM ldy ' ''l'~ dimillalinll h.ll(·lilj·. 11... ;tl llo ' " lh ill Ill\' 1. 1I1~ jusl
;lflN (·oK·1J t ier;(' and jil'l I..-fon- Ih(' 111'\1 <leN:' <..III rt·,tllil~ hI' 1';J <'III.' lt '(1: t1W'lol ' \ ;al....s t'l ,r·
respond 10 the- maximum t.\ _ . I and nuuuuuru C,\ _ 1,t!IMllIlih u" I,lilll'(l \\; I" ill ".wlt Ilt ~jllg
illll ·n·ili. n it' l 'llm"Sp')Iltlinl: \. llill'S ,IIlring til<' fi,...1 I"~ill!: illlt 'n,,1 an- IIKI lilt: 1. \ I _. l ,11111
.'iO 1lI~ (.-\I.-J, rt"Sp'...1 in·ly. n il' 1ll.1\illllllll ;U1M MIliI uf dmg ill lilt , ...... ~ 1I 1l 1 d(~ilJt: ill"'na]
(.-\.:._ .). lSI) TI1~. i.. tilt' ,II)'it· (wn m ~ ) 1'111\ lilt' ;11110'1111 n 'Ill,linill!: Imm tln- prt'\i,,,,, ,liN'
.. CHAPTEP7

(50 mJQ. 111\' amou nt rt' lll<li l\ i ll~ at tilt· {'li d of ti lt· St't1md dllSill ~ inn-real (A b ..,.). ';',') mg:.
is Ih al rt·lI1.un illJ,t (mill III(' first do.,t·, 2 5 Il\~ ( 100 III/.: X III X 1/ 2 , !)t'('.lII<;l,' t wo half- Her-s
han' t'lapSt"t1 Sj lll 1' its ,Ullllillisi ml io ll ) plus that rt'lIlilini n g From tilt, <;(,,(''011(1 dust" 50 mg.
Altt·m ali\'t>ly. tilt' value, i5 1llJ.:. 1lIi1)' simply 1)(' calcula ted hy n,(" ~ll il.i llj.( thai 1I1l1·· half of
till' amu un! just afn-r tilt' St'(:Hm l dust" 150 1Il ~. remains at tln- (Oml of that dosillj.( Interval.
Upo n n -!waf iuJ.:this p ml't'tlurt" it is n·"d i!y St '( ' 11 k lll'\'(' n, F ig. i - I ) that d m g uceumulution,
' ; t'\'l'(, 1 ill n-n ns (If ('itlll'r maximum or nummum amount in tlu- bodv. cont lruu-s lIu l il a
li m il is n -ached. At rlu- limit. rlu- ,IIIIUllll! lost ill each 1111('1"\'<11 e-quals tilt·
<1111011111 .I-:;lillt'tl .
Ihl' duSt" I n thi s exa m ple, li lt' maxtmum und till" minimum amounts ill Iht' hod y al s t('ad~'
stilll' an ' 200 1Il~ ami J(XI 1lIj,t, f('spt"t.1i\'..Jy . This m u st ht , ';0 sil l('(' rlu- d iITt' rt' Il('(' ht,tWt'('1I
till" maximum a nd minim um amou nts is tlu- dost" 1U0 m g. urn ] sinn' a t tilt' (' nd o f tlu-
interval. Ollt ' half-lift', t he amount 1II1l., t behalf t lmt lit Ih t, llt-gin llillj,t.
Fnl1O'\\i ng a constan t run- input, t !l t' I,l(l l nl/l is n-ao hed wln-u rOlf(' of t'li llliui(tio l1 lJlatdll's
raft' of input. 1111'1l till' Il'n ,l of dm~ in lilt' lltltly is constant. With d ist:rt' f(' d o sin g. tln- lew!
is not coustunt within a d os ing, Interval. b UI til(' \',(IUt's it! ; 1 ~n' n !iIIit' wi thin tilt' inte-rval
art' t ilt' smm' fr om O llt' dos in~ interval to another, t hilt is, wlu-utln- umoun t Im l t'1lua ls tln-
amount p;iliut'(! \\ i th in till' int t-rva]. 111t' term I,I(llnJU is also applied to tl.is illlt'n.losing
sn-udv-stan-condmon.
T1;(' ftm -going ('Ul\.sidl'mtiollS ran lit, {':qlillldt'(l for t h t, mo n - gt'lw ml sit uunon i ll w h i(·h
a d r ug ts Wn'll at u t10 Shl g, interval, t . whit-h lIlay t1iITN fr om rlu- half-lift,. 111t' g,l' IlN a l
t'(lliatiollS dt' n n '(! in Apl')('1II11\ I- E for t ilt' maximum a nd minimum amounts in l ilt' hody
aft{'r rlu- Xtli tloS(' (As.,.....: ,\ ., .,....~ ) and at plah'llu (A .......: A ...."..) art'

Moltimum amount in
body after Mh dcse, AN,.......
• Dose - [II - ee--Nir]
h

M inimum amount in
body oft8l" Mh dose, AN,min • 2

w.oximum a mount in Do..

body a t plateau, AIa. _ e h 3

nil:. 7_1. 1)o ..i "R rn~ I IN'fK, ~ull ",l. th.· ", ••
Kf'~' ur drug ;((,(' lTl llll..lin n , e"I'\" ". 1"'. 1" >1,,.
t ~ ...•(lUll "'10:1,..llIIiui. l,·n , 1 t",it~, ,.... . 1'\ halr·
lir..; ( '(] 1'\1' " . ~11'" 1,,>11\, ,....... ...lmini',,,·n, 1
A
." " f) h..U·li f,·. ~ , ot,· llMt ti lt"· 1\ ,.\ -
l' n ~1 ill l...If·lif.. unih

o 2 4 6 B
TimeIHall-lile
CHAPTEIl7 MUlT1f'tfOOSE IlfGW,fNS as

M inimum c mcc nt in A -h A n _
.......... e - .......... - UI:»e 4
body of p!ot8(lU, Au .""" -

R ('(.~d.1I From C ha p . :1 that the fUIl(.1 illll c - AI is lilt' [ruct ion of till' initial am ount n.> lJlaini n ~
in ti lt' bt l<l~' at ttnw t , Similarly. till' umouut ill tilt" ht l<ly at til(" end o f a dosill ~ int erval t
of <l multiple-dose n.~m(' n , (A.,-.",;..), is obuuued by Ulul t ipl~in~ rlu- l'()m'Slxmd ing muxi-
IlIUIll amount hy (" -It . thai is. A ., ...." " = A ., .,...... t' - A. o r A...,..... =
A ........ ,. -A..
To furtlwr ilpp rt"li illt>til(" phenomenon of accumulation. l"llllsidt' r all oral dOSlI~t' n1.rj.
Il W Il o f 0.1 1lIF; d,u ly uf d i¢ tn >;in . USl"l..1 in the t reatment o f certa in cardia c dysfuncnous.
Althnu ~h not as \\itlel)' us("l..1 as th e mo re pop ular d rug. di~n'(i ll . di ¢tm in lIil'dy Illustrates
lIIall)"o f the a~p("l...is of accumulation and d t'siK! I o f dosa~(' n.~ llwns . C,in>u tha t absorp nou
is comph-te and , -irt ual ly instautuneous, o ral adm inistrutmn m il Ix' si111111<1.1 ("(1usi n~ is. ho lliS
do S('s.
111(' a\'('nl~t> lmlf- lirt> o f d i ~ t mi n is 6 days : therefon-, Irmu E(I' 3 the maximum amount
at plat eau is 0.9 2 1Il ~, arul fmm El l. -I the nrinunum amount alplalt'.1\1 is U.82 1Il~. Di Wtm.i1l
<:It·'II'I)" . lIltl t> ~( I<'S considerable acc umulatinn when gin >1I dail~·.
These calculations o f tilt' maximum andmtntmum \·ulut·s at plateau strili l)" apply only
10 intravascular IXllus udmlnistrutlon. Tll t>y an ' n-asonuhh- approximation s follo",;n~ extra-
vascular adt ru nistrutton , when a hso rptiou is l~lInpl ('tt· an d ' i rtll:llIy Instantaneous. 11. t' ful-
lo"in ~ discu ssion ch-als with a h-ss l'e strit1in > view o f accumulation , whi<:ll applies to ull
routes of atl millislmtioll .

Awerag. Amount and (oft(fntration al Piateau

In lIlallY rt:'sIX'i-i s tilt" accumulatkru of drugs. admt ntsten-d in mulnpk- (1t )St*S is tilt" Slu m ' ,l'
tll at observed follO\\-i nl?: a consta nt-ran - is . infus ion. TIlt" an> l'il~t> amount in the- h(l<l)' at
sl('utl)" state, plateau. is I'(·atlily t"lIk llt llt"l..l lI.sing lilt" ste-adv -sta te l'tllll't'pt: A\'t'm~t> rtltI' j f l
mu st equul a\1.> r.I~t · r ate out, TIlt" iln·r.t~e r an- in is F» D OM ·/t . 111t> U\ 'e rd~e nih> out is
k: • A ....... wll('l'(>.-\....., is tlJ(' a\'t · m~t· amount o f d nl ~ in tilt" IXI<I)' m '(' r the d()s i ll ~ In terva l
at platea u. Therefo re.

f · Dose
, - cr . C ..
~
6

when- Cu ,... is the average pl.t'lllil rmux-n tru tton :11 lilt· plalt·al t . Sinl't· k = 0.69.1It 112' lt alst,
follows that

A ..~
7

and

F 00..
C......., - CL ' - ,- 8

TI J('S(>a re- fundamental I'd atiomhi ps; Ilw)" show ho-v til(" a\·e rJ.~l> amou nt ill till' htl<l\' at
. CHAPIH 7

sft·<ltl~· state tlt'ill.·ml" on mi t' of mlmin istration ( 1)1 ~ ·lt l. billa\"aitlhi lil~· . an d Imlf-lift" and
how tIl(' l'(J IT('spc Jlld i n~ a\"t' m~(' conce-ntrution dept'nds Oil tilt' first two fal 1or; and clea r-
utu'e.
D Ol~ accumulation 15 nut a plu-nonn-uon thai <1('1 '11.'11<1" t ill rlu- prupl.·rty of a tim)!:. flor
are then' t1m~s that an' ('u lIllI Jatin' and utlwr.; that art' not. ..k (;lIll1u lalioll , in p articular
till' extent of it. is a n -sult of tilt' frt'f IIWl\l'Y o f admini st rat io n n ·lalht' 10 halr· lift· lIit nr «
l/kt ) itS ShU\\11 in f'·i~s . i -I alltl '- 2 .
:";olil't ' that tilt' anm l!!:l.' .11111111111 o f di~t()\j ll (O.Hi TII~). (';l!t-l l tlll't l [rom Ell_'j . Iil's mid" 1ly
1)('1\\'1'('11 tilt' maximum 0.92 mg am i tl.(· minimum n.s2 mg. Si ll ('(' m k ulati llg the aH 'mgt'
valur- is lilt' uuu-h simpler p nl('(,-Iu rt" under these ci rcu mstances lilt' IIHlximUIII and mint-
mum ' ';IIIll'S (';11I t'a.~ily ht' (';Ileu b h'tl by <Iddi ll~ <lnd s lI btr;lt·ti Jl~ Illll,-Ilaif tln- lIlainlt'U<llll't'
dust· ahsorbe-d, n ·spt "'l1ivt'ly. 10 tilt' aVt' rd~l' value. \ \ 'ilb d i¢tuxill. fur t'xampl t' , ,\ ...,...... is
liB';' + 11.0.'> "" 11.92 lIlJt: A ",. NO/ .. is O.S';' - I).OS '" n.S2 m!!:. T his simplt' uu-rhod is a
n ';l'itlllahlt' appmxinumon us IUIl~ ux lilt' tlc" in!!: inn-rval dut's lIot t'M't't't I IIlt' half-lift,.

CornpariSOI of Maximum.. Awerage, and Minimum Amounts at P1oteou

Fhutuution in lilt' amount of t1mg ill Iht· hUlly, like accumulation. ck-pe-nds on bul h In-,
1IIlt'IK.,.· of dnJ~
udnnntstrunon ami houf-Iift'. Flul'Iliation also depe-nds 011 ratr- of ah sorption;
it is ~n';llt'sl for is . bolus adminislr.tlion . Fi ~l n' ';'- 2,\ illust rat es how nurdnuuu. mi nim um .
and an'rd!!:l' amounts in tbt· IMxly at plate-an dqx'ml 011 lilt' fn 'tjllt ·' It)' o f i.v. IMIllIS adnun-
istratton . St'\'('m l nhSN \'illioTls art ' pertinent : ( I) TI lt' <In' raw ' amount im-n-aws ill din-ct
proportion 10 fn 'tl' lt'n<,"of administra tion [iuverse of tl.l· d(ISill ~ inte-rval). (2) TI ll' maxiuuun
amount is JlO! much gn 'atl'r than doS{' if drug is admhusten-dh-ss fn 'ljlll'llt ly than OUl1-'
( '\'(' f) ' 3 half-lives, t \1ft "" 0.33 or less. 111('11 mos t of tilt' d m g [rom all previous t1oSl'S 1.,(\

5 A 5 B

4 4

3 3

2 2 ~+.

Average
" .",

o o
o 1 2 3 4 o 1 2 3 4
Hatl-tife lOosjng Interval Halt-litelOosing mterval
. " 11:. 7- 2. \ I"n ' fn~I''''' '1 ;oollll inht mh"" ....." Ih i" ;/, j!;n';4!t"r ("~n~' <of ,lnllo: ,,,,',m,,b li<o" ;/,,,,l l..·,..~ · 'I".•II,·r
n·btr..· ,lilT.·...·,,,.... ;/''''''''10: II..· llI"u,,,,u,, l.-\..,_ ). "'' ''r;l,lo:'' (.-\M....) ;4,.. 1'"i"i""'''' ('-\M,_ I .." ..,,, ,,I, "f <l mlo: I" II..·
I....f:-, .I !'L.to·;/,,,, s ,,~.· lhat r....\l1.·,,,':\' l' tI..· n'(; I,n..-..I <or tI,,· ,It" inl( i" I"""" '''l'n...,, ~ I IIt·n' ill Io.Jr·lif,· unih. A ,
R. ti" . "f tI..• ",.wm"",. ;/,"'r~' ( t ..l.. n ~I I Il"'), . ,,,1 "'i"i'''''''' ;mlt,,,,,I, <of <In ,1o: ;/,1 1'\;/'1<'''11 I" tiM" " ~,i "l " ,,,,"n'
....... f"I1" ..., i"l( d,n ,ui/: i.,·. I "~ ,,, ...IUlini.lr;/,li" n ' ;/, f,,,,,t il,,, ..r II.., .J,c " inlo: fn~l''' '''' :-'' H. H.<til .. " r "'..,; "",,,, I"
",, · r.t('· (n ,I" " , l li,,,·), ;/",,1"'ini"'''''' I.. ..wr;/,l(" ," .. "f dml{ I" 110.· h... ~· ..., ... r", ..til..,,,f ll ..· ,1t...i "lI: rn' I'''·'''·Y.
CHAPTEP7 17

III·t·1I dilllillatc'(ll lI·fn rt· tilt' llt'xt dnst· is admuuste rcd . (3) Dt' fi nill~ Huct uanon as tlu- ratio .
..\ ..,.."'/ .\ ...."... ~n'll hy t ). · (Eq. -I). tln- ~n.'aI N tln- n-huiw fn.'(IIIt·II(.' · of admluistration ( II
kt ) the s nud h-r is tilt' 1I 11l't tmtioll . FiWlrl' . -2 8 demonstrates how fluct uation ;11 plait-au
dt'I)('lUb till fn.'(llIt·nt" of ad ministratio n. T he maximum ami m inimu m amou n ts an.' I·al·h
' 't:IIIlI'J;lrt.'(1 \\i th tilt' aH· ra~t· amollnt ill lilt' hody. S o h' th at til(' ;1\·t·TaJ!:I· is arit hll\('tk~.J ly
d nst'r 10 tilt' minnnum th an to tilt' maximum value. This is part kul;lrly t"i de'lll for low
fn'l IIWlldt'!> Ilf adm inistrat ion .

Rate of Accumulation to Plateau

TIlt' ;\mOlIlII i n lilt' ht llly riws 011 mu ltiplt· dusill!o': ju st ilS it t1c)('s f(lllo\\in ~ a con staut -rate
l.v. infus ion (C hap. 6 ). That is. tln- app roach to tilt' plateau depends 5(l1 l'1~' Oil ti lt· d m ~' s
h"lf-lifc·. TI ll' clala fClr clihrilo'(in. in T ,\hlt' ';'-1 which shnw tht· ratio of the' minimu m amoun t
d u rin~ \'arilllls t1osill~ Intervals 10 ti lt' 1II11'(iIllU Ill amount OIl plan-au. iIIuslm tt' thi s IlIlinl.
O!.st'n 't· that it lak t·s I half-lift· (6 days ), or 6 t1OS(·s. In Ill' at .5()~' of the value at plateau.
2 half-li\'l's ( 12 d a~ 's ) . or 12 dost·s. to Ill' al ';'.')% of tilt" plateau vahie. ant! so 0 11.
AI'l.·lIl'nul.llion of di~ IlJ'; i n takes a 10 1lJ!: tum- I)('(.·allst· of its Inll ~ h.llf-lift·. 111l' dt·~n.'(· of
al.'l.·ullll llalilJl'l is t·\!c·I\Si\'l· . 11I'(.'all st· of rd ali\"t'!y fn.'(III('1I1 admi nistralioll . The frt"lII Il'1I1'y of
achuinetrution al<;t) den-rmtucs lilt' small llu!1uatio!l in ti lt' ;111'I01 11I1 of dm~ ill th l' hody at
plall'au: 0.1 Il'l~ is IlIsl t'\'('I)' dosin~ Interval, when then- is alllllli 0.9 1IlJ!: ill th e 11I1I1y.
1111' appm;lt'h til slt·ady 510111', ob<;t' n'('(1 for tilt' minimu m a moun ts o f di¢tosin in the
IlIMJy, "I-'\(I holds true fur tilt' maximum (p mo f in Appc.'IJdi.\ I- D), and a\'t· r.t~c· amounts.
Ihal is.

when- ' \,\ <I, is lilt' "\l·r.l~l· amoun t ill ti lt' l)lllly in rlu- dosh l~ Inn-rvul aftN tilt' .vtl l dosc·.

A«vmulation Index
If tilt' amoun ts ut slt·ady sta h ' an ' comp an -dto till' l.'l)rn.'S!ltmdinJ' vuhu-s ut finn- t afh-r lilt'
fin;1 dust ·, Ih(,11

10

Tl lI' IllIalLlily, I/( I - I' - h), is all index o f tilt' extent o f accamulatiou. Fur d i~ I ,,~dn (k ""
0.1 16 d..y - I. t "" I day). ti ll' (/("f'tmw!tlt ;oll indr x (n....) is 9 .2. 11l11s. t!l(· maxhnutu. a\l·ra~e·.
allli mimuuun amounts (anti for tha i matter til(' amou nt at any ttnu- wit hin tilt' t10S irl~
intl 'n'al ;11 p1a!c'au ) arc' H.2 turn-s tilt' values at tln- u lrn.·l> lltllltlinJ' thnt·s 'Iftt·r u si ll~11' dust·.

'abl. 7-1 . Approech to PI...... _ Dally AtI.I.I.tratI_ .. DI.lto.l..

T'me (cioyl.l" 0 1 2 3 6 12 18 2A 30 ,.
Nymber 01 dosed M 1 2 3 6 12 18 24 30 ,.

[~~::~: :=~;] "

or plcreo"
0 0 11 0 21 02Q 05 0.75 0 875 OQA OQ7 1 00

"1...., do. 1,,,,_

· , ..... ~ ~ •• • l_ ~ , ".
II CHAPTH l

Change in Regimen
SUppOM' thai the decision is lUoult· tn helve till' amount flf di ~l oxill in lilt' IlCKly at plait-ail .
11('('(1 for a twofohl n -dnct ton in tlu- nth' of ad lllinistr.!linll. to n.n') IIIWday. f(lll(Jw~
nil '
(m ill Eq. I .
As with i.v. infusion , it t ' IKt ·S I half-lift· to ~II HIIt··half till' way (m ill n,un to liAS 1llJ;{. 2
half-live-s 10 ~o three-quarters of tilt' way. and so nil . f or d i!,ritoxin it would lake about 12
days to go 75% of lilt' WOol)' to tht' 1lI;' W plateau. (TIlt' s.une prind plt· applit's to an i l1(:n ';Lw
in tht, rolfe uf di~toxi Tl udmiuistrat iou.] TIll' Fastest war to :It:llil'\"[' 11.-15 II\~ wo uld he 10
d ist:uutinul' dm~ fo r I " 't''('11 (app mxill1ald y I half-Iifel lwfon- i llit iat i ll~ till ' rt'(IUl'\'(1 mil'
of aduunistrution .

BIIATIONSHIP BETWEEN INITIAL AND MAINTENANCE DOSIS

It miKhl Ill' I hl' r.J.p(·t1l kall~· dt'simhlt, to cs tahllsh till' n -quin -d amo unt of di~tm:ill ill til('
body on till' fi rst day. \\1ll'n tilt, first o r initial t1o~t' is in h 'lItleti to lit, tll('rajx 'util- It is
referred to as tilt' " ti mllll!. o r lomlttll! dm(·. In this eot....-, tilt' patient would requi n - 0 .9 1lI~
i niliall~" followt'(l by 0 .1 1lI~ daily. For d i~t mj ll tilt, initial dust· ls often achmntsten-d in
divided doses. St...e ral procedu res an' follo\\ '('(1, hut till' t1i\idt'(l duSt' is (111ll1ll11ll1y ~i\"(' 11
t"'"('I)' 6 1101I ~ unnl till' desirt'f.1therapeutic Tt'SponM' is obtained. In this \\~d)" t'al'h patient
is lit rolh'(! III till' inilial tllt'mpt'lltk dost, n-quin-d.
lustead of t1t·t l'nllin i ll~ the loadi ng; dost· wln-u tilt' mai nteuanee do st· is ~ \"(' n , il is IlIOl"('
(.'O Ill Ul UIl to dl'l t·nniut· tilt' mainlt·lIalll't.' dow «'ll" in'll 10 sustain a t1lt'rapt' lll k amount in
tlu- body. Tlu- initial dost.· mp id ly ad lil...'e s the therapeutic response: subsequent do ....-s
maintain tl a- rt-spun st.' by rt'plad n~ d n lp; lost du ring: tln- tlosillp; illtl'l'"tl. TIlt' manueuaucc
dOM', D.v . therefore, is Ihe dtiference b etween tilt' In;u linp; dost·, V /.o alld IIn- amou nt
1"t,' lIlainillg at til(' end of tilt' d(Js ill ~ Interval , Di . <r - AI, That is,

Maintenance dose - [~~ng I'll - e-

l
1 II

Likt...\i M·. if the mainlt' lI,III<-'" dost· is known. tilt' initial dtlst· can he es firuated:

l00di109 do$9 -
.Maintenance dose
fl e- " ) 12

Thus, for diwtoxin , a da ily mai nu-nance doS(' of 0.1 1Il~ requi res a le);ldin~ eloS(' nf 0.9 1lI ~ .
nit' similarity ht'I\\1" '1I Eq s. 3 and II sho uld ht· 1I01t'(1. Frmu tlu- \it'\\' point o f l K " ' I-
mulatl ou. ECJ. 3 relat e s to tilt· maximum ,U IlOU Il I al plall';1II on <ld llli n i ~lt'ri np; a ~n'n clc>St,
f(·pt·t it i\"t·I~·. If the maxim um amount 'own' p nt into the hody in il iall~·. then ECI. II indica tes
Ihl' dost· 1J("l,(!c"llto maintain that amount. n i l' n-lanouships ure tilt' S<lIIW, al i lloll ~h IIII')"
we-re dt'ri'1.'(IIL~in~ di fferent Ic'We . Th ese equattcus fonn tln- Iwart elf multiple-dose d m ~
atl lll in i ~t r.tt i()n <lml mi~h l \\1.·lI l)('l-a1lt,l lh{· - dosa~{' n'¢lIlt'li equations."
nit' rano o f loading to mainteuarx-e doses depe-nds 011 the dos iJ, ~ Interval and Ilu- half·
lift' and is equal to tilt· accumulation index, J(..... For {'xamp lt,. tet r acwltnc has approxlman-ly
anl'}-hour half·li fe in ma n, and 1I dose.' in lht, r.mp;l' o f :150 to SOO mp; is constden-d to pn l\idC'
(·fT("l1 i\"(' annnucrobtal dm ~ ('o ll('t·nlm liolls. l1l(·T(·forl·, a n ':lo;ollahle sdlt'd ult· is .son 1Il ~
(!wn 250 -mg edpsult>S) initially, follo\\1.'(1 1Iy 2.50 mg t...·(·I)· half.lift·, ;l~ she"'1.1 in Fi ~ . j -J.
A tlnsa.gt· n '¢ lIlt'n l'( )lJsisti n~ of a priming duS(' t'(llIal tn ""it"· tilt, lll,eintt'!J;(II{'(' dus.(· alld <l
tlclSillJt inlt'n"dl of O llt· half-lift· <In ' l'()lI\"t'nit'lIt for t1 m ~s " itl. hal f-lin 's bdw("l'1l Ii and 24
hr . n it' fn "f!\I('IIl')' of admillislmtioll for stich d m~ 'o lITit·S fnllll 3 1i1l1t'~ a clay 10 unl't· tLeily,
CHAPTER 7 MUl III'tfOOSE lIEGME.NS
••
rt·li!'H.'1,:lin'ly. Fo r d nl ~s wi th \"('1')' short 10 short half-lh "t"S. k-ss th an 3 hr. or wi th w ry long
half.l in 's. !!rt'ah 'r th an 24 hr, this rt~ l1Ie ll is oftt'l\ Impractical,
Aitholll!h a load illl! or initial dn.\(' !!rt'i\tN than tilt' mumtenauce dosl' seems ilp pmp riah'
for tlm.gs \\i th half·lives lonKe r than 24 hr. such is often 1I0t th e l-.L\t.'. There art' il varid y
of n'<!j;(IIlS why this is j;(1. For piroxicam. an anal.gt'liid antip)Tt't il' \\i d l a half-life o f 4 ~ hr.
tilt" mos t eonuuun ildn'rst ' l'fTt'(1s art' !!a.\tmintes tillal reactions. Such n-act ums ilia)" lx-
illl"n 'iL\('l1 if tilt' llMd iul! dl l\(.' is thn 'l' to fou r times the mainteuaure dOSt' (JJ,. = JJ.~( I -
t · - 1I ) , t = 1 day ). Allotllt'r exampk- is tha t of warfarin (hal f.life = 37 hr ). for wh it-h tht·
i1l1til1M.glllant (,lTt'l'1 develops slowl)" wit h time. A t1linl example is th at o f prctnpryltm- (an
unttdcp rc ssant with a half·life of 7~ h r), for which larxt' r do l't's sluw l!il\lri c e lllpt)ing am i
.giLslminh's linal ad hit)" (im tid lolint'l},ric t'fTt'l.1 ), resll1till ~ in slowe r am! mort" erratic ub-
sorp tio ll of tlli.. allt! od ll'r t1 m!!s. Furthermore, for pmlript)'lilll', the de...elopment o f ther-
apeuttc I·ITI'l:1s is also dt'la)"t'll. IIslIall)" fo r 2 to 3 weeks .

MAINTENANCE Of ORUG IN TNE TNERAPEUTIC RANGE

J)OS<!.gI' rt'¢lIl('llli thai ill'!lit,\ t, tlu-rupe -ut ic ccncenr rancus are listl'll in Tabh- i - 2 for tlmJ.,"i
wit h bu lh medium to hi.gh illlIl low therapeutic illdit'l's am ! wit h vuncus half-lin 's.

HaH-lives Less Than 30 Min

C reat di llklllt~· is l' lll~ )II n tt'rt'1 ! in tl')ill~ to maintain tlu-rapeuttc con cem runons nf lillt'h
dm.gs. Tlu s is pa rt il"tI la rl~' true fllr a d m .g with a low therapeutic Index. t'.~ .• ln-parin. which
h,lS a half·lifl' o f app m xilllilh 'ly 3() min. Sm.- h it d m ~ must hI:' d tllt' r tnfuscd or t1i S(~lrt ll'll
uull'lis tnn-nntuent concvntrut ions are pernussihh-. DmJ.,'S with a hiWI the rapeutic ludex
11m)' lx- ~w n It'sS Ire-que-ntlv, bill till' ~n'ilt N tln- dosin~ illlt,,,,"..I, th e ~rt'ah' r is lilt' main-
!t' nallt'l' dos(' n-qnin-dto ensure that drug in the hody stays above a minimum I'lTt'l1i\'I'
\'alllt,. I't'nidll ill is a notahh- example o f a dr ug for which till' dosing interval (4 10 fi Ilr ) is
mallYtillll's l"lI~N than its half-lift' (app rm imatd y 3() min ). 111t' t1ti'>t' ~wn ~rt'al l)' ('U1'l'l!S
that rt'1 luirt'1l to ~idtl phsma conccutrnttons of antihiut il" 1'1 ll1i\'alt'nt to tilt' mluimum in-
hihil ol')' (111It'l'ntmtioll for most mlt'm o rxani sllls.

Half-lives 8etwftn 30 Min and 8 Hr

Fo r sud l d m gli. tilt' llliljor t'1 ll\Sitll'riltiolls an ' tln-rape -utk- index am ! t'l)lln' nil'nt1' of dosin.g.
A ( Im~ \\1111 a hi.gh tlwrapl·ul i(." intll'x llt'l,(! only II{' administe-red (IIlt't.' 1...·1·1)· J to 3 half-
li\'l's. or 1' \'1'11 It'sS frt'q llt'ntly. A t1mg \\i tll a low t1w rapt.'u tic index IIII1St I'M' ~\"t' ll appr oc-
Illat t'!~· l'H'l")' hal f.lift', o r uron- In-quently. or be WH'n h~' Iufuston. Lidocaine, fur examph-,

~
500 t·i~. 7...1 . Sl", ld, (If Ih., am'M,,,t nf 111r.lo(;'·'
.~ dill" in II... I• • ~' "" ,l.Ii " ... ; . 1" ", 1,&1;'", " f II" ,
A
"e
~C;
E
;;; -
t \ '. ...lmini, lr..linll ur SC MI Ill1/: illill."l1... ;tiM! 2.'50
"'If ,'\...~. " I,r 11,,·n·..!t,·,. ('(.,,~' A. \\1"'" ,I"·
;u"1 " loIi nh ·I.... M.... I],...-s .In· II..· '"Ill" ' ,
j" il i<al
~ ~
-
250 B l~'''t' ll. il taL.,. "Pf' nn.i ""'tl·I~· .10 I,r (3 I" 4
0 ~
0 h..Jf·l"•.,.\ ".·f" .... II... p1;oto-;ou i~ r r....1 it·..JI~,
-'" n-..d "~1. n "·n·aft,·r. ('1 ,,,.....\ ;0".1 K ;on' I'''''''·

.
0 0
0 -
0 1i..1" tl,.. ...."....
E
0
0 8 16 24 32
Hours
90 CHAPIH 7

has a half· life of 90 min, and the mngt' of plasm a couccntr auons asso ciated with tilt" treat -
"W ilt of ca rdiac arrh~1 Iun ia... is on1)" a),o ut thn -efold. Thi s d nl ~ must he.' ¢WII by Infusion
to ensure pm]oll gl'(! supp ression of arrh~1 111 11 i;L" undmmtmal tox ic.."ity.

HaH-Uves BetwHft 8 and 24 Hr

Here. t ill ' most convenien t and dt'simhll' n~ IlWIl is o m' in wt.kh a close is ~\"l"1I ('\'('1')'
Imlf.li fc . If im media te achievement o f steady stan- is des m -d, t1WIl. a.'; prt'\; ulIsly mentioned.
the iniH,l! dose must he twice the maiuteuauce <lOst': til(' minimum and maximum amounts
in lill' hod)' an' equivalent 10 One and twu mai ntenauce closes . rt>spt't1:i\'t'ly.

HaK-U·. .. Grea'er Than 24 Hr

For drugs \\;111 half-lin 's greater than I <1.<1)', administ ra tion (lillO(' lIai])'" is (''Il n n ' n it'n l and
promote s paUl'lIt ccmphance. If all inlllll'tliah' the rapeutic d Tt't1 is dt-sir('t l, a tln-rape-uttc
dose neetls to he ~\l'n init ially. Ot lit'n\ist' th e initial and lIlai nteuallt"t' do~'s ;lrt't l.c sallie ,
in which case several doses Illay Ill,' Ilt'<.'t'ssal)' lx-fon- the dnl~ uccu nmlates to tllt'mpt'uti c
levels. n it' decision whether or not to WH' la~I'r initial t\Ost'S is oftl' n a pract ical matter.
Side t'fft'<.:ts to large o ral doses (ga.\ tru illft's ti nal side efft 't1 s) or to acute-ly hi~1t couce-utra-
tion s of dmg in tln- bOlly may I\('t'('ssitate a slow accumulation.

'."•• 7-2. De.., • •.,1........ c..tI._•• M.I..._IIC •

., "'-,..tic e-............
R.A.TOCf NT\OJ. ..ro os
""WI"", """'0 OOSNO
I'oIT!:r.tAl.1Q

""'" HAl.Hf! """'""'"

oose "-"'U, Gf:I\lRAI. CCWME NlS Dl1VG !w.¥Us
floed'um fQ <30 mIn Ccrdcce lor com.fQnl-fO!e Nolfogtveefln
High odmmis/l'ollOn ond/or
lhorHe<m lhe<apy
30mmlOJh, 3-<> 10 be gIvenany leu aken Cephalo,.porl~
rhon fNefY 3 half.li~.
drug muSI hove '>It!fy high
lhe<apeut;c index
3-8 hr 1-2 1-3 Tetracycl,,'\&
8-24 hf 2 1 V~ommon cod Sulfamerhoxozole
ifObie 'eglmen.
>24h. >2 <I Once dolly ;$~oct>c.oL ChloroqUIne
Occcececr gIven once Iwppre»ion aI
weeUy, or leu malario)
I,eq,*,~ , IMIO! ceee
mc.Jyneed fQ be much
glea!el !han ma'""
eocec e dose
<30 min No! 0 callClidare excepl Nllfop'u»ide
"""" ;;;r do,""
conlfol infu$iOl\.
30 min to 3 h, 011." by ,nfu$i()ll l idocome
J-8 h, 1-2 - 1 11~6$ 3-6 OO!l6$ pel Theophyll,ne
. bulle» Irequenlly
...., conlfolled-releo!lot!
IormvlatlOO
8-24 hi 2-' 0.5- 1 C1a....d,rwl'
>241'1f >2 <1 l1equile$cOleful conlfal. 0'9 'IO><,n
once fQxl('Iy ;$ peodcced
drugcooceeeosce cod
IQxic'lydeclu-.e ~

......
~","""
............ _
............... tlooo/"""'~ " ... ....ooce doM
""'"' doug> ...... ~. ..-.. ............. _"'0 <> io<Jd,r,g doM doooogo .. 1"""'......... __ """ .... - . I ____ .,
 MUTIPLEOOSE RfGINfNS .,
Tn summa rize l ilt' fnn~(Jin~ di scu ssion . ccusklc r tilt' a ntihiotie dm ~ te tracycline, tilt'
nasal l"tlllgt'sta ni pllt'nylpmpiulnlamillt', and tilt' an tu-pilept je agt"111 plwnobarbital , a nd Iln-ir
dusa~t· rt""Il'IIS ~hl 'l l in Tahlt, 7-3. Jjsle<! in T ahle 7-1 art' Iht, {'OrTI's polJ(ling Fract ions
of lilt' initial amo un t rt' maill inp; al lilt' end of a dosing interv ul. tilt' average amounts .u
slt'ady st.ue. anti tile' maximum ami mtutm um values . Iustant aneo us am i complete absorp-
tion is ,l\Slllllt'{1.
Dm i ll~ inh'''',us for all t1lf't'(, dmj.."S all.' kh-ntlcal . 111{' dust'S o f pllt'llylp mpa uola mint'
and pllt'lIo hilrlJital an' alsu tilt' sa me , hut tilt' amoun ts o f them in tilt' bod y wit]! tiun- a n '
l'I.'rtai llly 1101. 11lt· e-xplauat iou is n ';l(lily \ isu al i1..l't.1 \\ i lll a ske-tch.
As wit h allY graph, conslderutiou sho uld first lit' ~\"('n to scahng tlu- axes. 111t' amount
uf d m~ in tlu- hod y should II{' scaled to the maximum amount al s l t"m l~' stan- . 111(' tlme
axis sho ilid II{' scah-dto -t In .5 half-Iiw s. by which tinu- plat eau is a<.'h it...ed.
Fo r It'trat) 'd ille tln- a mo un l in the htxly im mediately afh-r tilt' fi rst dose is 500 mg. At
l ilt' endof rln- dc )Si n~ Inlt·" a I, tilt' fruct ion rem, unillg is 0.5, a nd th e amount then-fen- is
2,')(1 Ill~. A maintt'mtlll't.' tillS(' of 2..')(1 mg returns t he It...'el 10 sou Illg uncl so OIl . FiWm '
7-..'3, t-urve- A. is th lls n ';\(lil~' drawn. Xow couskh-r the sketch had 110 le );llli n ~ t1ost ,II{'t.'lI
~\·t 'll. Tilt' initial amount, 2..')() m~. woul d th en decline to 125 III ~ al till' r-nd of the- first
in tr-rvu]. Tilt, .unoun t ill tilt' IMllly illlllll't.lia tt"ly aftN tilt" next d ust., \\'OlIld ht' 37.5 II1R. At t he
end or
tln- S('t..'u nd int e rval, I 1i7 1JI~ \m uld n-mam . am i so Oil (cu rve R of Fi~. 7-..'3),
Fo r phe nylp ropanola millt' the maxi mum and minim um amoun ts in 11.(, Ixxly at plateau
an' 40 1IIP; and 10 mg. n.'spt't..1in'[y . and a period of 4 half-lives is Hi h r. 111(' fraction
n 'IIl;lin illg: a t till' end of r-ach <losing: int e""ill is 0.25 ; therefore, tilt' "allies of A .. """. alld
'·\ ...",m a rt';
Dow Tillw (I.,.) A ...__ ( 111~) ...\ ...nW~ ( III).::)
1
,
0 30
7.S
2 H+ 37.5
lfi 9 .4
.1 IH 39 ,4

By tilt' third doS(' (24 hr]. tllt' plalt'au is virtually achteved. IX'i n ~ gin'lI en'l')' h \1I half-lives.
tilt' acoumulanon o f pll('nylpm p;lnolamillt ' is minimal. Fi~lI n' i -l is a sketch o f tlu-a mounts
of pllt'nylpmp,lIltllmu illt' in lilt' hellly wit h tunc.

500 250 8 8
30 30 8 4
30 30 8 100

, ...1.7-4. A••••• ef D-. I. a.4y 1.,1 ..... 1. . . . 01••• 1. , ...1. 7-3

' fACTION
.",...., "....,.,,,
Af H'() Of
..-mfa,/.'
"''o'f 9.AGf: "'I
SIEADY
ST"'TE&
""""'""
'"""
SlAtE' '"""
ST ATE~

""'"
~11rle 05 360 500 250
prop:mohn,roe 025 22 40 10
Pbeoobo.buc! 0901.6 540 556 526
oc;.- t>,- .. .. ' ··O..,l1 - .. '~
-I .:~ " ,.Ow. ~"'~_-I·O",
92 CHAPTER 7

TIlt' s anu- dosagl' n -gill1('l1 fur pl lt'llol l<lrlJital pn Klll<.'t·S It d raluatim lly cliITt' (I' n l result . At
the end of cad i dnsi n~ Interva l, tilt' fraction re maining is O.W fi Accumulatio n the-n IX '('urS
un til till o 5..1% losl in (';1<:11 interval is equal to til(' dust" am i til(' amount ill tilt' !Indy at
steadv state is the re for e ahout 19lillll"s till' <10 '\(' , From tln- calculated "aim' uftlll' maxim um
;ullm;nl at plat eau (5.'>6 m~) and the Imlf.li ft" it is appan'lIl Ihat a sk,·td l mu st lit, '0(;,,1('(1to
fiOO mg and to aho ut 15 dl.'~"S (Fig. j .....') . The cu rve is sim ilar to thalohlaillt'i.l \\i ll . constant-
rate Infuslou . 111t' a mo unts in th e bodv a l IOU h r Is 1I11l·-ha lf Hf till' stl'ild"-sfll!t' amount.
and at 200 hr the lew" is 75% o f the piatt'au amount. alid ~ ) 1111. Pr.l(:timJi~·. t !tNt > is Iiltl,'
IWt"(! to coushk-r tilt" min or lIUl1uations.
Tilt, clinical imp lications or tllt'St.' n 1.rim t'lIS art' manifold. TIlt' ft>lrilt,,·litw rcgtnwn is
dt'siJtIl{"(l lo uttuiu and lIIainlainlllt'rltpt'nl k levels. The pht'llylpmpa nolamint, rcgtmen W"t:s
rtse to la"Rc flllduat iolls that may lit, <Il 'sirahlt'. Tolerance to tile t1m~ ek-e-lops rt'ad il)'; llll'
maintenance o r h i~ , t'lT('(1i\"(', dt"(.'lIl ~I'Still ~ n llll , 'll tm!in llS is ' 11\('slionahlt,. " 'jill plu-n....

t"l,it. 7-4 . s1<rfd, nf II..· ,..n,..m t <of p}...n~1 .

1""'1>;c,.>/;t,ni'''· in thi' ".J:.' 'nt h ti,",,; <lmll'
40
1;.1,,,,, of 311 "'l/. .iti...n i." . ''''' 'f)' ~ "•. IJc".,.".. ·
11..· I...rf·lifl'. 41,.. in"....t ",·loti", to tI..' < ~ "i "!t 30
1" 1.·......1. tI..• ,I.'K"'''' of ",,·mlll' 1;.I ~., i~ ."...11
.....1tI... 'h..101"h"" p L.'W"
20

10

o
o 8 16 24 32 40
Hours

tllC . 7-5. Sl.·td, " f II... ;l.In''' 1ll1 Ilf p1..·,,,.t>;cr . 60Il
hit;d i ll II..• IM"I;o-' with lim..; .i m "t.t~ I" ,of :)II lUI(
~ n I» , ,,,,.. .,'!l hr. JWoooOl... II... l~df·bf.·. 4 '~'"
SIe-'dy·stale Values: -
P tn·,",,·J:.· 1<"'1: .... 61i>.. til II ..• <lII. illK int.. ,. ·..!.
tiM' ,I.""",," of al'l'l"nlll.. lic.., i~ Lu,;:.-. ..,..I t .... I1...;'-
hlOlti" n i. 10",,·. n M ' 'na.u",,,,,, '''III ," ini" ulI" .'al-
, t . 1.....1).' ~t .. I... 5.">6 allI l :'S2fi n,~ ;u't" ~1I""1'
'''' tI ri J,(l ll.

0200

I ' 00

o >----------~
o 5 10 15
 C HAPIEIl 7

barbitaltln- appmpriale n '¢ I1 U'lI depends 011 whether tile drug is 1I!it'(1 for sedation tIT "-'_
;tII,ml it·p ilt·pl k-. Fo r !it'(!.ttioll. tln- o missio n u f a loadi ll ~ do·....is rk-sirahh-, ill that lolt'r-IIl(, '
til till" !it'(I.ltin- d Tt'("! dt·w lops wil h lilll P ;Uld a laTgt· priming doS(·. finn mg. (-.III'WS 10 0
~Tt'a l a cent ral dep n 'ss in' t·ITt'(.1 . As an alll it1lilt·pti c. howe wr. a hltling tluS(' may Ix'
appropriate. A lt l u lll~h IlTt'\illllSly pn-scnbcd as such. chronic administmtillll u f pheuobar-
hital tim",' ti lllt' S dailv is IlIl Jl( '(.'t · s.', ar\"; OI K't· dallv administrat ion mav lead 10 la-tt er 1:1I<l111't· S
of com pliance. . . •
La{·k of « nnpltaucc is a major problem ill pharmacotherapy. l1 w 1II0si Fn-queut patten!
o f nOllu lmpliau l,(' is till' tlt.'t~l-siu llal omitt ed d nS{' or fajllln' lo ta ke several lUIl'i.('(.·u tin' do!it'S.
Ht"¢Tl1t'lIs " f multiple daily d n"t·s teml to p n klu{'(' lUt'a ter frequencies of missed duS('s than
th oM' ill whi<'h a d mg is taken (l m't ' o r twice daily. However. dt'(.· n';l-sing Ihl' fn'1IIlt'IIl)' u f
dosillg: (with lurn 'spo lltliug: inl'n ',l-\(' in ('ae ll dose) lIlay not improve Illt' matntenance o f
l"Olln'llt ratio ns wirlnu th t, d Tl'(1 i\"(' range. 111t' impad o f it missed doS(' is sho\\11 ill F ig:.
7-fi fo r Tt'¢ mt'n s of 30()' 1llg: (JJl('(' daily and WO.mg ('\ ·t·!) · Ii h r. In hot h n '¢mt'lIs tilt, total
dai ly dose is tilt' same. O mis.sioll of it .single (l uly 30()· mg dose produce s a much 10wN
min imum concent ra tiuu than omission of a l{){)·mg dose for twn reasons. First, til(' amount
lost d uring:till' If)n~N lnterv a l (If tilt' fomu-r r~ II1I 'n is gn ·ull'T. Second. t he aW rdgl' mill-
imum couccntranou a t ste ady sta te is lowe r for li lt' n!l{'(' d,uly n '¢mt'u . Thus. omitting: a
s i n~lt' tinS(' du ring: a U ll(~ ' (bily n-gtnu-n lIlay ha\'t' a much g n'atl'T Impact o n therapeuttc
n ·spol\St· than oTJlilli ng:an 1'l-1lOurly dOM.'.
:"0:(111' I hat ('\l'1I omitt ing t 11Tt'(, consecut iw' doses of the g· lulIl rly n "¢lI1t'JI (the t'1luivalt'n l
of a m w(·.t1.lily <lOst·) does not produce as Iowa concent ration as tilt' omts ston of a sing l.·
dailv do!it,.

A B
20 20
~ ~
E 15 ~ 15
<£ ~
0 ,g
~ € 10
~

11
10 ~ ,, ,
0
~ ~
0 0
u u
~ ~
E
~
5 E 5
~

i1. -"
c,

0 0
0 24 48 72 0 24 48 72
Hours Hours
1'1.11;.7-6. FrUin ~ kill il: pc·i"'pc..·h..... tI,,· lr"f"l'-1 "f a ",l~.. -d .t....... \.s 1/:n -.d. ·, 11..· L..1):t·r II... d....• ""ltl l h.· 1..",.
fn'(I''' '''1 tI..· ...1",illi,I tl lt..,. <:'..".i,I. ·, . h·.. ly.•tah· mlllti..J....• ('o ' Klilio m r...... . In'1I: with a 11..•....I'.."tit-...il ltlo-....· "f
7 I" 2n II,(fI. (....m ..-n..·,..'(11. .. ,,~ " "' •• "f .L.l rih" Ii.." of 2.1, I I ~ ilIltl a ',:.df·lif,' cof 1.5.9 11f, PlUM'1 A: Who'll "
.1111)." " 1/: , 10- ..... i . ~ •." "'K~' tlaily' I" mainlai" th,·ntpt ·"tit- '~" K~·lI t 1'lttic ..u . a "' i......J Jo.... n.. ull ~ ill • t"'''1I:1. I....' ·
("(·" I.-.tl ic", "f2.5 mw l ~" ,..1,......d l l...·I0-'" tilt· Ie",, ·, li",it " r t l..• tht " Iit- wi'.. " , P. ....I Ii: \\ l "'n a 11X1·n,!>:
, 10- .... i. l,'i"'n ......1)' " h. (•• .I.. " ..I Ie"'1I; .LuIM ..I Ii".·). tI..· 1e.........11'Ot ·lll ntlic..' ·hic 1art.·, a lJ ,,~' mi. .. .. 1.1,....
i. 7,:}"'!VI.. a ,.:.d"•• " 111"" II... 1I"' '''' I'''"Iil: , u K..." I....lic", ''''!t'-". If 3 ", ,Ii • .Ic "'" "'i •....! (o...Ie,,...I ,I>,,rt.
,Lt.,IIt..1hn.·)11... mi" i",,,,,, n KK.·n l r-..Ii,.., <3.7 mii',il.) is -.till .,}M • that ,>1 ·"' 1 "t..·" a .'''d<- .Luly.Ie...• "f .100.
fIll: i. "'i. .... I. TI,,· ~~lrt · " '11.
* Lph..1 fnll" ........ p.......,I I I':,'o· 1£0')-' G.• A pllitn'lO. ..oI<i'''1it' pc·I1Ip'..1i'..· u"
n .. .. III.....' '' ·''I ,.." ... >l I1I>1i..' •. ct., 11"'" " .....1. ",..,. ,54:U2·W. IW.) .
•• CHAPTER7

The ill l 'n 'il '>t't! pmhab ilil)' by olin' daily dm i ll~ is ("OUlIlt' rt't ! hy kim'fic
o f l'tlllJ p lia u l'l'
a'Xu ITlt'1I1s in f<l\ll f o f mort' f ({'(jl lt'lI! dn" i n ~ .
\\ 'hen- tilt" opunnun rt WIIII' Jj lit·s <!t'IWll{ls 0 11
mall)' factors. For exam ple. for phenobarbital. with a half-lift, of .. <bys. tilt' omissluu of a
si ll~lt· d uly dost· o f 911 Ill~ O f a n S-ho urly do !\(" of 30 111~ is o f m inor i lll p ortalll 'l' 1"-"<.'a nS('
the awrd~l' amount lutlu- hoJ)' at stt-ady sta le is SSfi 1IlJ.t (MO(' Fi~. 7- S ). l1ms. tilt' smallt,t
tlw mt io o f tilt' t1osil l~ in terval 10 half-lift" tilt" k-ss tilt" ki m't it, impal1 u f a mis<;t'tl l!1N.'.
Ot her den-rnunant s of th e opttmal rt'J~hm' ll Illc!lI(lt, fact ors such ,L\ those a ITt'(·!i Ilj.t tilt'
lilwliholJd of ("Il1lip lia lJl ,(' (M'n 'n t)' illlt i llillu rt· of di M':L""' , oceu panon ( If path-ut. !It 'NlIlill ily
of p;i1ient ) am i t!lOSt' rt' lal in~ to tilt" pll<l nn;K·()d~ll a lll i{' d mrad t'ri"ti{"!i of 11ll' dnl ~ (sh "t·p llt·ss
of ("f)IJ{'t'lJlrdtioll-n'S!ll llJ\t' cu rves . \\i d th of tllt'rapt'lIti(' "ind(lw).

PRACTICAL ASPECTS OF MUlT IPlE·OOSE AOMINISTRATION

So far, {"f)n.sidt'ratioll Illl\ lx-eu J'iH'n p rimarily to ti lt' amount lIf drug ill tilt' hody follo\\in~
mult iple l.v . ho lu" iuje-ct ions , o r tln-ir equivale-nt. at ("l itlally s!l;l{'t"'l.1 intervals. In p r act ice,
ch n mk- ad ministm.tioll Is usually hy till' o ml route. Furthr-rmon-, 1I11ly d nl ~ couccut rauon
in plasma or in blood r-an Ill' measun-d and not amou nt of d nl ~ in tilt' Ixxly. T Ilt,st, <l.Spl'(·ts
an ' lIlIW considered. I' mhl l'llls n-lated toum-qual {lost's "'I t! dusill~ iutervals ami to missed
dust's ure coer-red in C hap. 1ft. Concentranou \ I olli torill ~.

btrIYascvlar Administration
Tln- oral (also iut rumuscular [Lm.]. lnucai. SIIIIt:'lItalll'tlll\ [s.c.], and rt'l·tal ) utiministra tillll
of d nl~ n-qulres an add('t.1 stt'p , «leorpnon. 1-:'1\ ' I to -I appl~' to t·xtr.l\·;l'>('ular administru-
non, pnJ\idl'<! that ahsorptioll has t""st'n tially t'n <l("l i within a small frati iol\ of a t111\in~
Inn-real, a {'(1TI(litinn similar 10 i.v. bolus adm imstrutiou. En- n so. a co rrection mu st hI' nuul c
if hinl1\·ailah ilit)· is It'S" than I , \ \ 'ln-n ahst''lltinn conttnues t h rtlll~holli ;t dos i ll ~ inn-real. or
10I1 ~t· r . Ilu-n tilt' n ·l;ttio1lShips of Eqs. -: ami k ..till appl~·. 11.1'''1.' rt'!atillnships ullow t'sli-
marion of tilt' un·m,gt· p late-au amount in tI "'l x xl~' and tln- an ' m~t· plateau {'(111(,(·lltm tillll.
rt'Spt't.·lin·I~·, 111{, sltMl)t'ss (If dn l~ absorpttou alTt't.i s lilt' dt·,gn 't· uf lInl1l1atinn around. hilt
not va hlt' of. til(' avt' mV;t' {'llll(...-ntration. T Ilt' t'xt" ptiun is \\'11t'1i ah"u rpt inl\ Ix'('u l!wS so
l i lt'
~ 1(Jw rhat then- is illslllTk it'nt ttnu- for comph-te abso rption. (' .V; .• wln-n !imi!t"ll hy tilt' transit
tim t· within tht' ~;l,tru i nh's t i l lill trotti ,
111(' dlt' mpt-'util' imll;l<1 of <IilTt-n'n('("" ill absorption ki m-t ics , hul nol ill hioavailahili ly.
of t ·xt r.t\~l'it.1 1I.trl,· ;111111inisft'n'll d m~ prud mis J'iH'1l n 'pt'lIlt't U" tlt·lll·nds ou tilt' fn '(I"t'lIl'y
uf tln-ir adnnnist ruhon. As illustmlt'll in Fi,g. 7- 7, major d ifTt·rt·m,' s S("t'n follO\\in,ga "i n~lt·
diN' unl"Ill,'rsisl and un- ofpuh·ntial lllt'r.llll, -ut it- ('lIll,·rtl at pblt'1111 ", 1It'1l tilt ' <Im~ prt M:lutis
an.' J'iWlI illfn "llllt·utly. n·btin.· tn tI.l' " alf· lift· of tilt· t1 m,g. » ilTt·n ·lIt...·s 1ll,·tWt't·l\ t ht ' lII
alm"" t Ilisuppt.·lIr at platt'all wllt'll tilt' pn xllll'fs <trt' ~\ 't ' n frt"ll" t·ntl,., In tilt' b ttt'r ( 'IN'. as
"talt'l l p n'\iousl~· . " i lh ('xlt'nsi", a{1.·ullIulatiol\ of d m~. l!lt' ( ' III( ...·ntr.ttiu ll at pbtt'lm is
rt·btivt'l,. Inst·lIsilin.· to \1lriatiollS in ahst'f)Jtiun ratt',

Plasma Concentration VHSUS Amounl in Body

Dll ri u~ ltIultiplt· dnsiuv;. tilt' p l:l\ll\ ll ('()Jlt't·lltr.ttlnl\ (~m lx ' t~\I('lI l a h't l at allY tilllt· hy d i\i din v;
tilt' (,( ,m'S pollt li n~ t"lluatiom dt'fi n i n~ amollllt IIY\ul ulllt' Ilf di,t rihlltillll. I>j"trihlllion t'tilli-
lihri ullI Ix·t"'t't·n d m~ in ti lt' ti"SUt·s ;tIld tlMt ill p1:tsma 1"I(('s tilllt', T hu s. ob st·l"\'(·d m;l\i rnmn
n lllt'('ntrd!iollS ma,. ht, app n't.·iah ly ,gn 'alt-r lhan t! UN ' (1tlt·lIl..h't l hy d i\ idi ll ~ E(ls. I 1111113
hy \ ' ( St 't' C hap. 19),
111t' a\"t.· m~l' pl.tlt·,ltl t, mn'ntralioll 11m,. hi' (·;tlt-lIlah 'l l llsin,g Ell' ~ . 'n .is t'(ltl;t1ioll is
ilpplit'ilblt· to any ",lItt'. IIlt't llllt:l u f iltim illistmt iuli . or t lt lS;l~t· form , 1l\ I,," l.: ilS h ioa\1lilahilily
illltl dt·ar.tlJt'(· rt'lIlaiu ('(lIlst;mt wid l Ixltll tilllt· and dust,.
CHAPTER7 .s

DESIGN Of DOSAGE REGIMENS fROM PLASMA CONCENTRATIONS

(). )s,,~t· n '¢IlIt' Ii S {'; 111 lit' desiWIt't1to maintain ceuneru rutlons wtthm a tht ·mpt·lIlic window.
TIl(' \\i lldnw is dl' filll'ti hy a IOWt' f limit (C" .........) and an upIX'r limil (C ..,,,..... ). TIlt" maximum
d()si ll ~ int e-rval. T"..... and maximum maintenance dns('. V\I ,"""" ran he n'ad ily computed
frn m tln-se- limits llS follow..:

13

whe-n - 1:""" is lilt' maximum lime Inn-rcul ove r which tl w~' Ilppt'r and IO\ \'t"f conccntruuons
cnn oc cu r. By n'arr:Ill~I'IlI(' 1l 1 of Eq. 13. ti lt' value of T.-. is

14

and. Imm 11\l' rdaliollShip. k ::: Cl ,69.V t 1l2 ,

15

TIlt' n ) rn'sp0l1(li ll~ maximum mainlemlllt't' dose, D \I,,,,,,,. , tha t can 1)(' ¢\'(' II ('\'(' 1) ' T""". is

C....,I 16

\ \ 1)('11 J).\ /.""" . is. ad1l1i nis.tt' n'(l t " l ' f)' T...... , then- ts au a\"l' rJ.~l' n Jll('('ulmlioll pmdut't'tl
\\i lh in till' dosillJ.: interval . t1I' l111t'tl by

17

10 10 10

8 8 8
.,;,
oE
2- 6 6 6
~~
~, 0
"
~ ~
"
0
• • •
0
u 2 2 2

0 0 0
0 6 12 18 2' 0 6 12 18 2' 0 6
Hours Hours Hours

. 'i ll:' 7_7. D,ll.·r.·'....... in tl..· . 1"'''1>1;'''' r..t,... I..'tvo...·" tv." ,L J.," · f" n,.... ~·r.." '(I Il<'n· f"f ;1I11,tr..t;" . ' pur-
p",... . f"lI',"; Il~ a 'i"~'" ."tr..,a,nIL.. ,L"... (\" ft 1"',..·1) "Ill I · It m..;".. ,1..·....I..·utk· i" 'I_i ..t pl..t...." <Iunull
"",ltil't.· ,L.. inl:. n ..· n ·bti ", " 'Ki lla linn " f ,IK' r 1a-'l,litl." ·ntr..ti..n " t 'N) the' , I ru~ pn "ha.-t. an' l:i" 'T1 Iufn-.
' 111t·",~ 1111;,1.11..· 1....",·1) i. "".. ·1, I:n·..."'..tl..." wI...n ~",n fn~ II l<·,ll ~ ( n~' t 1"',,,,1 ).
. CHAPTE R?

By d i\i ding Eq . 16 by E'I' 14 and (,o lllpa rinv; this ratio tn Efl. I i . it is appan'n l tbu t t11('
vahn- of C.._ Is ~\1.'1l hy

18

A dfJSllgt· nWIlIl'1l ma), be.' dl'silQlt't) hy Slotting ti ll' d ll~ i ll V; mIl' ('itllt'l' lu ad.it'\1· tilt"
average conce ntranon . C.. AI • or to maintai n a pl.," k concentranon. In IXlth approaches .
couce nt rat tous an:' maintained wi thin th e tlw mpl'lI til' window thruuV;holll tilt' dos illV; in-
terval.

Maintenance of an Average Concentration

Choosing ti lt' a\'t'rdv;e conce ntration within tht' dosing inten..,,1 at plan-au 10 bt· C...... allows
till' grt'ak sl possible dosi ng Interval. This dosing interval (Ell. 15 ) and tilt" ('()rrespond ing
tnalnteuauce dose.' IEq. 16 ) mil)' nol Ill' practi cal. howeve r. Bot h values ilia)' II( '('() to be
atljllsh"l:! to llIalt· the fn"({'lt"lll) ' (If administm tion coowment for pat il'llt (1)m p limlt1' and
10 accommodate tilt' tk)S(· strengt hs o f the dnl ~ p roduct s available. TIl(> ~llid i ll~ prt uciph-
is lu maintain tlu' sa me rate of admt ulstrattou am i tllt'n ·fon · tilt' same chosen a\'(' rd~t'
steil<ly-statl' l'0Ill1' 1I1ration.
lI a\i ll ~ chosen a conventeut dosi ng iIlIN'" !, t smaller than t ...... ' till' lIlain tl'lIalll" do~'
is

19

ami the l(}i\(lin~ dose, appmpriatt' to attai n the stl'ady-statl' concvntrunon, initially, is

20

If mo n - (or If'ss) \igomllS Illf'ra py is desi red. res lllt i ll~ in the st' U i ll~ o f tln- an'ra~l'
largt·h·d conccn tratlou 10 lx- highl' r (or lower) than Cu .... ' till' d()si n ~ rate canbe increased
(o r decreased ) pro pcrttonatcly. However, one may wtsh to adj ust till' dosiJlK illte r'\'ul to
l·I1SUn.· that concentrations remai n within the t1lt'mpl'utic wtudow.

MaillttfKlMe of a Peak CHc:entrRtton

TIlt' second approadl 10 till' design o f dOsagl' rt1Q lIIl'lIS is based on tln- IIt'sin' 10 maintain
a gi\1.' U p -ak conceutruhon . 1111' pe-ak concenrratton chosen . C,....I. depcuds 011 how ag-
gn'Ssiwly Oil(' wishe s 10 PUrsllf ' therapy bul usually ltes in till' upP"'r ha lf o f till' t lu-rapeutie
wi ndo w , The maxtmum dos ing Interval is:

I'IC.,../C....,I
MoJilim um dosi ng interval - k 21

O n d lllosing a conwment Interval. r . less than tilt, maxi mum dt'fill('! ill EfJ- 21. ti lt' main-
n-uance dost· the n be comes

anti till' loading dust" if nl":t' sSUI)', is \ ' . C,.....l. Note thai C,ond is tilt' same a.<; C This
met hod o f rtOWlllt'1l dl'siRll It·mL.. III 1)(· snupler than the p n...-ious om-.
CHAl'TEIl 7 97

For t-', amplt" lunsit!t'r a t!m~ wi th a tln-rapentte window uf 2- lCJ IIl WL. a \u IUIIW o f
di slrihutioll of 2.'i L and a lfi-hr llalf-Iift-' (k = (J.04.3 lJr - I ), 111t' maximum dosin/;t Interva l
is 111t'1I .37 hr li n (l O/'2 j,1I.04:l 11r - I), If an Interval of 1:2 hr is c hosen. tIlt' mutnten ance d uS('
».
llt'l'llt"'ll is then ahollt lCJ(J 1Il ~ ( \ ' . C,.....I(I - t· - lr TIll' load ing duS(' (V . C,,,,,,, ) is 2S0
lJl~. If till' rq ;lIlt'n is dl' si!{lll"'l l llll till' hilsis of alt ai n i n~ and lll ai Jllainin ~ the a\1'rll~e ('( JII-
rr -nt rution , till' maiun-uauce doS(' (Eq s. l"j and 19) is then 6.'5 1lI~ and till' l ()ll(lin ~ dose (EcI_
:20) is !fi(J 1l1 ~. F i~ lrl' 7...), Illust rates 11](' dilTt'n·Tl(.'l'S ill tlll'5e two approaches .
Following r-xtr avascnla r adnuuistrutjon, fluduatioll5 in till' plasma eonrentra ticu of dnl~
an - II'ss thun thost' aft e r iutravuscular admi nistratio n. Dqx"lltlill ~ 011 ti ll' slo\\Tll'ss nf rhl'
absorption prlJl 't ' s .S, it lIlay Ill' !'lt lSSihll" III adminislt'r tilt' dn'g II";;s fn"'ll' ll'lIlly th an lmhran-d
in IllI' rl~lI1t 'ns dt 's i~lt "'l l by I'itl ll'r of 11ll' last two 1l11't1I()(ls.

W1tea BioGvG~abili1y and Volume Are Unbow.

Orul t1llSllgl' rq..ri l111'll S 1~1Il " ISl l Ill' 1 II'si~ Il"'l 1 \\i tho llt ddl'nnining bi ();I\'li labi li~·, Thi s is
accomplislu-d usilLg tilt' an-a nnder lilt' plasma comvm mnon-ttnw l'U1YI' (AVC) fnllu",inR
a singlt, d osl'. From th e n-lationslup F ' Dose = C I. ' A l!C after a si ll ~l e duS(' (Eq. 7,
C hap. 4) anti tilt' rt,latilillship F . D llStvt = CI. ' C...... du rinR slt'ady stall' lIftt'r Illultipll'
dost's (Eq. 6 ), it follnw.. thai

C• .
L..-_ _- " ~
AUC (single dosel/f
':..-__'_..;...-"- ... 23

Dose
Loading Maintenance
Upper Limit A B A B
10 ~---- -- - --- -~-- - - - - - -- - -~- - - - - - -- - - -
" ,B
"
,, " ,
II ' ,,
,' " ,
"" ,
250
r, .-
,
, I , I , ,
8 200 ,
,
" I " I "
,
',
I
I
"
-, I
,
-, ,
' I " I ,
A " ..' " ", 0;
6 150
.sE
4 100 -c
~
0
E 1
Lower Limit
2 50

o o !
o 12 24 36
Hours
. 'il/:. 7-'1, I),jT""·'M1~ in N t> UI.1'"xl. n( .101'Wl..... n,.;nx-n ,Io~i!:lI. Il''!:ill w n ..\ b n li< I I>I. d :. lmd 10 .Io-ri~II ..I I"
m.<.inlaill 1111' "'''11' .,,'r"l:" 1111111·nlral"", ;o., Ilw "I>I.<.i'1I11 "~II'n II... ~1"1I" "lnati<II' ""11........ "''1\00...." ti ll' " I'lll·.
l lll "' 1.','1.> ,....\ J....rr (2 IIIWU Ii'nih It ' '''nll·'' It ((. >I. .r...1 ~tipplo..lli'll' ) i, c lo~ilQ ....1 In ,·u'u ", dUl II ..• p"a~
('"'I1>lI1r.tllll' ,10,,·. Ill" ,·.........1110.· Ul'pl·' limit . Of l'''I"''' , a 10....·, ,..."" _-..)'11' n...~· I",,," ""'" d ..... ·n, Tht·Ic.. I; n~
,10..... " "lui"..ll" <ll~,it"I' II.., '11'.ll~ .•t"l r ('"II.. ntn..ill''' i lTlllll..li;atr~' llIIIl till" nW"IMIiUII"'IIoJIM (II' '.-.Ih "":l:l.
" " ,'' ' a n' i'1I1I1o",... 1"" II.., '; 1.01'1 ,itlo, ..1" 11.., l(npI,-
•• MlATIF'tf-DOSE RfGo'liNS OWTH7

COIIM'( jlWutly. l'i tllt' r lilt' dllSill ~ inh ·ry"IIlt'l...·ssa ry 10 adJl e\'(- a dt'sin ><! an·r.l~l· s h ·atl~··st.l tl'
conccntrauon or tilt' a\"('m~l' roncent rution res u ltill~ from ad illi ll btt' rill~ tilt' doS(' (...·I·I)·
dnsill~ interval can he 1'llk' II,,!l'(1.
By definition nfC....... tilt' vahn- of t . C M .... is tIll' £\ t'C ....-it hiu a dns in~ iutervul al slt' ady
state. 111\1s, t his a rea is equal In t hai flllluui ll){a s i ll~I(' duSt,. This p rind ple is SlllM11in F i~ .
i - 9. and a pr actical illllstmtin n is SI1I1\\11 ill Fi ~. ' -In.
Giwlll h(· plasma concem ranou s \\ith tiuu- a ttN a si ll~I(· o ral dost', lilt' ('(IIIl'l'ulmtiun at
allY lillie dllrill~ repeated "dmillisiratiull of tilt' suuu- duSt, ran he n ·mlily calculan-d by
atld i ll~ tilt' c uicentrurtons n· IIl,l.i ll i ll~ From (·ud . uf till' pn'\;u us l!1)Sl·S. For ecnn ph-. if dO'w s
lin' Wvt'll at 0, 12, ami 2-t hr. then tlu- concentrunon <II 3n hr is {'(!llal to tilt' SUIll l)f Iht'
values iI ! :In, II'; , lind fi hr after a singlt' dUM',

o 12 24 36 48 o 12 24 36 48
Hours Hours

t' It. 7-9, I>w"'" l""In·"lr..hn", of" ,Inl~ 1:1"''' illlr.." ·"..,,.ly (I.·til ar.. 1m ally (ri!tl,l) "" .. 1i",,1,...... " I" .')41 m~
..,..I Ii" ..1," "'i,,!/: inl.·.... -..I nf fi hr . nIl' ""'1"·lil",· i. 12 hr. :'\,,1:<' 11 1 tI..· A ( '<: ,Iurinl:" '''Nn~ ill..·....... ;l.1 ,It·;,. ~ ,1..1,·
( 1i~ I" r ..ru.lih ~) i. ... I•....J lel tI..· 1111;;1.1 ·a ,u..lo·r tI,,·(" I",~" ; ,,!/: .. ';"1:1,.•10....• « \.trl .·• .J,...Lnit).nil' t\'1l1u..lit,,,
or tI,,· (UK"." lnt lit", i. e1im;"i,I l "1 ,, ~"''' "r..Uy (;l.I ,'1>1 it" . 1....J 1".li f.· i. 1,4 Io rl. 1...1 tI,,· ..",r.. Jo:1· ,"';,.1:•.",..,,·
n"""'1,lr..lit,,, i, II..· ... " ll' 11> 1 ..1"1,·r I.•·. ...lmi"i ,l r..lio". ,,·I,,·n. ...' in Il.i' •·...u"I'.. -. F - I. n ..· '''I .",l it" " ,,,... 1
I"ur II... . im" \.tlit,,,S""· l(i " in "I,,,·,..h.. I-I)

t ·IK. 7- 10. T" "·"l)·.f,,,,r . ,,1.)'''1' •.",-h n" 0.5

.. sin~lt· :zt:l-m~ or.ll ,10....• lIf th. · 1"'11" "
n .... ·.J
.1;<lIJ1"n.·. d ell OOlJ""" " . f,~""..,,11 '''' ''' II. \.tlt'r I~
.." "...J n~ "><·,, "f W "'!/: " I" ("'~OOIJ"';"" ll.tiJ:.' (u . 0.4
2:! (...." . ....'1;\1· ,~~, n ..· ,>I ..J """""1:" pLa-
I,..." (·.. ~OOIJ" m ('{"",,·utndit.., " ..·11 pn..IK1 1
I,,· tI... . -..1, ntk"I" I... 1 1"",,,, 110.. '-inlt!<· ,), . 0.3
•L.t"."hl;t.i' 1loy .L' i,L"" II..•..H ·C I~' II..· -
i,,!/: i" I.·....'..! ..",I (·"m..1inJ: f" • •),..... '1 ..· .. ~ ..I .'
Ii,..• i,t"'· 1"·rf'''1 pn..l it1if", ( I "'Wi . •."J,1 1l. \l )
(11.,,1...1"'" (n ,,,, <:n..·"I>I" u. l>.J. Ui" ~1. \I ..
I'uri. S K.. II... I . i'.i ll ll~'. \I .A . "'KI SI....It·r. H.I;
H... I,K....I .i '''I:I. L..••• d.·..nu • .. I" clt~OOIJ"" '" ill
....l..~' nK·" 1' IK1. it"·n· ,,..1 llUlltip..... Ic....
lIIl'l"U muLatit,,1. e li" . 11...nt""..l.i'><1.• ~; !l.1-ij.j _
11J'jJ. H., .... h" ....J. " , I" po' n" i"';'II' or .>\ I>IS
1'"", .>\u. lntLt.. ", ,,,,,. I.i,, " h..i.)
o 0.2 0.3 0.4 0.5
0.1
Predicted Average Clobazam Plateau
Concentration (mgIL)
CHAPTER7 .
Useful n-lationslnps han ' 1."' ''11 tI,,'ri Wtl fnr d... ~ i)!;n i n,g uml t"\~l l ua lill)!; a dOS;I~t, n-ginu-n
ill which tilt" tloS(' ami tin' dus ill)!; int erval au' fixed. Tahlt, i -5 summarizes som ... of Ih...
mo rt' important rt ,latinllS h i p~ umltlu-ir lilllit;ltiuns.

CONTROlLlD RHlASE
TIlt' mailllt'nalil'(' of it l't"'sl<llli plasma couceutrutiou. and uS\litHy a n 'lat i\1--Iy const ant
n "'poll">t', is "ellit,\-t"tl hy I'tJllslanl-ratt' ittllllilli... tration. \\1Iilt, su mt' I'tJllst'U1I-mh' rdt,it.';t'
"i}, tt'ms ha\'!' )I('t'll dt '\1,lol)('t1 (C hap . 6 ), othe-r dusa)!;t' forms exist From which tim)!; r""t'il-'it'
is nnn-h slm\"('r than From ullI\·t'ntional tlos.<I}!;l' form s and for whit-I. the n, lt,wit., kinet ics an'
dn">t'r 10 Iirst-onk-r. than to ;/'.l'Il.l-tlnlt,r. Suchcont r olled-release p roduct s donot completely
IIhlitt'r.I!t, h' ll d,) n-duo- l't.lllsidt 'mhly theHuctuanon in the plil'ima concentr ation ;tt p lat eau.
when l'tllllpall."ti \\i lh conve-ntiuual the-rapy. ami an: pa rticularly useful wln-n maiuteuauce
of tllt'r.lj'll.'\It il· n llln'ntr.ltinns is diflk-lIlt or illl't.)Il\l'uit'nt,
Til illllsirah' tilt' poll'lIllill vahu- of ('tllltnl lll'll-n ,lt'il'il' products. consider tilt' t'\l'nts at
plalt' all simulan-d in Fi!!. i - I I fnllo"'i n)!; oral ad ministration of t1n'uphyllillt·, which has a
tlu-rapc-utk- window of 6-20 mw'l. in a elrild with a half-lift, o f 4 hr. With tlw IIsll,,1 dtlSil)!;t'
form s, ah'\.tllVtio ll is rapid und, In lTlilinlain ti lt' plaMna l'U111't.'IIIr.llion \\i thi u tilt' Ilwf'dl")('uti t·
window, tilt' t lm~ must II(' ad minish 'll.'ll t'\ l 'f)· 6 hr. an inconvenience. ,-\ d m i n is lt'ri ll~ thr-
corumlk-d-rcleaw d' lSa!!t' form at IIII' "',1U1t' frt't IIlt'Ii''Y as tilt' conventional fun lllll<ttinll Il'atis
Itl a mar k,'" R'tl llt1inn in lilt' IIm111atiun at plateau. Intk"t'll, t j n- cout rnlle-d-n-k-ase for-
ruulation can be )!;in-II al a mort' {'t)ll\'(' nit' nt dnsin )!; interval . 12 hr, aml slill maintain tilt'
plasmu l't.III('t."nimlinn wit hin the Illt'r,LjX'ulk \\i lltltlw. To maint ain rlu- same a\'('r.I)!;t' con -
1'('lItr.ltion at plait':... lilr tilt' 12-hr inh-rval. Ihl' dns" of the less fl't'lllll'utly at!ministt'n'll
controlk-d-n-leuse product mu ~t lx' l\.\in' th ai of the conventional p roduct. Oll\i oll.'ily, eon-
trolh-d-n-leaw pn l(lLll'ls must perform rehably. If all tilt' dm,gwere released inullt'tl iOitt'ly.
an IInOlt'l'('pt:lhlt'1l 1ll1I1alinn ill tilt' plaona coucentrution would n -sult .
For orill .ulnuniv trution , t)lll'(' or twice t1ilil~' is t1t'si mh lt,. Al'l'tln lill)!;ly, for llm)!;s with 1I'llf-
lin 'S ~rt'aI N than 1211r, oralcontrolled-n-lease products may Ill' o f [itth- value , 1101 o nly

,.1,1.7-5•••latl......lp.f.......I...... D. . . . . . . .1•••••
EKTUvA.SC\.W
1oICM' All.'iQIf'lo-.
rv "'"
"""""'"
'0'"'
No'nlenonce dose •*"
» 11
·.
" > 1I II> .

N"
ActumuloJt,on
... ... ••
",d" ,
PlATEAU
AYE!loge omo.....l • •• •• • ... N
•••

• •• • •• •• • •••

No . imum
C()I'(: en " ohQl'l •• • N
Mnimum
conc.:en"Olion
... • •• •• N

,... . ...
'J .,. '"'9'"""'"
, ~ ~
<J 0'<>UCll doo.o...-d
"""""'*""appmo~
~ --..::.i>

'""""",, - -
' ~ ,., ~ ... ~ ~ d o.. ~ , .,., .._
"'" N.:IV<M
100 CHAI'TH 7

25

20 f
I
I
I
I
I
"~.- -- - --case A
~ .
..... case B
Case C
5
Case 0
o
o 3 6 9 12
Hours
HR. 7-11 . ,\ ,I",i ni, lt-ri ll /.: " limit. lil ,· 11 .".,) l1i"... in" .,onlmll... I·n·l,·",,· ,1<",,1:" f"nn er..I l li"'.,,) "'..~·II"t
""I), ,1o"TI~"'" ti M" " ' K1 11.. lil'" ill 1'1.."", "ot...."I ....til ..' ;1' 1>1 ,·.." ,e · III n""l"'n..lto .ha' , "'tl, tiM" "'11..1
",¢ITI"n j<:..... .\ ),1",. m..~· "t... I,,-nnit th.- limit to ' '' ' !Quo" fn"I" ,'l~' «:.... 1>), C.....· C . 1"...... tI..•..."......,·
Ir.dic,n.litlll' l,n.fil.· ..rkr tI,,· ,,,,,...J do.JiWI.,'t. f" rm (3nl) "'It) 12 hr , In ,I,i••.••""1'"', " .2 - .. hr. \ ' - ;}.') I ~
,.. - 1,11.. , h..Jf·lif.· lO r rd.~.....· (rnm tI..· n trul..'(!.r..l.·..! I'" "lud ;. J hr. alMI tI..· II,,·r.4l""'I": "i".I.e", 1. 3 In III
,n~ ~ n ..·,.. ~. n,¢ IIIt." . "". Il,O '''It ' fj hr (C ;\ ...., I tU ;1,"1 3fill "'I: ........... 12 I,r (C........ C ...,..1 Il ).

h("('allM' tilt' llsua l rt' w men is convr-utent hut IJol'l.'m lSt· pmlr-dl'Il'l1 rt·le.N· ma y pUI d m ~ into
tilt' Inwt' r in!t'slim' o r perhaps out o f Ihe hudy lx-fon- lilt' rl'lt 'll"l.' is compk-te. DI 'l.' n'<L"l.'l.!
bin'l\"ailahi lit)" then l x-conu-s a major couceru, l's pt'l.·ially in pat il'n ts \\ilh d ist'il\I'S in whh-h
~a.\t mi ll h·s ti llal transit is shortened.
For II d m~ Ihat is usually "rin 'lI i.m. or S.I'., 1Illlltiplt , inje-ctions un- i uconvenn-nt anti iI
1'tllll m llt'l l- rt·II·;l<;f.' illjt'l.1ahlt, ( I(JSll~t' form may IJol' ad"U1la~t'olis . Dt'I)(' nd i ll ~ lin rlu- tll!;ll
d oSt, rt'fillin'li and o n t ht' IOI..tl d Tt'l.1S of tilt' injt'l.1io ll mixtun-, il Illay llnly 1)(· Ilt'l'l·s....tf)· to
admlmste r till' illjl'<.'tiun \\1.'l' kly, monthly. or pl' rll<tps as a Si ll~II' dosl' ,

Evaluation af a Multlple-Dase Regimen cmd Asseumenl af PharmcKKlnetk Parameters

1111' dl'n ·lop lllt·nl u f dOS<I~t' n"¢IIII'IlS p n ll'l'l'l ls in t\m st a~t'S. 111t' fin-t imul\"l's l'St;thl ish i n~
wllt' tlwr t ht, events 0 11 multiple dosill~ an' p n 'll it11'l1 from si n~lt' -<lost· dat a. O fh-n then- is
f!;(Jod accord IJol'lwt'l'1I Ilhst'l'\11tilllJ and prcdlcuon. im lil'atiuK Ihal ti lt' pil'lOnal'llkiTlt'lk 1l<1-
rameters 1Ia\"t· lIut d l ;Ul~t'l. l ll pn n mulnpk- dosi n~. ( K"l';lsioll ally, p n 'll it'lio ll is poor, si ~ll i ­
f)i n~ Ihal oue or mon- phanllilt"llkint,t il' panllllt' ll'rs Inls d IiUl~I'l1. l'\id l'Ill'l' (If SUInt' dost,
o r tune del)( ·nt lt·nl')' (St'l' C hap. 22). If pn-dicnuu is good . ti l l' second slagI' is ft·lat in-Iy
streightforward. It ill\uk es \.u')i ll~ till' n 'WlIlen to adlil'\'l' pn rtk-ular plil\m<l coucentmtj on-
tinu- profiles. which ca n hI' t'\ "alllall"(l a~ai llsl IIll'mpt' ul il' rt'SPOIlSi-' a mi toxil'it)", The task is
1II11l'h mon- t1illk'ult when d ust' <llld filllt' t1t·pt'ntlt·nl"it ·s prevail.
11 lis sect ion deals \\; Ih how to both eva luate a multi pll'-<Imt ' n'¢Il11'Il, \\i l ll or \\i t ho ul
si n~lt'-< lmt· data. ;u ll l l'~ l il ll att' plmn n<llu killt'til' pa nUlwh'rs . It hu ild.s ou whut has IJol"('1J
covered in tlu- prcced mg pa rts of l ilt' chapte r.
C lean mWBiua\·aila h ilit)·. Siahilit)" ill this ratio (CU P) 0 11 lIlult ipll' dmiJl~ is Wn'lI hy
t he equation

AUC.. .. AUC (single} 24

CHAP1H 1 MJ\TlPlf{)()5lIi'fGl,','.f NS ,.,
wln-n- AC C" is till' ACC withiu a dos illK iute rval at plateau. Equatioll 2-1 is a n'<.~lsli lJK of
El l' Zl. \\ liN t· Al l :•• = I: · DI)S(·/eI.. A plateau is takeu to IN.' n'at:llt'd wlwu M...·t·m l
t'fIllM'<.·uli\t· t ru u ~h l"llllt"l·lIlmlinlls. dd"nnim't l from bluod samples taken jmt lx-fon- tilt'
1It'\t di N', show l U I tn-nd \\i th tune. TI ll' at't.:ural'," of tilt' esHma!t·s of Al:C.. und ,\ L'C
( s i l l ~lt') an ' Ill';l\ily tI.'pt'm lent on lilt' numlx-r und t i m i ll ~ o f hlood samples . If needed. tilt,
('slima te of ;\ l "C" can ht· imp ru\'etl usin }: st...e ml d(Jsill~ Intervals, which in turn imp n nl-s
til" ('stimah' llf C [J F 'II plateau. As Shl)\\ll in Fi}:, j'-~J for dl" J;v~un , C[J F dill'S not d m ll~t·
o n multiph- dmin ~ .
1IIIJr-U fe. T his pa rallll'h'r llIay Ill.' d ilTit'u lt to cstnnute t1ll ri ll~ multiple dos i n~. Ct.·rtainly,
half-lif(' canuot l«- ('sti lllah"ti wi thin il dosi ll~ iute rv a l with all)" 1"l 1ll ~ t1(·1I1't· when th e dm iJl~
int e-rv al is short er t"<II1 tlu- half-life , 'lSlilt' .Ied int' in plasma l"lml"l-ntm tiHIl is too small en"e r
this limp intr-rvul. Tlu- pr obk-m is IImelt· illlpus sih lt· if ahsu rptiem l"lllllinlies I hruu~"uu lt llt'
dm ill ~ interval as nflt 'n lll'('u n; \\i I1l ("l mtm llt"tl-n ·lt·'l\(· product s. Theore-tically, half-lift'
t"l mld Ill' ('sliIiMIt"l1 fn nJll ntll~h values taken oll l hl' approach to platea u. lnru uch till' sa mt·
way ,L\ dOIlt' wi t h pl'l\ ma eli l a obtai m"ll 0 11 tlu- riSt' to plateau follu\\in g a constant- rate
inpu t rl~ Il 1l'1l (I'p. ';'0- j' I ), III p ract ice, howt'wr. th is met hod is ~l' lJl' l'ill1)' nnl \ 1:' 1)' prt"l·ist·.
t-s!)t'<.'ially wlu-n tl n- dmill ~ inn-tva] a ppnl<ild1l' s tilt' ha.lf.lift'. n'Sultin g in nnly a few tmugh
\';ll11t ·~ 11l·111ft.· plate-au is n-ached.
Tilt' l)t·st \\~t~' 10 I'stim ah ' Imlf·Iif(· is aftt' r stopping d m g admillistmtio ll. AI plat eau.
plastua l"l Ill{"I'ntratiom an' ofn-n much h i ~llt'f limn thlJSl' ad lit"'\'l'tl aflt'r a si n~I(' dust, ami
sn 1',Ul Ill' lrlt·asun"tl IJ\N IIIUdl IOllg" r !wril M.ls lIf tune afh 'r dtlppi n~ dosin g, t1n·n-hy Ia-
d l i l al i ll~ an a("I'lmlll ' e~ t i lll at (· llf half-lift·.
De ~n"t." of Accumulauon. :\('l1unulialinn al\\<I~'S occurs.Tln- majnr question i~ wlll'tlwf
lIlt' c1t ·~n 't· nf il('l'UIIIUblioll dilT('r; [nun Ihat <llltidpatt'C1. O ntOpredicto r uf till' d(~n't· of
iIl'l'Ullllllaliou, ~\'l'1l in Eel' HI. i\ tht' II"a nti l)' 11(1 - (. - h ). lhe <It'l1Il1 lUlalion iud ex (n ....).
T his Iluan tity pn "lli('lS till' r.ltio of tlu- umouut ill e1w Illllly at SOlllt' tin lt' within ti lt" clusill~
intr-rvnl al plate-au to th ai at tlu- sa m(' tiuu- afh-r 11ll' fint dow . 1I11\\'(","(·r. phlsma concen-
Irillinll s ;11111 no t illllUllllh al'l' measu red . and till' r atio of ar nonut tn ("llI\("I'llt mtioliS is onlv
("IJllst,lIll \\ Ill'1I rln- Illllly ad s ,l\ a singl l' (,()1I1pa rt llll'1I1. In pmdi('(.. 1}(,(~dnSt· di stri lmt io;\
('tluil ihriul1I 1M.'IWt't '1l dnl ~ ill ti\Sllps and tlMI in ptlsma !ilk(·s tim( ', c1ist.'n ·!lilllt1l'S ari.\(·
11l'lwt't'1I " hwl"\"(·d l"l lll('l'ni ration ancl l111111lah"ll \11Int·s. a.\ slll n i ll~ {"llll1 plt'l (· dlst rilmtiun.
·n ll· di SlTl'IliUll'y is J.:rt·att-st at (·arly tiUlt's . For this n'IL\(J11 alltllM."l.IIl M· ti lt' \<llul" is eliffil"u h
10 I'sli ma lt- ill p ratii('f', C".... is a IXlllr d lolt'(· to l's lim..tt' Iht" d(~n't· of ,tC.'l·UlllU b lioll. A
t n Jll~1l \'allll' is a IIt'th 'r t'ilui('(·. ;IS di strihul ion l'llll ilihriUIIl is mon' Iikl'I~' 10 han ' IIl't'1l
at'ilil""("ll at tilt' {'nd of tIlt' c1llsing ill!t·I"\·al. TI lt' OhM'I"\"I"l1 { I {~n't· of '1('l.111J1Illat ion is C.......J
C I ........ wllt' f(' C\ ....... is till' tmll~h {"IJ1l("I'ntm tinn al till' ('m l of till' fin;t dl ",ill~ illh'r"'al.
II c;\\"(-\l'r. this I.LSt IIlt'lh, "1 n ,lit"s on \';thlt's ohla illt'tl at on ly o nt' lim e. TIlis Iimita lion is
a\ (litl l·c1ll sill~ a ("llll1l1lonly " l1l p IU~l"l l Jlll'tlllM.llliN "I1 elll ~\ [:C ("l lllsitll·ratiu ns. lIan l(' l~·.
Obwved
occumulo tion 25
inde x

wlll'n' .-\ ['C ( I. t ) is lilt, an 'a IlIJIII'r Ill(' pJ.l\ l1lll l"lJIlt"l·IIIr.llioll-liIlW profil(· c1 n ri n~ IIII' first
t11 ",in~ lntl'n 'al lo hll ll' t . l 1w pn ll."I"tlnn.·. anal{)j.~ons 10 IIII' Ust· of " ... vlllul'S ( Ell, IOJ, is
iIIm lrah"ll ill FiK , -1 2. Oh\i nn sl)'. a pn't li(1inn h,L\("t1 nn till' m l i n AUC ( sin~le )l~\VC(l. t )
\\ill lilait'll lilt' uhst'I"\'l"l1 mhu if ,'\ L'C" = ,\ L'C (silll.:lt· du.se). TIl(' I.l\llt'nn is tlat" total ..\ L'G
afkr a s i n~lt' dll\('. Tilt' vailI\' t1t'lI'rminl "ll by El l. 2.5 i.s llppru'lilll<ltdy t"llll.-J tn 1I( J _ ,. - .1.1)
if '- Ih~nrpti c m is \i rtnally ("lllllpl('h' at tilllt' t afh' r 1I sinJ'lt, dt)S(·.
() C",n.·l· o f F luct u a lio n a l Pl all·au. F IIII'lllatio u is all importan t l"l lllsitl" m lioll of an y
dosi ll~ n·¢uu'n . It is lIsnall~ I·\ ~tlnah "t l al platt'all . O Ut' ("lJlllmun IIlt'lLsun' of tl u' dl~n'l' o f
102 CHAPTfI1 7

f111l'tna!ioll is tilt' m!io (C - C m)/C..,,,•. An ad\'all la~t' o f this uu-as un- is that it IIt'als
wit h <lirt 'l1 o llM·"'<ltiollS. C _ , > C u... which art' thl)lI~hl In havt' n-h-vunce with rt·~ I)(·(.'1
10 l't , m· lalt~ of sa fetv and mtntmum (' lTil'l ll"\', :\ d isml\1U1l aV;t· of th is IIlt ',t'lirt' , 110\\'('\'(' 1". is
that it rcln-s nn only' roll ObSl.·l"\~ollillns. t lllt' 'o f which (,'...""". ) is oftt-n difTil111t In tosti malt'
i11't.·lIntlely. unless mOillY hlood s amples art' taken wtth!n till' dosin ~ interval. a n ·lati\'l·ly
uuconunon cliuiea 1 pract ice . Anotlu-r 1I1Oft· stahh- nu-asure of Huctuatktu, wilieh is k-ss
dept·ndl·nl Oil si ll~lt' observmous. is ~n'lI by

26

wlw n ' ,\Ue (al)()\'(, C........ ) aud AVe (belo w C...... ) arr- till' ,m',lSabu\"(' am l l"-' ]el""tilt" awmV;t'
concent ration at plan-au (A VC•.'t), n.·spe<.1iwly. Est hnat iou or tllt'sl' values is SIlO\\11 in I!\('
inset I" Fi~. i -1 2.
Other Parameters. Equunon 2i forms a usefu l I l;L~is rur
t11'Il' nllillill ~ rt·lali\'l· bin-
a\'ailah ilil)' or it t1m~ adll1in isl t'rt't:l t-Xlnl\1L\I:ularl)' ( t·.~ .• u r.tll)'l. bcotWt"t'1l t\'" treat nu-uts
( t" ~" dnsa~t' form s A and H), l f dea ra lll'C' n-maius llIl('hall~I ,(1. tlu-u

IAUC..Js IDose).... 27
Relative b ioova ilobility
IAUC.,}• . IDo..I,

AUC (above c....)

"
50

40
~
g 30 o 2 4 6 8
c Time In Dosing Interval (Hours)
5'

~13 20
c
0
'-' AUC(I . t)
10 - -__<:: AUC(single)
AUC"
0 --- ---
0 24 48 72 96 120 144 168
Hours

tl,lt. 7_ 12. E\~Mti.." u( a II1 Ull l"" ....Io"'· " ,Qn,,'1' , 11,.. \I .. hihl~' of till' CU r rdlio "ith llo" i""('lJ,I..•..\.. 'S .... I I~-
(~ltllp;uinll: Ih. · m .. t1llrinK .. <1o,.jnK i ntc·l'\~ ..I p1atf''''' (A t·C..) I.. that ..I' till' tol,.] ..n· fit·, a 0111"'" , 10...•
(Al'C(oiu0t- »). n..· ,~ ... of *,~,"mlation il la kf'Il"" II..• nolioof' Al'e .. 10 II..• an 'a t1"n"KtI li"t ,1o,.,j"Klnlt·I'\"..J
to IiIlM' t (ACC!1. t »), ".,.. I.alf-lift. io h,'S! ,Io-l..n"irM ~1 a(h'r ' '''I'pi"To: ,In' f( a11", lnl\lr.lic>ll , n..· in...-I .1" ,"" II..•
""-11,,,,1 f"r ...tim"lin" tI... d.'W'... "f 0'" 1n"'I" " 1.........1 ,>I, Al'e: (E' I_2fj ) .. I"......,..II,,·",", II..• ..... r.f(.· (~Il K~ 1.tr. ·
tWItI. C..... " it IIi" I...• <1o"'lllK illh·",'alllf p1al.·..u. " Il<'n...li ....~-. it ('lJ' h(· (~..llall..1 frum II... ' .t""·r....llIwU mu m
llIMI minim" m ~~"M~·llt nolic".s "I pLol.·.." . C ..,_. C..,_: (10,.,....· ..( 0,"1,wt i.." - (C .. ,_ , - C..._J/{ :..,_,
CHJ\PTEIl 7 10>

Ih 'ual dt'i\r.UH.>t' t-au lit, t'sl illlilh-<1 from tilt' amount o f dnt~ excreted unchanged in a
l lusi lJ~ Interval al stt'ad~' sta lt' , AI'.... and tilt' \"aillt, o f A UC ...

l1:enol clearance = 28

The rt'la m '(' h iua \'aibh ility o f ,lII extravascular dos(' lI\ay lit, dl't/.'n nint'(l from uri ne, us \\'(,11
,t" phSlll<l , dala itS follows ,
(Ae....)B (Dose)"
Relative bioava ilability "" 29
(Ae.. ..1.. . . (Dose)s
STUDY PROBLEMS

(Answers 10 Study Problems ore in Appendix II .)

I. Ct lllllllt'nt »n tilt' , U.'( ' lI l'oIl 'Y of tilt' follU\\in~ statements " i tll n~lrt l to d nt gs gin'lJ i L'
a n ural multiplt'-doSt, « 'I.'; IIIt'II.
a. :\('('lIl1l ula tinn '11"1I~~ IK,('UI'S.
II. l1U' t'xlt'u l of ,t('( 'ulIllllatioll increases whe n drug is giW Il It~s fn'llut'llll y.
c. 111(' ti nu- III n-ach plat('au follouill g: a multiple-dose ll'gi IllI'1l dl,pt.'nd s O il tht' In "
l lll('''t~· u f dmg adm inistration.
d . ,-\1 plalt 'all. the amoun t Ilf dm g: lost within a t10silJR interval equals the oral main -
It'n au ('(' deISt',
I'. T Ill' la rgt'r' rlu- \UIUIlII' of dis tribution. tlu- low(' r is tilt' a\'('rag:(' plat (""1t'UIl('t'ulmtielll.
f. 111t' il\l-mgt' plateau coucentratum depends on the ahsCJ rp tion kint1it's of till' d nt g:
fol1O\\i ng admin islration of a r~n1t'1l o f a fixed dail)' tlc)S{',
2. ( ;aITnt'r'I'1 al. (G alTm'r, G . JO!IIlS.S0 1l. G ., am i SjOj,.tn'II,
. J.: Pharmacoktncncs o f procdn-
am idt· intm \l'Il11mly alltl n mlly as t1mn'ntional and slow- Il'lt,,'-\t' tablets. CUll , Phar-
nmml. Ther.. 17':414-12.1, 1975 ) compared a rapid-re-lease wi th a ('(mtmU(,,!-rt·IC'<l.'\('
furul1ll.llinll of p n K'a inalllic!l' at stt'ady state. To ensure (,(lIlipamhilit)', tilt' dat a (p re-
St' n lc-<I in Tahlc' 7 -6) WNt' ('(,111'(:\('(1 O\'('r an x- hr interval at sh'atly stall' aflt'r admiu-
islralioll of 0.5 R 1'\l' I')" 4 hr ;'-s tIll' r.tpid . rt'lt'<l.'>l:' tablet an d I g ('wI)' S hr us tilt'
cout mllc '(1- rt'll';(w fonnu 1<11ilm.

AUCIO.81
.....IU
Ropd-relea1oe lormuloll()rl 226
Conlfolled-releo!oe formulol,on 211

a , Cakulan- till' n 'bth '(' hio<lvailahil it)' of IIIl' coutrolk -d-n-lease Ionnulanon compan-d
wnh th c' mpi cl.rt'1I';L\t' pn lllud: .
h. Calt-ub tt' till' n -na l ch-anmce o f p rocainannde.
3 . The- po pulation phanwl(ukilll'lk s of th (' 01""011 d iun'til' aRt'nt , chlorthalidoue, for a 70-
kg !Jot'r'SOIi an';

F = 0 ,64
V -280l
Cl - 4 .5 l/hr
.04 CHAPTEi 7

a. Givl' n Ihat abso rpuon is instantaneous n-lative 10 eluuinarion. calculan-tlu- f{lll ( l\\i ll~
wilt·" a 50-inK dust" of d .lnrt lmlido llt' is taken da ily at breakfast.
I. TIlt' maximum and minimum amounts of d nl ~ in the- hody at platt'illl
2. TIl(' accumulation ratio
3. Th e mini mum plasma couceutration al pl att'lUl
4. The timt' reqoired to 'ie h il"\'t' 50% of pbtt·au
h. Complete- the tablebelow for tilt' t10S<l!!:{' n'~ Il1t' n o f d llllrthalidol\(' ¢Vt 'lI in (a) .

, ,

c . Pn -pa n- a sketch Oil ~ llar grap h p;.tlx· r of tilt' amount of {'hlo rthalidollt, ill tlu-
bod y \\illl ttmc. Show the salient fea tu res of il( 'l't lll lll lat itm of this dnl ~ dll ri n~
tht·mpy.
d . If requi red. wha t is t1 lt·lu.l(lill~ dust· of dilurt halitltllll' II(·('{I('<I to illllll t'tl iiliely at tain
tilt, ('tllldi tioll at plah'<lu ?
4. ~1r. ].\1.. il llonsll1oki n~ fi().· k~ pat ient ....'ith chronic " hstn ldin>pulmonary di ~ "lst '. is
to lJt>start ed on an oral regnncn o f alllinopt.ylliJw (&")<J, of whlch is tllt"(lphyllilw), 111t'
plmm llK''f)kim'!ies 1l<lramMer \"alm>s fo r a typicoll pal it'lit popnluttou with this ,Iist'jl'w
an.' :

F II: 1.0 (lor theophylline}

V . O.5l/kg
CL .. 4 0 rnl/hr/ lr.g

l)esiWI WI ora l dosa~,> rt~lIIt'li o f fllllirwl, /.yllilw ( 100 - ami 20n-llI~ tablets an ' mar-
keted) for this p atien t to attal' l ami maintain a p ia-u na cono-m ranou ....i thi n rln- tlu-r-
ap -uuc window , W to 20 mW"l.. TIll' absmVliull of tl ll'oph~·lt illl' is complete- and rapid .
5 . T alll.· 7-7 Iisls a l)pkal plas ma concent r ation- time p m file ohtailll,(! f()llu.... in ~ an oral
500- 11I~ doS(' of a d nl ~. 11l(-' A l 'e is f)U.fi m ~- t.r/L. and tln- h 'n llinal half-life is 5 hr.

Time [Iv] o 2 4 8 12 36 48

o 23 47 52 40 28 06 01 4 0.0 3

a. \ \ 'hat o ral dosi n~ mit' of dnl~ is 111"("(1''1.1to maintain all a\'t' m~e plate-uucoueeutration
o f 10 m/ifl. ?
h. The decision has 111.'1'11 m .ll lt>l o ~ \'(> till' d nl ~ Hnl'l' ('wry 12 1Ir. \ \ 11011 is:
I. 111l' unit doS(>s t Tt" n~ h o f product IWt"(I."(I?
2. TIIC p lah" lllt rou~h concentrunon t':o: pt"l1t'l l?
6 . Tl u- tlwmpt,t1til' do",,>o f a mpid ly (compared to ,·limilla tioll ) aud (,(llllplt·tdy ab sorb, '!1
d rug is 50 1Il~. A conrndled-n-k-aw dUSlI~t> fon n 10 h(" ¢\'I'll ('\"('1')-' f) hr is t!esiWlt'!! to
rt ·I. >il<it> its con tents I 'H " l / y and cmll/lff'fIo/y (nn IOiUli ll ~ dose) over IIIis dos ill ~ inh-rvul.
Giwn that the half Iif.. o f til(' drug is 4 hr :
a. H ow much d m ~ should the ('()lIt m llt'(l- rt>!t'aw d()SiI~t · form l,(lIllain?
 , ..
h. To ;I("l.it"\l' a p rnlllpI I' ITt't1 . a rap idly ab sorh..t1 dOS<I~1' fon n is ad m inish'rt"l! in ilially.
\ \111'11 should till' fir!lt controllcd-releaw d(Js.a~t· form be ¢wn?
e. FuIlO\\illJ.t Ih l' tIlJ~I~(' r q ?;irnt'll in (h ) wh at is t hl' 101111 d oS(' (i) for ltay I ? OJ) for day
2?
d. In tubular form or 1111 tilt' ...U1U' ~r.lp h . pn l\id(· till' rl'lativ(· amount s of d nl ~ i ll tln-
hntly vr-rsus tilllt' ('IIT\t'S l'Xpt'<.1 t'1l wln-n till' (.'u nl rnll l't !-n ·]t·.L'it· pn'pamt ioll o llly is
¢H'T1 (iJ ('\l' ry -I hr (ii) ('w l)"!'i hr (i ii) en' l)" 12 hr.
' . Adinai'nbm is it t1nl~ nmh-r iliwstij!;at ioll for the treatment o f depn-ssion ;tllli pan k
disun lt·n. Tahle 7--S summarizes v um- nftllt' salient p lmr m 'll'o kilw l i<.· info n na tinll flll-
ICl\\ill j.( sillj!;lt' a nt! 1l11lltiplt· d OSt' s o f immt"tliah··n,lt>a.<;t· and (,(lIIlmll('(!. rt'lt 'iLs(· product s.

'."'.7-8. M_" A..I_••I PIMI _ ••I....c ..........._ ••I II IIHI

M.ltlpl. D._." ' .......I _.IIMII e-trelletl•• • I__ ,.INtIe .
Orevp .. '6
Ivltlech-

AUC Img-tn/ll o 57b 1.72< 088 b 1,57<

C"",. lmg/ U 0 15 020 007 0 11
T""," (t,,) 1 00 250
Te<m; rqll> / l (hrl 220 550
d f .......... . . JC O"\d W'<jo C E ~.,."'"""."..;~~_d ... <J' _O"\d ....... <J._
04"""'*"" ......,.,..>:Jt>l<o>,;.,.~"'"'...;"p&o.o-~ ~~.. 9 . ~ 7- 0t61 . 1991
'AUCIO-,
J.UC 1O-14i _ 'do¥ <I ~

a. \\110\1 mh '-limits III(' t1(·(:lillt' of pJ.~\lIla atlina/Jllam coucent r anon fnllouin ~ IIIl' ad-
ministration nf lilt" controlled-release p m(llId?
h. 011 multiple do~ill~, han ' tjn- illllll("(lialt·· rt'1(·iL\(' am l l'Ulllmll("(!· n,ll'a.w products
11("('11 ¢n'lI I(JII ~ (· nnll~1. In ('J1~lI n' that II plate-au sho uld have lx-en n 'ut'hl"(l? In ytJur
an swer, indi (~lh' wlwllll'r iUl~' diffen-uce is eXpt'(1("(1 in lilt' tinlt' In n-ach plateau
11('lw('('1I Ilw " \ 11 product s.
c. For both p n ll!lll1s, an' ti l(' p1<l\lll a concemratiou data nh st'rH"(! Oil mult iple dn" i Tl ~
(T ah lt' 7-8) Ihost· pn"(lid l"(l fmm si ll~Il'.( I()st, (ltla?
d . \ \ '.at is tln- n ·lat in' hioa\'a il"hilil>' of adill:t7.nlalll of III(' {'tllilmlll't!-n·!(·a....• IJrll(Illl1
('()lIlpa n1 1In till' illllllt·diah'·n,ll';l'i(· pnl(lll{1?
e. {\ n ' IIIl' phart lla('()].';m1ks of udiuaz olam afh-r udmiut stranon flf til(' Iuunedlate-re-
It'iL\p alll! tlu- (ulltmllt1 !-n,lt'il'i(' products such that tilt' terminal half-lirt' m il II('
tll'lt 'rtnillt"(l \~i l i l i ll the- n ',,(x"(1i\'t' t1u"ill~ Inte rvals at plateau ?
f. \\1...1 are tln- d( '~I't "('s o f accumulation a\StM :iaft"(l wtth the illllll("(!i;lt('-fl,It"l..'it' anti
lilt' coutrolh-d-n-lease n'WlIlen~ ~h l' n tlml IIJ(' AVC(O 10 N IIr ) and AVG(O to 12 1.1')
f"llu\~ill ~ tl.t' ~ i ll~II' 40-m~ imm(1Ii;If('-n·ll·a..'it' product and Ihe fiO-m R conrrolled-
n,II'a\(' pnM!lll1S an - II,-l.') and U,-l.J mg-hr/ l.. n'Slx"(1i\'d>'? Ba.'it., >'tIur calculations 011
..\ l"G (~IIl~ i dt'm tinn~ ,
 I Se c t i o n III

PHYSIOLOGIC CO NC EPTS
AND KINETICS
 MOVEMENT THROUGH MEMBRANES

OBJlCTlV£S
The Ieode!' will be able to:
1. Define PJuive and focililoted diffusion. octoe tronsport. 000 permeability_
2 . Di!>l;ngui!J, between perfusoon role-limited and permeability rote-limited passage 01 drugs
through rrembecres.
3. Descnbe the role of pH in the movement of drug *lfough membrOr"l8$.
4 Describe the cceseqceoces cl the levefsible IlOture 01 ~l 01 drug$ through men't
bra~,

So far ill tl.t· honk. emphests has lx-en placed 01\ k jud i<:{...-en ts follu"; I1~ dn l~ itd m i ll i s l r.l~
fion ami applica tion of pluu-macokuu-t ic princi ples to tilt' d t·siJ.,lJI and e...-aluatiou of dC lSa~('
n.';Illt'IlS. Littl e has ht't'll s:u<l about how lI11d(' rl>;n ~ physinl f ~l'lm ll"t"Ss('s control phar-
1Il00(:o kilwti c pam uwt Ns . }l ·t such infonnaliol\ p n l\;dt"S an illSi ~ht into the intern-latinnship s
lx-tween d m g and bod y. It alsn la)'5 a fOl!mLltioli for ilJ(li\id ua Ii7..at ton o f dnll?: themp)", tln-
sllhj('(:t of th e nex t sect ion.
Thls section explo res till' physiolo,,; c l"Olll't' ptS I l<L~k 10 pbarmacokmencs . It hegi n s " i lll
a chapte r dt'alill ~ "ilh 11ll' lla-~s.a~e o f d nl ~ t1l rnll~h membranes, p roceeds t1 m Jll ~h rlu-
pnK'('!i..'it'S of absorpuon . dislril mliol\ and elimination . ami ends willi a chapte-r 011 tilt" in-
k "!-,:rdlio n of knu- ncs and ph ysiolt' ;l' concepts. Sudl lufcn nat ton helps not (111). to inlt"'l)rt·t
ph ;mmK'tllillt'tic da ta, obt at ned under a va riety o f ct rcumstances. h ili also to pn'tlid Ihl'
Iikt'!)· 1I111t., l lIIt· when phannal'tikint' lic P;1r.J.lllt'tt'rs c hallg:l'.
AbS(I'l Jlion , di stribution , and elinunation an' all p n x"t'SSt.'s that require mo vement
thro ugh membranes. Tl ris 1I10\"('III<.' nl is kmJ\'T1 ,t.. d m g tr ansport . TIlt' an atomic and ph ys -
iu!ogil' factors that deknnim' 11ll' mp idil)' o f d rug tmnsport all.' till' substance o f Ihis
chapter.

TRANSPORT PROC£SS£S
Cellular mr-rnh ranes ap p('a r 10 be l'tIIllIXISt'l1 of an tnm-r. predominantly lipoklal, mat rix
covered Oil r-ach surface by d t!ll'r a routtnuous lay('Tor a latt ice ....o rk of p rot ein ( Fig . S- l ,
up pe Tsecnon of d l"d",ing ), TI lt' hyd rop hobic portlons of IIIl' lipid molecules li n' nrte nn-d
tow a rd tlie center of th e me mb ra ne and lilt' outer hytl rnp llilie n.~ollS fare tlit, slIrrnu lI(!ing
aCJIIt'()1lS envi ron ment. Xarrow a{lllt'olls-fillt'tl channels exist be-tween some t't' lis ;1-" ill lll p-
iIIary membranes a nd intestinal epitlJl'Iia .
TIlt' I rdn~lx l rt o f t1n1 ~S is n ftt'n viewed as 1II0\'('lI\t'lIl u<:nlSs a wrie-s o f membranes uud
SP;K"t·§ wh ich , in UAArt-gutt', 5( '1"\'( ' a.~ It "funct tonal" lIlat'mst~)pi t, nwm bra ue . TIlt' ('t·lls ami
interstitiul SP;lt't' S rhat lit' ht·l\o."(,('!1 Ihe ~;L'lril' lumen and the ca ptlla ry hlood and rlu- struc-

...
110 CHAiTH 8

tUIl'S 1)('1'\\'('('11 the sinusoidal spal" and the hill' canaliculi in tilt" liver, ,tS well ,lS till' skin
(F iR. 8-1), art' examples. K.lch of till' i ll h''1)usi ll ~ cellular nn-mhruues and spal"" illll)('(II'
dnl ~ transport 10 'll.I)ill~ dl'g n-cs. ami allYone uf them can rate-limit the o\"l'mll pIlK'{'SS,
In the skin, the stra tu m cor neum is till' major ..itt' of impt'(!a lll't·. It is th is (·'Ulllp lt·li.it)' of
struct ure that malws quanntatlve extrapolat ion of dm~ Iruusport (mill O Il(> IlIt 'mlmlllt · I II
anot her d ifficult . A des<:riplin n o f the qualltatlve feutun-s of lilt' pm(" s<;t's of lim).': tra nsport
ac ross t ht·S(' "Iuuct ional " membranes follows .

Diffusion and (onvectio.

~ I ()!it t1m gs pa.ss thmugh un-mhranes by tliffll.vloll. tilt' natu ral !l'mlt'lIlT for molecuh-s 10
1lI1l\" dO\\1. a concentrurkm gmd it·nl. ~ l l '\"l' lIl t 'll t n-sults from til(' kint'l k ('Jlt'~. (If II\("
molecules. <lml Si lll'(' 110 work is (·);.I)I;·ndl"<I hy lilt' system . lht' pmt'('ss is kno wn us l Imos/lA.'
djffll.~jon .

Cell membrane

- - - - - - - Hair shaft

Stratum Sweat gland duet

Epidermis corneum Hair follicle
{
- - Papillarylayer
- - Tactilecorpuscle
~ - cap illa ry

Dermis lIf:7f-::::::::I=:::::-=
".
Sebaceous gland
- Nerve
- -f-- - - - - - Arreetor pili muscle

Subcutaneouslayer

Fill:. H- l. FllIll.1 iun.l n..-ml,roll""1 '<lJ) ' ...... IfT"'..,,!>· in ,1" ..1" .. ' anc! tlud" 11..,y (":II.n I..· a., ,hiu ", .. . inlt"'"
<Til ....·mb of appnm malt·!:o· J X 10- 6 ('m Ihil..knc"SS (1,'1 ' ). Ill ..... ,hil..k 11.' I · ll1Ulhn -lI"L.rh..rrit·r of II..• . kiu.
TI,i. lll" hic. UuLu loaTTit-r n l"11t1s frum tI... <t ral"", ('On ..'" ", 10 tI..• "1'I1t'r p.trt uf tI"' papillary ~"r "f tI.., ,10·nili. ,
...lpo;...l11 In tilt' c"l' ilJarit"1 of tilt' Ink'rll" n. ILIlie>ll; a ,Iht "l" " · ,.( "1'I,m~ ",al" I:o' :2 x 10 - I csn (I. lt l " m). TI..· ( 11
nlt'", l>nult' ro rnl,ri..." 1I 11i1"'.oI."("ULu lo,aI!('t. "ilh 1I lipitl inlt'rinr ;<IltlII l"oLar t'l.h·rit,r, di' i"'n<.. lll.m,,~ ",hie'" .
1tIo.l:..,w l ri n•. tlo'J'k1....I... ~ .. ..it.I im 'J1;lllar .J"'I I I""Ii....((;,.11 mt·"' lmUlt- "l'""llI.......1f" "ll Sinl:l·r . S.J.
"", I S ir. C:.I&: TIlt' Auiel ""....k " "Kk·1 uf I 11, ...1111'1' "I' (.· 11 IIJt'mhnm... , SCl f.SCf:, 1; 5;720, 197:t
" 'P:'"'I'i¢'1 II}'l:2 to,.. 11K- A1\A S; . kin ....... kiIK~' drawn by \ 1;4"'!>' ~ "rt ld
CHAf'IH a
'"
T n app rt'(;alt' lilt' pm p..'rtil"s of p.tssi\"l' d ifTnsi..m l~ JIIs itll'r a »ruplc- s) 'SIl"1ll ill w!lidl a
IIlt'l1Ihra rw 'W 'llarall's I\..u \tl,lI·stim'll ,UIUl'lIIlS l'(lmpartmeuts, TIlt' tlrh ing force for d m g
tran sli'r is Ihl' ("Illwt'nlra!ioll of tilt' d j fTu si ll ~ Spt't.; ..... in t'adl of tilt' e unp urt ments on t'itlw r
sitlt' of tilt' mt'lllhr'lllW. TIll' li d r an- of penetr ati on is

Nel rete o f penetration ., P SA . lC..o. 1 - C..o.21

Permea bility Scrfoce Conc entrati on
c rec di fference

111t' im portan('(' of lIlt' surface urs-a of til(' membrane is n 'lillily ap(litrl.'n l. For example.
tltluhli ll ~ lilt , Slln. lt't· an'a dou hlt... III(' pro hahi lil)' of collision with tilt' membran e and
tllt 'n '''y ill('n 'aw s tl.... !It'nd rollioll rah ' hmfold . Soun- dmgs n ·at lily (lilSS I hnm~h a
uu-mbram-, others tin lint. 111is tHfft'n'n('(' in t·,('\.p of Ilt'lIt1roltio ll is flullntital i\'t'!y ..-xprt-sv -d
ill !t' f11I S of 11..., }wnlll'fJbility. ~ o!t· th at lilt' p roduct r · SA has till' un its I)"pil~.ll of How.
I't'nnt'ahilil)' then-fon- has unu s of , '(,Jot..nty, distance/time.
'~ ll ll mt'/l i lll ".
T Ilt' tlm't' lIlajur ....lIln '(·s of variatiuu ill pt 'nllt'ilbilil>' of a "'';\1·u lIlt'm hr.ult' 10 a drug an'
lI1ol"'('nlar sin', lipo pllilid ly, anti d largt'. \Iolt'('ular size has lilt1t' imp'1l1 till d ifTusion of
stlhstalln 's in '\111t'r h UI l ias a majo r d T..'<.1 n il 1II0\ "t'II lt'nt Ihn MIRI. IIlt·lI1h r.lIlt'S. 111is is
pn 's ulll ahl~' n, lall'l l tn lilt· struct ure of membram-s. For SO IlW membranes . wah·r ·solublt·
materials mu\'(' pamt"l'lIularly tI ln m~11 narrow channels Ilt,ht't't'!l cells . Hen- ilgOlin, moh-o-
ular ~ i7.t' is important. ,l~ an' shapt' and dmrgt' of tln- lIlolt'('\II,' . For t'Xilmplt" oxytocin, a
(.,.,·Iit- 1Il0lIUllt'plitit', paml'(· lIl1lar ly (·ms........ tilt' n 'lati\"t'ly looSt·ly I.....n it nasa.l lIK'mhr.lllt'Sfluitt·
rapidly hilt is almost totally IIna"I.., 10 cross tln- more IiRhtly kn it g'oLstmi nlt'st hml IIIt'lIl'
brutu-s. \ IO"'lIlt'lIt of \\1111' r thn mgh tilt' pa racellulur channels (a ('(JIl\t'(1h1.' p r ocess) aids
in li lt' trallSport of suhs lall('('s hy th is rout e. The second sonrre o f variation, lillt'philid ly.
is ofh 'n d l<lr'lI('lt' ri/J'l1 hy pa rtitio n ht'I\\"t'(' u oil and water. Smallhpid-solubk- un-loubr-d
tl m~s tend 10 Ilt'lIdratt' bpid nu-mhrane s with ea...... This tendency and Illl' d Tt"C! of IIlO-
k-cular Si7.J.' an' shown ill Fi~. S-2 for transdennal pas.w.ge of a variety o f IIllcha~l'(IIII()I ·
t'('IlI..-s, Chargt· is lilt' tllin1 major const raint to trausuu-mbraue !);L.SSilKt'. A ~ain , th en' is
('(msidt 'rahlt, variation in lilt' illlllt'llanl"l' o f t1ifTt'n' nt memb ran es to d mrgt'(llllolt,(11It'S. bul
tI.... ..·ITt",·1 of tilt' dlarg..· Ls, wit h ft'\" t'x('('pl ions (t -.g. ca pillary 1lI"'lIlbmnt 's), a1wuys la~t"

Molecular Weight t·l ~. H-2. r..· m ll·....hihr;.....·.. M ~li tl

(Olmolej ...... r"'....i i" o of " 1I.......~J Lo.r \i n> IUMI

' 00 hl"'l'hihdt,., LiI"'l'h ll ll: ity i. /'\ -

-3 1' 1 .... , Ill' '1I'f;lnnl/wa " 'r f"' r1i.
200
-4 tkMI ·ffit...·n l. E....... lilJt' " 'P""""nb

L
u~
-s ""
600
."I lll tll:"· S o r Ihl' Sin n/, " ", I<"('1 ,lllr
.....Ilth! b" l t1 ilT..... nr hIM'I'I,lhd t,..
( ~I ,.li fM ...1rnm' Puth , "0, "'MI Guy.
,,~ -6 " II .: r ..~ Ii<'finK .lm I"·rmo...loilily.
~! -7 800 rt rm. H,.. .. 9:ffi~. lW-l. " ,..
E-
• -8
I' I"•....Iwi lh ['I'" " i..io" or PL'nllm
1'1.I'.li"'i,'II: ( :.....p' ...." '.. ", .)
-,
c,

- 10 "----4--~-~
o :2 .. 6
OctanoVNalerParlrtiOO Coetllcient
(log sea!!)
112 OWTEI!8

Thus. t he la~N an d mon- po lar a moh-cule, til(" slowI'r is its lIlUH'lllt ' ul <l(;ms s 1I1("llllmu ws.
~lt)\l' Il1 I' nl is slowr-d , '\"l'1I m ort' if , hI' 11I011'(.'1.11(· is 1·lIa~I'(I .
AuolhN determinant o f jlenJwahilily is memhram- thlckm-ss. tilt" di slalll't' it 1IIoll'('ult'
IllL" to Ird\"("J'W from t ill" sill" o f int t' n 'st «-. ~.• a n absorpuon SUrf<lI't·) to a h louo:l l"ltpill:ll)".
TIll ' s!lurk r the d istalll,(', tiM' h i ~l lt'r is tht'l'N'nlll'ahi lity. This d istan t't ' cau va ry Irmu a ho ul
0,1105 to n .nl I1I1l (for o -llmcmbmnes) to S('w ml milliuw lt·rs (ill SUl Il(' skill sin-s. Fi~. ,1).. 1,
lowN fi~ur(' ) .
D nl~ Ir.lIIsport contin ues toward equihb n um. a condt tfon ill whit-Ii tln- coucentratiuns
o[ lilt' difTlisill~ speci es a rt.' the ~ lllt' in tln- :uIUt'(lLIs p !JiL'>l' S o n hoth skh-s ll( till' membmne.
~I O'''(' III{'ll t of dmg IIt,twI'1-'1\ n-W0 lIs still continues a t I"<lllilihrilllll, bUI tilt' lid flux is i'.I' m "
EClllilibrilllll is ac:h it'\l'(l lIlon' mp i<1ly ....n h I l i~hly pt 'mwahl( ' t!nlj.,ry;, when then- is i l liI ~I'
slIrf;K't" area o f contact \\i th tlw me-mbra ne, am! Whl'lI tilt> \lllllll W S of tilt' ll:J1 l1 pa rt lllt' lIts ,
to and From wlJidl til(' dm~ is transported. a n' small.
Initiall)', when all tln- dnl ~ is placed Oil Ollt' sid t, of tilt' lIlt'lllbr.lllt' , it fnllllws from Ell .
I that ra te o f dm~ transport is t1in'(:tl~" pmportionul to ronce-ntrut km (Fi~, ~ ) , Fur I' X-
ample , rat e o f t r.lIISpo rt is i lll'rt"L~'(Il\\,lfold when conccnr rancu of dm~ is dlluhlt'll. Sta h'!.!
difTt'n'utly, each lllolt'{'u !t' dHTuS('S iudl 'lx ' udelll l)"o f th e otl u-r. and tilt' sph 'lII c umot lit,
s aturated. Unk-es a dm~ a ltl'rs tlw nature (If tilt' mc-mhrau e, tilt' last stat euu-ut a l ~ l a ppls-s
wln-n th e uther lIlo lt'{'ul(· is a diff(' fl'nt dOl~. Both ahS('II('t., of l'l llll!X'li tio n III'tW('t'lI 11I01·
t'1-'lIl('S alit ! Iaok of soll uml io n a n ' t'ha r.lt:I('risl il'S of p;L\ sin ' di ffus io ll.

Carrier·Med"lCIIod T....porI
~It' lll l mul('s are 1101 inert barm-rs: lilt .,.. han ' a s!x'!.'iali/.('(! function. ~It'lIIhr.lllt's maint ain
the- Internalcellular environment hy l'ld \l{ li ll~ or n 'llIo\"iuj,t sonn- mat e rials and 'it"lIIlI'SIN -
illJ!; Of st'lt"i.1:in'!y n'l ai ll ill ~ \i la l substances. ~I any of tilt'S(' compounds a n ' po la r, ....-ith low
lip id sn luh ili!)" )'t'l Illl'y pene-t rate membranes IlUll.·" f:l\h' r than anl i{·ip' llt'l l fnr fl<l\sin'
diffmion I hml1~h a u Inert lilX)itlal barrier. Spt'l.i a li/A'tl I·arrit·r-mt'tliah ...l tfampurt S~'!;!t'I IiS
appt'ar 10 lit, n'sptlll'iihlt" TIll' subs trates a rt' oftt'li ('II(II ~t'nOlis compounds . Of d ost, ana-
II ~S ,
TIlt' l.'1 ll1('t.·pt of a carrier stems from tln- observation of a ltnnn-d mtl' of t ran sport a t
inl'rt'<l.\("(! suhs l mll' concentrations ( Fi~. S-3). T\\u 1)1x's o f slx"i.i "li;o.('(1 transport P"It'('sS('S
have IIt'('1l pmlx)S('(1. I~l\si\l' fildlilillt'( l d iffu \ ioll uml ad in' tmmport .
PaHln' ! nciJitntnl d iffinl'IIl is l·x(·mpH fit..1 by tln- movement of ~h l{'I)s(' intu ('l)t lln x., t t's.
It is a passive pml.'t.'Ss; p;ltll'lISt' mee r-s { Il)\\ ll a eonc ent rution W'-ulit>nl \\i tl.o lll t'!Ilpt'llll ih m '
of ('Ill'fK\·, a nd a t ("(Illilib rilllll. tht' {'1 )l\('('llt ml io lls in ami surmtl lJ( li ll~ Iht' n 'll hlolltl ('I'lls
an ' t"lpml. Al hiRh pl.mllil Rlul'l)s(' ('1 J1ll.'(' ntml iolls, IIt1'\\"(,\'('f, tht' mit' of t nlll sport of ~1ll('11st,

n,;, /01-3. I nil W M " u{.In'l: Ir""'l'urt P 1'~ Jl "'t 1 Passive Diffusion
It(.li''.1 tiM' .~ >rM~,,,t r,,liun n{ tlnll': I>I...~ ..I un ,,,...
\lt ~. til .. n .. ·mh........·. With P'-" r.•. ,lifT",itl", tI..·
...,,1., of 11'lU"1">t1 itlO."",""", h,..·lt1!:-· ..ilh IO.... n-
I r"liun . Will, (...rrio·r .n Ii.th~ l lr""'l'un . tI r.lt'
,,( Irall' I" >t1 ..Pl'.."" ~ II 1illlitjn~ ,,.J, I l,ilQ'
" >"t~'''t ralic>" •. limiting
Rate
Carrier-Mediated
Transpon

Concentration
 Il3

into tlu- ('1')1I1nll.')11· TPill, l. t· " a limiti lll!: value or tmnsport maxinnnn. Furthermore, ill com-
mOll wit h otln-r (. lr rit·r-ml'i.liah 't! S)'SIt'IIIS, ~I II(.·()S(· !rdmport is n-asonably sj>t'(:i fle ami is
inlrilutccl "~' ulliN slIll!olrah·s. FI"WdmJ;ts IlIl<!t''W' Il<l-..... ,i\l· fadlitalt"t! diffusion . An exampk-
is tln- transport o f vitamin B12 ilt'ruSS tln- ~a'il rui ll lt'st i ll:u t"pi111t'Iium .
E\il mpll's (If (J(1in' t n"'-~IH 'r1 ahound am i ind ude renal ami hili,u) ' seen- non of IIlllll~'
adds ami !JoN 'S. see n-non o f certain ad tls 0 111 of til(" central 1ll'I'\ U lIS svs tem . and int estinal
absorption of sonu- amino..~·Iat1alll ant ibiotics and all wo!t'l\sin -<"'()!l\'{:rtin l!: e nzy me illh ihi ·
Io n; via tln- dipt·p tit lt· trun...po rt sySh' lll. C llamt1t'ristks in eonuuon wit h p,l-'ish'(' fad lital('(1
di rrll ~illn an' ~I t llr.thilir:o·. ~p(·(..ifk it>', and competitive iuhihition. Acnw trallSlx lrt is d ist ill -
!-rlli~ llt'( l From p'l-\ ~i w f"d lil" h'( l d i fTlI~ illn hy th e Iwt movemen t of su bs ta u(:t· a~ai llsl a
u lIIu: n t ra tio ll !-'T;ul it'lIt, which ran he la~t·. 11 1t· maintenance of tllis Wadit"lIt requires
mt't aho lit' t·l\t·rl{v. At1iVt >tran sport m il tl lt'n ' fo n ' be impeded hy lIlt"tahol it' inh ih itu r'i.

BLOOD flOW
Blond . pt · rfllS i n~ tissllt·s, dr-llvr-rs a lld n'llIon's substa nces. At'{'(mli ngly, 'it""i ng any tissu e
:l\ a wholr-, t ilt' ml "" ll\t'lIt o f d Ol)!; t1lOm.e;h nu-mbram-s cauuot II(' divorced fr om fIt·rfu sioll
t' J1l~ide ralinll\ . I't'rfllSio ll is usually expressed in un its o f m l /m in IX' r \1llt lllW (o r Jl\olSS) o f
lissut·.
\ \ 11('11 Illt' l1I hnlll tOS o fTt>r \irtually no barner. tilt' slowtost o r ral c.limit in)!; sk p is IX·rfllSio ll,
1101 IX"Olll'ah ilily. a.. .. sllO\\1l ill Fi.e;. k--t . This pt·rfusiou limitat ion is exemplified ill F ig. 8-.')
for t ilt' !lil\S;I.e;e u f certain sub stances across th e jcj unal nu-mlmmes o f a mi . From lu me n to
hlood . T ritiated water mo... es fn >t·ly thn m.e;h ti lt· 1IIt'III Im lllt', a nd its rate- o f pas~.e;l' Increases
\\i lh illt·n ·.l\ill .e; perfusion. Thr- p<l"~.e;t· o f et hanol and lIIillly small dmw; at'nlSS Iht· small
hllt'st int' is simila rly !X'rfusicm rate-limited.
..\ s n ll'lIIh r;ul(" n ·si ~ t allt't· til dm.e; increases. t ilt· ratellmttatton 1ll""\1.·S aw,ly From U III ' (If
pt· rfllSion to 0 1\( ' o f pt'nllt'ahility , nit' problem now litos in pt'fl(·t ralill~ tilt' membrane, nnt
in tlt·lin·ring:tl m g to , or n 'mtl\ing tt From. Iht' tissue (Fi.e;. I'i---J B). This ill(' n 'aw in n...isla ut , ·
lIlay ari !'(' for lIlt· sanlt' tim!?: t'mssin)!; rm-mhram-s o f int·n ·'L..i n~ thiekm-ss: t·.g.• tilt' lIlulti ple
t1:lI la~1.·n o f thr- epide-rmis an' 1(·" peruu-uble to a tl m g; than is tilt' singlt· t't·ll la~l.· r u f tilt'
ea pi lbl')' t"p ilhd illlll. For tilt' sa me membrane, n -sistance increases wit h i nc n·a.~i ll~ sii'.e. a nd
polarity o f tilt' molecule. Thus. Imuspo rt ac ro ss tilt' j<'j Il Il UIU is SIOW N fo r nh uel and llIa ny

A. Perfusion-RateLimitation Fi lt . 11-4, n...limililllt .t, l' mnlmlh,,): r..l.. IIf II.....••

( ~~~- - - - - - - - - - - ~ )
Tissue
B. Permeability-Rate Limitation
""'III of .In l!' "'-.......... II...mhr-oll..•• (n)fl' hI....I h. h..,..•
.... tI..· 0'(1""""". ,ouio:"..". If II..• ''It''mhr-,uM' (llTt'n T..'
'Mh l........, tim): in II..• 1>1<..1 It.,,' in lt 11M' Ii
virtu..! nl"ilil.rium .,.ill> 1h..1 ";lloin h
i. ilt
·; hlt l aI..1
IT"'''' nl~' t....~ a.' U'It'. 11m ' " m...'1 of ,In llt
i.Ii"'i1...II~· 1.",,_1 R< n, .'l l nn I>.h~· .r"' .. lirnil...
h tl" M:I". if n.. ·"' I> n...i " ' · Itl tlml{ ·" .. ..,1
I....", .... ~ hil(h; ,"' ·lnt·"1 tw· i. 1..",10 .It...· 11""..,•
•iIi,.· I" (-h.."I:''' ill ....rfll.it 'lI" I, ' ..-pli],hriurn " ,,,'"
;l( -h ;"....... I I~· tI... tin'" II... hlt..II. ·..... .. II... ti ..,...; "10..1
al..1 h' " w ",,,.l 1M"""' I,.. , it.......1.., " ,,,,r.. l.. ('''''I'''rl·
!l..·"h .

Blood

Tissue
"' III()VE MENT fHI1QUGH MfoYBiANES

orhe r larger polar com pounds than for ethanol or water, whkh results ill illS('ns ili\; ly to
changes in pe rfusion (Flg. 8- S).
Some co mpounds. likt· urea. have inte-rmediate pt'mlt'ahility charactensncs aenl'is tilt'
jt'jllllll lll . At low h l(XM! flow mit's. till' compound h a~ su lli dt'1I1 time 10 Ir.l H '!"St.' tln-
membrane so that pe rfusion lx-comes ml e. lill1i li n~. At h i ~hl'r hlunt! flow rate-s. !ltl\\1" "er.
membrane 1N.·om·ahility !JI.'<.'fllllt 'S lilt" !"llll o. lim iting step. an d abs(J'l.Jtioli 1"'''('(lIIlt'S rdilliw l~'
luwnsttlve 10 blood IInw (lo"i ~. S-S).

IONIZATION
Most d m gs are weak adds o r ....'·ak bases and exist in solunou as an r-quilihruun hdwt 't'li
lln-iou i7.l't! and Ionlzed forms . lncn-ased aeeutuulatkm o f d m g uri till' sk!..• of a Illt'lillmu l('
when- p H fa\'Ors greate r i(Jll i7~lti nll o f d m~ !IlLS led to the I' ll parlltul/i 11I.I1H It1lt,.~ i.~ . Ac-
L''Un l i ll~ to thi s hypothesis. only un-kmized uoupolar dru ~ pe-net rates till' lIl('mlmuw. and
a t eqnilihrtum , the concen trat ions of til(" un-Ionized species are equal Oil both sitlt's.
TIle majo rity of evi dence s llppo rt i ll ~ tlu - p I! p artition h)lx)t1l1'sb slt'IllS From stud ies of
gd-st nl intl's ti nal ebso rp non, renal exerenon, and ~iLst riC se-cret ion of d n l ~s . The- 1"11 o f g.L\tril:
fluid varies lx-rween 1..'5 an d i .O; urine pI! fluctuat es I)(,tw('('u .1..'5 a nd i .5. El ~'wht'f(' ill
lin.' body, chan ges in I'll ten d 10 he much smaller and to show h-ss dt', i atio ll Frmu tln- 1"11
of blood. i A .
TIlt' un -ionized fonn is assumed to 1)(' s u ffi<:i('1Jt l~' l i pop'l i lil' to traverse membmm-s. If
it is not , th('()!)' predicts tha t tln-n- is fl O rrans fi-r. irn'slx'l1iw of p ll . 111(' fmdioll UIl-
iOIl;:t. ed is ('(IntO/I1('l1by IXlih the I' l l and tht.' 1'M of the d m ~ al'(-,ort li n~ to Iht' II('udt' rson-
Ha....sd lmlch equation. T hlls. fo r acids ,

K ( Ioni zed concentration )

pH '"' p a + Iog, o UrHOtIized concenlrolion 20

and fo r I"L'it'S

.11t. I!l--S. TIM' ""•• of I"'L~' "I' a .ul"la'...•

...·m... II... jo'junllm of .. n ! ",-a,. ' ..'1'·m 'i..... II~·
nM'II."lrin~ ih r..tr " I' apP'·lIl'll.llff" i" int,-sli".,] Tritiated Water
\ TT 'OUS ' .....1. n il' P"- """Il'"" bIo:..J K."",·lit",t.,t1 6
"'t h~l' lritiat,ocl w ..ter , II... IrlI.Io"l'Ult- f"oc'~'
p"'m d .'S tlo.. " ..·"'hroll..-. Wit" I"" '"YI"·",M ··
;ilil,r ' lIl"'liU IITS, Ii~r tl.... l".Lu nll.k"l'U lo:' ,;hilul,
tl... p;o."~ III limitt"<.J I~' Irolll. "" ·,,,bnuM· po'''.
,'1rati u" , not Io~' 101, ,,><1 lI""' . IR...lraw" fm ...
Ethanol
WI" "... 1>.. .."d Rl'miw'h,," l y, J.: I" lr . linal
hl...1 lI"w 11.,,,,1 ,,1....,'1lti..n uf 1,,",..lh.. ,,;;.bl..
..,I..taIKTS. J. r1...rm . Pham...,:,,1.. 22:f>.m...M I.
Ilr.O.)

Urea

• • t- Ribitol
o
o 1.0 1.0
Intestinal Blood Flow
(mUmin/g tissue)
CHAl'TEP8 I1S

H ,. Ko + log (Un-ioniZed concenlTOliOn) 2b

P P 10 Ionized concentration

As h ~ lt l(l ) = 0. till' pl\n of a compound is til(' pI! at which tilt' uu-iouized and iOlli7J't1
romx-ut rutions an' equal. T Ilt' I' M is a characn-ristic of tilt' dn,~ (Fig. S-6). Consider, [or
('''Imp]t'. tln- alltil11;IKlllall i w' lrfari n. \ \'arfarin is all add with I'M -1 .8, i.t-.. equintolar con-
re-nt rutions of un- Ionbr-d am! ioni 7J't1 dmg exist in solution at p ll -I.R. Stal!'(1 d ilTt'n'ntl)",
50<J u fl h(' d m ~ is uu-iouized at th is pll. At one- pltunn luglu-r. 5 .8. 111(' roltin is to to I
ill [a\ur of li lt' ioni7.l.'i.1 d mg: i.e., 10 out of II tot al parts or 9111 of till' dnlg now exists ill
Ill(' ioni7.l.'t1 form . anti o nly 9'1 is IIn·ioni7.l.'t1. At Ollt' p l l uult IOWN than tilt' I'M . 3.S. Ilu-
pt·n,'nl,.gl's ill till' ioui 7J'i.1 illlll lln -ioni7J'i.1 forms an ' 9 and 9 1, tilt' l'l 'II\'l'r~-' of those ill
pH S.H.
Fif.,' "n ' ').-'; Sllll\\~ d langt's in tilt' I)('n '('ul of IIn·iolli7.l.'l1 limg witll p I! for ,Ki tls of tlif·
[l'n'nt 11M \"allit's. 111t' p ll r.mgt' l .u to S.Ot'n('lmlp asses values seen in th e ga...troinlestinal
Irat1 <l1lt1 till' n-nal 111111I1(', St'\"('ml t'(JIlsidt 'mtiolis an' ill onk- r and an- t'xe lllplillt'i.l hy
transport ,K'ross tilt' gastrotntes nna l harrie r. Fi rst, \"( 't)" \\"('ak adds , sudl iLS ph en )10in and
Ulan y barl uturan-s, WIIOs(' I' M values an' gn.' att'r than ; .5 art" l'sst'lIlially un- ionized at all
p i I values . For tllt'se ild d s d mg tmnsp0rt should II(' rapid and Independent o[ pll . provick-d
IIII' ulI-ioni 7.l.'(1 form is perua-eblc. Sl'UJIld , ti ll' fr.lt'tion un-i onized only dliUl~('S dramati-
t'<llIy for adtl.. with 111\/1 ,"<lhlt's 11(,{\\'t'l' n 3.0 and ; ,5. uud for these compounds a ('h il n ~t' in
rate- of Iranspo rt wi th p i I is I'Xpt't1t'(l and has 11('('1\ ohst' I'\'l'lI. Third. alt llO lI~h transpo rt of
still sln mgt' r add.., IllOs(' wi lh 1'M values IloSS tha n 2.,'). should thl'()ft'lit-a lly also dt'pt'nd
UpOIl pll , in pmd it-t' tl.t' fradillll 111l -iulli7.l.'t! is so 111\\' thilt Imn sport across tilt' ~Il t 1I1t'1ll -
" milt's mav IN.' slow eveu untlt' r tilt' most ,K'idie conditions.
:\ si\lli"~r ana lYliis indicates thut a hiL'i<' must ht' \'t'I')' w..ak. I'M less than 5, for transport
tolx- iudl'lN.'ndt'lIt of I' ll. Ca lTt'illt, {I' M (Ui ) is all l'Xitmp!t' of a hlL<it.' that is rapidly trans-

AcidS Bases .,~, '1--6. n... I'M ,,.],,.~ n( ..;. IK· ;uKI " a' K:
Strong Weak .Imlt' ' '''Y wiclo·!:-·. SoI1M· .ln,1t' IOn' "mph"t.'rk- \"I.
pKa i.e' .. lhc·y h.>.. hnth "d.IK· "'Ill 1\;I., it;· rUll<1i..",.1

::1:, V 1:"'''1''

,
, .-
......-
•
, --
"'-

--
•, ----
•
•
--
......

Oii' -c,

"
,!l,
~
Weak '-' ==.. Strong
116 CHAPTER 8

t "llit. "-7. \ '1'1'.\' .......~ ... ;. I, . !,"" ,;l!, ..It ·r

~· 100
,11;111 't.Il• • ,.,. I,".. ~ .. "in.ml~· (.... "' .J I Ii" d pKa 10
",,·inlli,...I . ...., I' ll ,'il!,"", 1"1Vo1"'" 1.0 .,,<1 ~.tl, ~ 80
1'" oI"...n,,1dlil/'Jo:I~ ill II..• fr..d i.." nll·i,,"i.....I ...·• .~

..... "'ill. pll fur ;/'/' "d ,1 ...1. ....· I' M ,..J'M· lit" s
";;; 60
"'il!.i" II..· r""!(t' of :l .Olo \ ,fl. :' fll " ..,~l lt ..· fr ··
,i,...
Ii"" n".it .. 1"f '"f''' .I n 'fl~·r "" ...,. in..·,..· ... =>
...,110 1,~t1n 'l:t ·" , ·"1....11"". tl.., .......~ "It, ~ 40 pKa 2 pKa 5 pKa B
.,,1...- "·"wi". 1e · ..1 ,,, , I'll " .1.......1.."",
.r 20

2 3 4 5 6 7 B
pH

ptll1("(] and sl,uws lin p l! -tlep,r-udelll ah'oll rp liull. Only \\; 111 "Im ng,· r Il<L\t ·S, tho....· with l1Nl
m lut"!i h..tweeu S am i I I, is p ll-(I"pt·lltlt·ul tra nspo rt (·xrll.'dt"tl. AI Iht' usually low p H of
l ilt' ~asl ri(' fluid , t1 I(~' h;l\t ·S ,oxis l almos l r-xd ll si \"t'I~· ill 11ll' iOlli.... '< 1 fun " , ;1I,d for t1WM',
~a.~ lril' transport should hI' sluw. l';l"S;I~I' of theM' I);l'i('s slllmlt! hI.' unsre- rapid From a k-ss
addit' r-nvinunm-ut. All l"\id('iIl'(' suppu rts 11l('M" ('\)'It"('taliUlls.
A" ori Wllally proposed. tilt' p ll partitioll IIn )()lh('sis n-lan-s 10 ("\l'nts ut equilihriutn. ~l 't
it has be eu appli('tlmusl \\i ddy to pn -ds-t tilt' illllu('IR' >u f pll Oil tI u- run-s IIf abM)'1)lioll
and di strillllliun , TIl(' Iilt, I, · inlh ll' nl't' of p H 011 a mIl.' pmt" "s dt' llt'lItk hO\\'I'\'I'r, on wln-n-
tilt' ralt ' lim itatiun lit'S. O nly if rln- Iilllitatiun is in 1)('fIIwahility is an t'lTI't'1 nf p H 011 mh -
l'xpl't'tt '(l. If tI.... Iimila lioll is ill !)(.'rfUSioll, tI.... problem is nul OIW of movr-nu-nt of dnl~
Ilmlll,!!:l, lllt'lIlhmll('S and. tllt'rt'fllft" any variation ill pll is 1I 11 I ikl 'I~' to ha \'{' much t'lTt'(:1 on
1hl' mit ' p n It"{'ss, \ \ 'hen- IhI.' t'(luilihriu III lit's, III )\\l '\ x-r, is iml('1)('m il.'Ill (If wlMI pnlt''ss rute-
limits II.... appn);(('I, t()\\-,m l t'Clllilih riu lIl. An :onlill,l!:ly, pI! is p n-dicn-d tn aITt'<.'t tilt' dt strt -
IJllliun (If all iClll i;r~lh l(, tim !!: ;(('m s.s ;1 nu-mbram- al ('fluil ihriu III ill all ('<LM'S ill wh it'h tilt'
nwmhr.1l1t' is )x'n1lt'ahlt' un l~' to ull -iuni ;r.('t i tim !!:,
Ill'spill' its ,!!:t'!lt'ml aplx'al , lilt' p l l partition h'llC )lllt'sis fails to expluiu certain OhM'f\'a-
lioll s. :\ \"ll ridy of fl" .Ilt'n1;lI'Y .1111I11011;1111I t, m1llCmllds (t'.!!:. , p n spuntln-liue- hrr uuuh-] ", hid l
'In' alwa,s iuni;r.(, !l'1 idt s,,,,It' m il' ('IT("(1s when j.,ri\'l'II o mll,., \1 0\'1'11I('111u f III('M' t'(lmllClIlnd.s
Ihnll, ~h IIII' ~a."l n)i " l l's l i ll;(I III( ' lIl hr.lIJ('s occurs. ah hougl, at a slo'" and ('ffal it' m it'. Anunul
slud i('S '11M ' ludknn- penetration of tilt' iOlli /~'l1 form o f ma ny adds ami I ); ~sl's t " mu ~"
meutbrum-s, Ihou~h al a Sll)\\"('f mit' than lilt' uu- ionized [or rn, TI lt'S(' observanons sll ~t's l
tllal 'llianlitalin ' pft'llidiUIl u f lilt, in OlU'll('(' of p ll on 11.1' 1lI0n 'lIIt'lIi of clm j.,n; at'mss .1
1II('ml mll)(, is unlik r-lv 10 II(' accurate.

PROT!lN BINDING
~ Iany d n l~s hillt lln pl.l\lIla pm!t'ills and tissllt' t,(lInp(IIIC'IIts (d ist'IISSI'(1 ill C hap. Ill ), s"d,
hindin!!: ts R"\'c 'n>ih l(, ami Ilsu ally SCI rapid Ihal an e-quililmurn is c<>;tahli slll"ti wit hin milli-
Sf.'(" mls, CUIISf."tIUl.'lJlly, 11)(' ;~s M I('i alt, ! (IJ(lum h and t1hSfIt'iall "t1 (ullho llm l) for ms of tln-
dm ~ {';m lx ' .lSSllllll,l lo lit, al l'(luilihrium al ulIlinw s 'Ultl lllltl('r \i rt"all,. all t'ift'lllll"I'U1t'(·S.
O nl,. unbound d m~ is Iholl,!!:l.t to II(' J?;t'lw mll,. (·.11);1111" u f p'Lssill,!!: 11m ",!!:" nlt'lIllmu l('s,
rlu- pmlt'in -Iltllllltl for m IIt'ill,!!: h ltl lal"J?:t' 10 do MI. -11u- inllul 'IIt" uf p ml( 'in hilltlill,!!: UII lIlt'
ra lt' o f I1IU\'l'lIIl'lI1 tlm ltl~h il IlIt'm lmuw t';m lit, \il'\\l"t l ill mllt'l, lilt' \;.11I" W;IY ,\-" llml of
lilt' inllu('''('' of p l l u u tltt' IIIO\'l'III('nl o f wt';lk adds allt ll );~M''' . Hul l. himl in~ allt! ion i /~lt i oll
a n ' ,i rt llall,. insla lll;uwolls n 'atiiulIs, \\i lh uuly 11I11' Sl'lt"l'i" s (UUho lilltl , u,, - iun i /~ '(1 form )
('apa M(· of Ira \"l' n>in,!!: nlt'mhr.ult' s. If t"t' n ' is a IlC 'r fusinll Iimilalioll , c!i\MIt'i"lioll (If lIlt'
CI-tAPTH 8 117

hu um l d m g am i di ffusion uf lin- unbound d r ug lh mll ~h tilt' membran e mus t occu r so

raptdlythat ra tes of dd h·t'l)· and transport are t'<{IJa1. 11ll1s, all alt eration in p rolt'i ll conten t
is not expected to alTt'l1: rate at a gi\"t'lll'O Jll'('nlraliuJI . If p -rmeabihty ts ratt'-lillliling, littlt '
uf tilt' d rug p rt'sl'Il!t'l1 IlIUW S into lilt' tissue . For a ~,"('n rate o f delivery. altered pr otein
I )i fl(!i ll ~, h~' <I lTt'l1: i n~ tilt' unbound couce-utrutmu . now intlueuces lb e rate o f transpo rt .

RIVIRS IBII NATU RI OF TRANSPORT

It is importan t tu n-mcmber th at dmg transport is gl'm'r.tll)' lndin-ctioual. Om- tends, for
t' ~ l1I pl t', 10 think of d n ll{ absorption in the ~ast mi Jlft'sti nal lra(1 as betng unidin-ct lonal.
1'\o nnally, with \"t' r:' higll coucontrunons o f d rug placed int o Ibe ga.~t roi ll t t'st i llal l rad , Iol-
lo\sing ora l udnunistration . tin- net ran- o f tra nsport is loward blood in mesenteric ca pil-
lam-s. l low eve r. important applil"ltiolls ca n be mmle of transpo rt in the oppos it e dtn-ct ion .
For e-xample- rq )('ah 'l! oral administratio n of charcoal can hast en removal Irom ti lt' hod)'
o f d m gs sueh us tligoxin, phenylbutazone. phenobarbital. and digitoxin in cases tlf dmg
U\l' n IUSl', Ut'l',ltISl' o f extenstw ad.sorp tiun uf d m g to charcoal, tilt' lu nn-n of tilt' ga.stm in<
tesrinul tract ads as a sin k for removal o f d m g fnnn blood . In this case, th e site o f tmn sft'T
may 1M.' n-strict ed to oll l~' a small regi on of the- ga.stmintest inal trlll1: or Illlly apply to a milch
lary.:t'r un-a. TIlt' rest rict ion depends Oil th e dist ribut ion o f charcoal alo ng tlit, gol~t mi n !t's .
tinal tract . E\'('II with t.ump lt·tt· d istributiollof charcoal. whether till' ove rall tran sfer Irorn
hlo(xl to ~ I t luuu-n is p~,' rfusi oll rute -lhmted or 1I0t depe-nds on the pt'nm'ab ility of tilt'
various ti mdion alll1 t' lIIlmul(' s along tilt' It'n gth of Ihl' gnt a.. \\"{'II a." Oil blond fluw to ti lt' S('
various silt's.
As prt'\iuusly statecl, lilt' concepts o f th is chapte-ron p;lsslige of drugs across me mbranes
art' iIIlIM.Jrtalit to all undcrstandill ~ of moee ment of drugs into, within . am! out of the b(xl)".
In lilt' next th n-e chapters . tlu-se concepts are mccrporated \\i th ot he r p rind pll's tlt.'aHllg
\\i tb d mg absorption. distribut lou. am i elimination.

STUDY PROBLIMS

(An ~wer~ 10 Study Problems ore in Appendix II.J

I, Dt'fillt, till' terms: pol\ siw d iffusion, passtcc factlttatcd diffusion. active tran sport, and
pt,T!tw,11,ility.
2. How accurate art' ('<teh of rlu- followill l' statements?
a. \\'ht'll dls trihutlon is perfusio n-ra te lim ited, the ratio of concem rutums al'm.~s lilt'
l"lpi lla r~.. nwmbmll(' uf tilt' tis."lIt, is \irtllall)' one at all times.
ls. \\1lt'1l11lt' surf'll" an-a of a nu-m hraue is doubled , so is its Ix' m lt'ah ility.
c. I',l\ si\'t, diffusion across a uu-mbrane stops when tilt' concentrations Oil hnt h sid('s
art' tilt' same.
d. Carrit 'r-Illt't lialt'll tnlllsport is Ollt' in which t' I1t'rg)' is 1J("t"tlt'l! to tran sfe r dmg across
a rm-mhruue.
e. Pmn-in h ind ing in th e '\(ltlt'l)lJS phase-s dum nlshes Ih l' IX'n1lt'ah ilily of IIwlll hr.uw s.
3. ~1 ()l t'l·t1 lar siZt, is all importallt ddt' n nina lll of pemwa bility. F igu n ' &-2 sUllllllari7A' s
tilt' n 'sults of skin pt'ul'lmtion for a \1I.rit'I)' o f tlll-ioui7.('tl l'(llllpnt llltk USill~ the fl ~ul"l',
dt 'st: rillt· tilt, t'fft'l1: of t1ollblill~ lllolt.'l'lllar wt'ight O il Illl' pt'nnt'abilil)' for a S(, rit'S o f
t.,(llllflt llllld s of ('(fual lilltlp hilil'il)' (od anolM"d!t'r part ition l'(x'flk i t' nts o n I t~ M.~dlt.· art'
all t'(llIal to 2 ).
4. Brit·flr d iM.'us.s tIlt' roll' of ioniza lion in tht' 1Il0\l'lIlt'nt tlf \\'('uk udds anti weak l"lo;t'S
al'nlS~ I1\t'lIlh nult'.s.
5 . Tilhlt' 8-1 shows til(' ('1Tt.'l1 of o rdl ad ministr.lfio ll of ild i\'alt'llehart:oal Oil rt'lllo\ 1I.1 o f
p llt'lloha rhi lal fnml tht' lxx ly.
111 CHAPrER 8

Teltle "'1. Iffect . . .~ ........ &(th,.... CII.". .' ...... H_H.11fe (Heunl
......._ ......Itw..

36:l: 13 03 :!; 7
"""""I ,5 M ('JI".",, ~ ' .~.JD .<>"'IT""'i.lIG ~"""'<J"'_<J ~."*"",W"""",*,,,,_~doMocio<~
etoooa:d jNM, 25/ 31000l-3 10ll 1QS4
.179 d ~ .. 70 ..... cJ M ooob«lI ..-; <I Iv - . . tww</' a """O!P'"'" .....

a. KIllMing tha t tilt' \'o IUII II" of d istri butio ll o f ph t'IlOha rb ital is I)..~'j I A~. ('ak1,lah' tllC'
clearance o f phenobarbnul into til(' alinw llllll)' canal during t reatmen t with d Mrt'tl;11.
lIinl: C I. (d uring In 'a l lllt' lll ) "" C L (no frt'af llw lI l ) + C I. (hy d lan:: oal ).
h. 111t' ck-uruncc value delefmillt'(l in ~UM should apply us wdl to lIIo n ' lIIt'II1 o f dmg
Irom the hmwu o f t ht· ~a:~I ",i lltt-st i llal l m<:t into tln- h((JlMlsl n -'lIn. If til(" llIajori l~' of
d r ug rt'1Il1M11 and ahso rptlon O{'(1 Irs i ll Ill(' small inlt'stint>, es timah ' the- hiM·lifc·
a.'i..'\(Ki all't1 wit h abso rption wln-n IU L of lIuid is in th l' small mtc sunc. Fo r th is
pr obk-m. concetve rlu- small inll ·slillt· as iI sillJ?,lt' l11lllpartlllt'llt .
 ABSORPTION

OBJICTIVIS
The reader win be able 10:
1 Describe !he sepsinvolved in !he ceclabsorption of a drug
2 . Distinguish between diuoluhon and pelmeability ,ote-limilalioo!i in ob!orption .
3 AntiCipate !he influence 01 ~iCOChemicol prope!tie!i of a drug on ,ts ob5orplion from
diffetenlsile5 of odminislfolioo.
4 . Anlicipole!he role 01 goslric en"plying and intestinal trom;1 in thego!Jl'oinll»llnol absorption
of a drug, with pCJIlIcular relereoce to !he ~lCochemicol pt'op9fll8S of !he drug and its
dc»oge lam.
5 . tis! the Ioebs Influencing d,oouhon rale of a dll'9 .
6 . Descnbe ibe inlluence 01 decrecsed permeability and surface oreo along !he i~lf101IfOCI
on the pedcercoce of ool COflslanl"fole release 5~5 in vr.o.

Drugs an' m os t fn.'(IIlt·lltly ad minish·n ..1 (·xt r..m L<;(.·ul arly. Tilt' majority a rt" Intended to ali
S)"Stt' lIlk'l.tlly. and for these, ahsn rp tilJlI is a p n >rt"Clu isitl' fnr ad h it)', Dd ar s or los ses o f 11m ",
dllrill ~ abs orpnon may cont ribut e to , .uiahilil)' ill d n l~ rt'sl")(lIlst· and. ul't'asiuna ll)', m ay
result in fajlun- of dmg tlll·rapy . It is primarily in thts e urn-xt. us 1I sou rce of va riahilily ill
systemic Tespm lst' am i a.s a means of (111ltm lling the conceut rat ion-time p m fil(' of d m g in
the body. that abscrp non is conskh-n -dlu-n- and th mll gl.oul tln- n-mainder o f the hook II
should I., k('P1 in mind, however, that ('\ '('11 for IlJost ' d nags jnte-nded to act IOC'lllly ( '.g..
mydrialil's . local am-sthcncs , IIlL~al d (>(1J1lgt'slallt s, topi ("11 lI~('n ts , and ,!l'mso l Immd ll. li·
lators], 1lI ( l\'('IlW IlI o f d m~ From till' sih' of app!i<"lIlioll lo tilt' s)"sk mil' ci rculanou inllut'Ill1' S
tillw of onset. intensuv. am i dll rali ull of t·fTt>(i .
11lis chapte-r <leals' ....i ll. tilt" gt'ut' ra l p rindpl t'S gm'l'm iug mil' and extent of d m !?: ah-
sorption . A I I I.()II ~IJ abso rp tion fmm olher sitt' s is di scu ssed. l' lJIpha~i s is placed 011 ahstllV '
lion follfMi ng oral atlminislmliun . l1lis is lIul only h(>("lllst.,t llt, o m l llKMlt· o f ad m inislrat inll
is tilt' mo st prevalent for sysh 'rnil"llly a(i iu ~ d n'gs, hut a]S(1 lx-cause it iIIustmh's lIlallY
sou rces (If variallilil)' t'Il<'1 11I1ltt' R11 ill dmg allSorp lillll.
Fi~u rt.' 9- 1 depict s 11ll' mnm-mus slt' ps il\\l ll\l'd in the " hso lVtiull of a llmg g1wu nT:.llly.
Ilt'i ug a complex struct u re. lIIallY uuatmnic and ph~'SioloW(' fadOl'S afT("C..1 the ove-rall mit'
and extent of dnlJt abstJ'11tiuII Fnnn till' gil.s tminlt'sl illal lmd . maL.i ll~ a pR >(1s(' IjUlllllitllli\'1'
pn'llid iull tliffk llit . XOIwt!1('ll'ss. much can lx' IIIJ(!l·n;I{M.! lIlid appn"C.1. 11lt"C.l of tht· (" ,'nls
(x>('1 l ni n~ al this lim! other sites of ahsorpt km .
Ahsorption is fanJR"C.! h(>('llUSt' tilt' I . JtI~· ads 1I.S a b ~l' sillk. A cone..-nt ra nou Wadi t·nl is
pn·st.'111 until \i l111all, - no dm ~ re mains 10 I.· absor bed. Till' gnuli('lIt is Iwulltai ll("C.l lolIgl' f.
IIU' lafJtt'f lilt, \'(1111 111(' of di st rilmt iull of III(' d nJ ~.

119
 120 CHAPTERQ

P;,-~ ..ag(' (If dn ,~ thnmgh tln- mem branes di\itling tlu- absorption sln - from thr- hlood is
a pn-n-quisite for a!Jsc)'lltioll to occur. Til <In sn , III(' dnlg must be in solution. Most drugs
art' adm illbh'n"(! a.s solid preparanous. COIllIIIOIl e xamples art' 1.a h11'15 am i ca psules. Be-
( ',II I \( ' so lid IMrtid l's cannot p ,l-SS through membranes. a d nJg IIIl1 s l disso!n 'lo he absorbed.
\I any factors in fluelll'(' tile rdt"L<;t· of d mg fm m a solid phanll <lt't'uticaJ fonnulanou. Hi,...
1,lw n lltlCl'f l tiC.f is a compreln-usive tenu tlt'fluting the study uf the in fluellt't' of phannnceu-
tical fo nnulanou variah h-s nil III(' pt ' n o n llann ' of a d mg in dr·o.

ABSORPTION FROM SOLUTION

St'\l'ml ph~"li i(Jl()¢c am i ph)'sim l factors that dt'l t'nllillt, movement of dnll{ tlmlll gli mem-
brum-s han ' ht'('11 t1iS("l.lsst'(l ~t'lle rall}' iu Chap. S. lncluded a mo ll~ t1WIII an- the physico-
chemica l properties of tilt' molecule, Ihl' uatun- of the uu-mhraue, perfusion, ali(I pll .
These f,,{'ton; ; 1II t! oth ers are 1I0W {'ollsidt'n"{l \\; Ih respect tn drug eleorptlon.
Gastrointestinal Absorption
In al'(unl;u ln ' witl. the p O'l li{1ion of ti lt' p i t partition h}]x) tlJesis, weak adds an' ah~orh('l l
111 0 rt'rap idly From lilt' stomach at pi 1 t .Otha n at p H H.D, and tilt' co nw J"S(' holtL~ for weak
haw-s. ;\ bso rp tioll of adds. hO\\'t...r-r. is always much f'l\ ft'r from the I('!is acidic small Intes-
tillt· (p ll 6.6 to 7.5 ) than from tilt' stomach (Fig. 9-2 ). 111t'S(' llppan'nll)' l,(lTlfli{1 inR obser-
\".IliOIlS run lit· n'l'(JlIl; lt'l l. Surfact· an-a . permeability, and for perfusio n rate-l tmued ab-
sorptlou. h loc ltl flow an- imp ortan t determinants o f tilt' rapidity o f absorption. TI ll' intestine,
l's lx'l'ially tln- small mtesnne, is fa\u n 'l l o n all accounts. T he tot al ah sorpti\l' urea of tilt'
small illh·sl ilw. l11111post 'll lal).:t'ly of nucru..i lli, ha~ lx-cn calculated to he alx llli 20l} ~ 1 2.
llml an t'slima! l'{l I L of blood p'L'iseS t hrull~h the intes tina] l'llpillarit'S l';lCh minute. TIll'
(1Irn' sl,)(l1It1 i ll ~ c sttma tes for tl.t' stOlllad l art" nnl)' I ~l i: ami 150 JIl l Imin . TIle pt-' nllt'llhilil)'

Gut Wall

liver
Portal
Vein

To Site of
Measurement

Metabolism
Metabolism

To Feces
t 'IK' "...1. :\ ,Imjl., \.'1>...II .l. .... .lid. " 'K'(Ml ll h' n .. ....·r..l l...rrirn ..,KI Sl iM uf 10-",. in ito .... 1'.....Ii.,] ItMM"" ... ,,1 .h llillit
jl.oL'ln'illlt"Ii " ..I ..I"'''l lt i''fI. 1>i.." .I"h"u. .. l' n·""'llIi'i' .. ' " " MM·" ... "I ......"'. ,Iv· JI:Ill "'all , i. tI... li..... '<ttT" I lltu m _
p\t1" t",...I" h"" or " ..1......li' m in d"' lt\,I I" " n tit I,y '''U::-' 'M'' ill tiM' ~,,' ..-.II is .. t.l1I... " r I" " '" tno..' ·II.iI" hility.
11I-11I"' oJ " r ,Inol:"" il fin ' p;l, .... Ihr" ujtl. 110., I, r rurtl... r " ,,1111.,'" I",,,,\:ail..hilir:-'.
CHAPTERQ 121

of lilt' illh'siinal llll' mh nlllt"s 10 dm~s lIlay aisc i lJol: ' fi!:n'ah'r than tlMI nf till' stulllat..h. 11wSl.'
iucn-ases ill surfat" un-a, !>l;·rmt'ahility. ami blood flo,", more than t'llllpl'IlSllh! fur tlu-
dt"t'n·:t\t "ll fr.lt1illn of un -iollizt"ll add ill the Inu-sttm-. Indee-d, the ahscl'l,tiult of all ("( I m -
pounds. Iw tltl')" adds, hav-s. or neutral compound s. is Faster From lilt' (small) inh·sti.w
than [rmn th e slo tllad l. Bt"t'all sc' absorption is J;': rl' alt"f in the small inl l·stim·. tln - ran - of
~.t\ t ril' t'lllpt}in~ is a l"l llltmllin).t sh'P ill III(' SIW('l1 o f dOl ~ ahsorptiou.
Gast ric E m pt)·i n~. ( ; 'l~lrit· t' lI1pt)i ll~ of liqui ds is app mximall'iy ...x-ro-onh-r. Food. cs-
pl'l'ially fat , slows l:'l\ l rit· (· lIljll}i ll~. whk l. expl.dus why t1m~ an' Frequently n "t'OlIlllw nd t"(l
10 Iw t.lkt·1l nil an r-tuptv stomach when a rapi d ouset of at1inll is desired. Dmgs that
inHUt'II(,(' J;':asl ric ('lI1 pt}i n~ al.\u alTt"t1 tilt" mh' of lIhscllVlinli of urln-r dnt ~S ( FiV;. 9-1).
Hdt'ltliort o f dOl!! in Iht' stomach i n(·n" t~·s tln- percentage o f a d ose ahso rlJol:'l1 t1Jnltt~h
tl ll' g.tsl ric muco sa. hil i usually 111(' majority of d m~ is still absorl Jol: 'l1 t1 JnJtl ~il ti lt· int estiual
t·l' illlt'litlllt. lit litis Hog.m !. lilt' stu llIad l lIlay 1>1;' , it'WI'l1 as a rt."[Xl'iitory o rga ll From \\~I kh
pulw s of t1 nl ~ an' ('jt"(1I'l1 h}· lw ri.stalsis onto the absorption sil('s in ti lt· smal l inl t'slinl·.
Intt"sliu al Ah o;oJ"p lin u . Th ruu ghuut its It·ll~h . tltt· illh'sti ll(' va ries ill its lltllltif<ll't·ft'l i
pmperties and luminal compoouon. 111t' int estine lila)' Ill' bn><ldl)' d hidt'll into tilt' sma ll

t·l p:. 9 - 2 . 1>" ' l' il (";/,1I 1·...·; ro" "'1' 1I1 f~,'ori ,,~ ;/,
jI;rt'll!t'r po·n....,I;/,K!'· of " " _jo ,, in ..1,lruK- "' ...."l>t io. , .. f
'l;I,/iI..,fit- ..., 01 (, ' M 3) I. ,10.""''1' frunt tI,t' ...\1 <ot." "Ol/.~'
ill I'll 3 (. ' than [r um llJol: ' ...at i" it.. ti"I' ..1I'll fo (0).
i Mo,lifM..1frum I>ol,," it•. J T.. HIlI"I'" S F.. l>itT.. rt.
I ~ \\' .. suiOl". F..C:. ;01..1 s";,,t<..~·. I X .: I>",~ a1..
Stomach, pH3 "''1ltio.., I, ., ,, ill . it" ..... ~nt 1t,<-hU" IIl" ~i,·lot" 'l: n--
"' I<otic ..t.,oTtit'" II"S. J. I'tu.m,. Sd ., .'i1S J 100-1 199.
11Hi1l.." I..ptood ·il l, p.. rmi.. i"" "f 110.. n 'p~' ril':h l
,,,,,,,·r.)

Intestine, pH6

o 20 40 60 80
Minutes

15 t·la . 9-.1. Slo.",,;,,~ ~;I,.Irit.· ""'I't~i"lo\ I~' pn..

," ' l>4Illl.. -I.i'''' (3111 "'K i .•'.) . It...... II.......II· tI( a1..
m"..
t, " !It>rplit., ,,( .....i .. ' l1..·" (15C1O "'K) lnriu-
h'r" ..1onoll)'; lI. 22.~. '..r-<oltl " ...10· \( , I ~,
, ,,
,,
~ .10"(..........., in tilt' maxim um p r.... m.. I'<.",,·n-
,,
,, , ,, l rah " n "' HI .. I"n~..r Ii,,,.. I" " ,..ti, Ihi. 1'<"" -
,, ..."IlI..... i"" (·····1 (" "'1,""..110 \ -..),It.. ... 1..·"
, ,
,,,
.....i .. ml' H'>ho·" i. ""•." .. It....• ( - -l. M...

,,
.... ., ~
-. lud " ,...l1nitl.- ( I ll 1I1~ h '.). whil-l. h....I t.. u~.
llit· "II1I~l"~ 1.....It·". tl.., ..I>">tp! it,n o( Ol/.'{"('
, a ",I"np h .." (---I ( I ",(I I. • 6 .6 1.l ~1) .
, !RI.,I.."",n rn,," ~ illlmo. 1-, 1I.·...bnll.. H e..
T<>t lnll. 1'.• "' ..11·" .....,(1. I ~ I', : 11..nn>Ol.t1t..;-
~-.J tI .. "bllt...."., of 1I.",Ir;'" " '" IIt~;"l/;' Eff....1.
oi I'n'P"'nll",li'''' ",..I It..i od"I' ra"'itlt· olt par·
o 2 3 4 5 at......",,,1 (al... I."'i ""I'I"," ) al.. "rl'tlm,. Hr .
M•..t. J.• h\\7.....'»\. Hli3 .)
Hours
 122

amlla~t' i ll{l ...lilll· ~·par.d l .. 1 hy tlw ih-ocecal j llll(:tinU. Snrf'K't· an-a Ill" umt It·IIJ..'1h tit··
(·n 'a.<;.(.,;; (mill the- <Iuudt"Uliln In tilt" rect um . Ek-ctn cal rrsisl all('t' , a 1Il(·ll.~un· (If Ilu- tlt1-'Tt't.·
of liJ:llln(...~ o f tilt' jum:tinlis bv-tWt"l'1l lilt" t' llit hd ial <:t·!ls, is 11I11(·1. t. j~wr in 11.,· ('0&'11I than
in ti ll" ' lIIilll inh'stillt". P mt("ol,ti(' a nd nwtaholi<- c' n7.'. lllt"l; , a... w{,1I as ;K1i\,. and fcKi litaft'C. l
tr.l.lI'pu rt s~"'h"ms an' di stTiIJlltt-d altlll~ th t • illft"!Ot iul' , 'o f ft'll in n-...lri ttin· ftl.,tKIIIS. TI .., <:u km
alltMlIld.. wtth an al'A )"i,: mic·T1Jflnnt. TIlt" IllFoUl p i I. 6 .6 ill t he' pn":illlal s mal l in h"lOt ilU' rhiuJ;::
10 7..S ill IIII' It"nnilla! ik·lIll1. falls !iharpl~' to 6.4 at lh,>start of ti M' 1"('(11111 I.·fun· ll llall~'
rhilll: In 7.0 in Ill(" d,-<;(.'(·m ling ('okm . Tr.ms it ti llK' of lilah-rial s is an"lm l3 to -I lir in tll(·
slII;.1I inh...tuw alltl (n )ln 10 In 24 hr or eve-n lun ~t'r ill tlll· la~l· huw..l . Ahhuu gfa th('!\t.· and
utllN l'Ulllplt ''\iti.~ 11I;11.:.· pn"d !\(' (I" antita ti\"t' pwdif:tiull u f inh"'tilloJ dm!: ah\ol'r ptiun di f·
fK'llt. v-veral ""Iwral fl"<Iotlln~ l·IIl(·l"gt·.
n il' po·mll·ithili t~·' ~lIrfan· area p mdlK.1 (p . S.,, ) h'TKl~ In .k'(Tt,it.'w· pn~"5~i\l· I,.. fro m
lluUI...·1lI 1l 11 tn ('Olu ll. n,i,app lies to all (1m " Tno k'Ctll.-s Ir.l\l· nii ll ~ tiM' ill h ... ti IM' l'{Jitlwl ilim
I ~' IMMI c.">lm.·r-IIM'!li;I!t·c1 pnx,"S"'f"S. ",tlt'tht- r \ l.a the transeellular nr poardl"t'lIl1w reete. 11M"
( "''{' n'i(\(' in p , S." i~ !lot'!"n d.\ a (k'<.Tt·it.\.t' in tI ~ IJ nt-til-s uf ainurptiull wl M '1I dnl ~ <Io n' pt Kffi
ill (!IIT.·n·nl pa rt s of the - i ll h'lotillt~. it.\ illustrated in FiJ.:. ~ for r.m itil lint' .
I'I·m w..llilit)" ill ti M' \111all inh.,..ti,K' (""a II hot' ~lI ffici.·nl ~·ll i~1 0;0 tl ldl <Io1~ u]>ti( "' Irom tilt'
111 1111'11 i.. po'rfll!>ilill mlt-·limi h-d ( Fi~. S-S . p . II -H. UIJ(...· r tlK'!\(· c.'ullflihul1\, fl\"t'r.J1 ~;.L\t ric.'
1·IIlIlt)i lll.t " 'Mlk l ra te.. limit :lh'"0'l)ltun fn llll an oral \Olutiun. As shown in Fi ~. S-5, at an)"
UIlI' ..itt· alu lIJ.: 11M' inlt...;tirM·. ill this (""d-~' tilt' jejun um . ..mal l mnk"l,llt... pt.· mwalt' mo n' fn '!' ly
tha n L.rgl·r (11M... . nit· i\'SII(' (If In(tk'(,,Iar ..tze is (Mrtic."Ia.~· important for pol ar d m lt'. n M"5ot"
\ lIlntillK' ''' IIMI\1' 1l;lr..,· " "larl~· \ia thl ' ti"ht fUIJ(.'t ilNl\ Iot·t\lol " ·III-pitlM·lial ('1·Il... Pt·nrwa hili l)·
,tllpl' ;' ni In (Imp n IT shotT I)-' with flM.It'<.'lla.r \\loj ~flb a1. 1\1' 3,'50 Wmo !,·. \lolt'(, 11ar sb.l· ha.\

500

400 Stomach

Jejunum

Cecum

100

o
o 4 8 12
Hours
1-lJ:. Y-t . n..· ","~I "li """' lrwl .J >tpIi<", ..r,..."t>clillt· I....... \0, 110 .. It - .. I' "I1>1.. -..Ii<." .. 1.....11 ....· Ih.· n_n pLoo.1\lI
......•..I...t .. ... -III1..• pn.lil. ....i ' "1101"..• ,>1_.,.,•• 1;«1.., pI..~ lU' 1' ......... ~"Ii,'" l6 "'I.) (..,I"':" i,'II: 1.50 "'It ..(
r"'''I.. li ,,,' I,~.I ". ~II. ,", Io. i" l" II 1""....", . -'. ;"';" " 01 '" t & 1. .... 1 11, •• -, ,i n¢'1..>1"',I_n. . ..... Ilolt" "",I~
1,,1 , n ", ~ .It.." t ...h",'i>~ J_>tpIi<II' ,i II... ~maIl ( M. W . • .11.1 Wnll"') I"oLu "".1.·.,,10- (n 'lIl II.. " ..'" ..
" \t , 'I, tl,,· " Io"ll ltwt tI... P'""'....hil~·-Rlrf >IR".. lP· S., ) p". I'''i ~ h 10....... in Ihr ....... dlolh in
!I ",••11 ;"10"'''..·. \:.,. " .. II ..t-"l""'" IIf .....'I>di · o:-fTf'(·ti ·~'I't'"._ (in Irnni dt.-I'I" ph-l"'" 3 hr hm
lM.nl'h lho· \t l..' ...... ' II'" ;rj "n. ... ..,. 11".,e, tI... druil; i lIp101t~ 1 Lot IF - U6 . ,w.. not "", tl l
...q:. "''''lI: tl... tl..· , ,,wll i.. l h ...· " 11,,· " loIj.. t" til . ' of .l- orrt" MI ...1..... ralll"b I. lioILrn '~" (" 01••",,,,01 ("111I
w ,II..." .. Sl t-., n"l..-<. (; t:.. II...,.., . W.. Il.on . " · 11 .. II..rman.. . n J, '.. n'rbn . T., . ...1 11..... I.J , I" ft......... IIf
~""-.; "I~i .. J "t... i ,In l( . I.-In..-ry . MI If.... ..I"'''J'f''''' ~"",in. IIf 'an....L.... 11wrm. H.r. . flIIYlI-I IY-t .
Jy.J'~ I
k-ss of all ('Ired HII 1)(' rIllt ,,,hil it~· fur lipoph ilic d mWi' which lr.lSV('Nt' ImnM'f.'lIu!arly. The
ultimate limit 10 pt' rIlwahility is Si7.t', llOWt'H·r. 111l1S, la~(' polypt' ptid('S, proteins , and ot he r
macmmok-cular drugs an ' \i rtllall~' un able to p<l~S t h ftlll ~" tilt" int('stint' wall (...·(·11 if the)'
art' mt't alMllkally stablt" lIult'sS til(')' can lit' processed by OIl(' of tilt' specialized sysle ms
that traffic vi tal materials. such as vit.uuin BIz, from the apical to the ha.....llatt'r.il surf,K' -' of
lilt' t'pit lld iill cr -ll,
Causes of IA)"" Oral Hioa millibilil, ·, \ \11t'1l a d r ug is given in solution and p<L'i.<;t'S
n' adily al' ro~s lJI(' TIl h rallt~ , ah smplioll from most sib 'S of ad rnini strution is com plete. 111is
is not always so, es pecially wllt'll d rugs are placed into the ~;l~t mi n lt'!i ti naI tract.
;\. tlm g mu st p,L' S st'f lut 'lI tiiln~· Imm the ga't mi nlt~tin ai l u lllt'll . t1lnmgh tilt' ~ut wall.
ami tllwugh IIIP li\'t'r,llt'fon' t' lllt'ri n~ tilt' gl"lw ral ci rculation (Fig. 9-1). 111 i ~ st"(l"t'II('(.' is
an anatornit' n' tIIIin- mcnt 11t'('iUlst , hi llt Itl [X'rfusing \i rtll.ul~· all g;l,1mintt'slinal tis~ t1t'S d rains
into tilt' hn'r via tilt' ht'patic po rtal will. If lilt' a ni)" cause of loss is incomplete lillie for
"hso!'])l ioll, tln-n the hitJa\'ailahililYis less than nne and the cc rnph- ment . the fr acti on ap-
pl'a riu,g in ft'('('s IJIll'han,gt'(l. is a measure of luminal n-tenti ou. D m ~ lIIay .uso ht' Insl hy
dt't'lmpns ilioll in lilt' 11I1Il1'n: ti ll' fml'lioll 1'IIlt'rill~ lilt, tissue s, f"F' is then tile fract ion
m-it lu-r 1 1 ~1 ill rlu- ft'('('s nor dt'l.' J11II'MIst'l! ill till' lumen. Of Ihis 1'M' m l('lIti ll~ drug. only a
fml'tio ll 1II:1) ' C' SCil pt' tlt'sln _dioll wi thlnthe wall.. of tilt' ?:a'ilmin lcostinaltmd. Fe. the-reby
reducing till' Iractto» of (kist, n 'ad ling the- portal vein 10 Ff · ' Fe;' If (Img is also l'Iimil1alt 'll
ill tilt' lin 'r. lU I "ddilional fmction , f'1I' o f thai n' adlinF: Ihe- liver t'st:~\lll'S extruct hm the re.
Tilt, IIlt':L'illfl'l l owrall systemic- bio;l\'a ilahi!ily, F, dearly is then

Fur t'\1IlIIplt'. if51I'l o f lilt' d n lg is Insl at {' ;I('" sltop. Ihl' hit li.I\1u lahil i ~· o f the d n lg, measured
syslt' mali('ally, would lit' 0.5 X 0.5 X 0.5 or 12.5%, Xote that the d rug can lit' n-nden-d
totally nn<L\'ailahlt, at any 11111' o f Iln -se sIt1)s.
Tln- IUllgs an' {'u,llld{'1! from the foregoing consideratlnus of hifJa\w lahilil)' t'\'( ' 1J though
tl.t'y may ol,.::L'iioTlally lit, an important site of r-limiuanon. As t1is('us''i(·t! in Chap. -1 , dnl ~
~n' lI intrawllollsly is IIst.J :l~ a standard 10 measun- hi oa\11ilahil i ~·. \\ith calculation bused
on measureme nt of dn,~ al a peripheral venous site . Bolh illtr.\n'nollsly am i omlly admiu -
istt'n 'tl t1 n1F:.'i IIII1St Ilrst POl'iS througl) the lungs to n 'adl rlns site of measurement. C ouse-
que-ut[v, lilt' t·fT('(1 o f tilt' IlIllp 0 11 tilt' meas ure ment o f hi(la\ 'ililahili~' I1t,('11 not be cousid-
en-c l.
' mtllfficielll Time fo ro AbflOrp'iOl I_The P , SA term for drugs appc'ars tn drop sha!'])I,.
\\i lll movement fmm lilt' small mn-stiue to (,,1011. 11 ll'\\' IlUlI·II of Ihis d rop is tim ' to a
dccn-ase in p(' rlllt'ahihl)' and how much 10 a dec rease ill surface an-a between small and
largl' illit'slim' is not kIl0\\11 for certain. Fo r !ll'mwahlt' (Im/{S. ahSl I!']l tion is r.lpid am i
prohahly IUlIlplt,tt' \\i thin tht' slll;11l intt"slin{', EWIl if SOUlt' t1m~ Wt'rt' 10 t'lIh'r till' la~('
inlt'sfi1lt" lilt' pt'flllt'ahility tllt're wOllld ~ti ll he snffidl'lIll)' h i ~!J to ellSlln:' Ihat all Ilud
('Illl'n'ti W,L\ ahSllrIM'II. Ah:'>ll!']lti un t)f 1I's,'i pt'nnt';,hlt" W ,IIt,ntll~· l'M l];tr, d mlt" slill primarily
t)("('lIrs \\i lhin tilt' sma ll illh'stint' bllt is unlikel)' to bl;' l'Omplt'l(, \\i thi n tilt' limilt'll 2- 10
-1-llr tr.msil Ill'ritM!. E\idt'II("(' SIlPl'M lrl illg this lIolioll is pn " idt'(! \\ith tilt' 1I 1 -a ll ta~olli st
ran itid im'. Thh rd alin 'ly I'M lIar slahlt' l'IIlll'M llilld i ~ ;ulllosl totally I'xert'It'(l lIlldm ngt'l l wllt'll
¢ \"t'll ill'ran 'Il(l1 l s l~·. \\1lt'n W\"t'll o mll)", 6U% is ahSllrllt"d hilt all \\i thin the first ,'3 to -1 hr
afh 'r atiministratillll (Fil!:. 9--1); tht' n '.'it is Il'(' '''t'f('t l lllll'hallgtoc i in ft'l,,('S, f.\itlt'lIlly, w ry
littlt, ra nitidi nt' is ah'iorllt't l fmlll tilt' la~t' in!l'sti nt' ("'l'n l hou~h d m /;?; mn lit, then' fo r up
to 2-1 hr.
Tahle 9- 1 lists repn'st'lltalin' t1 rt1~S for whieh om l hi(li.l\'aibbilil)· is n'f)' !ow (0.1 10
14%), most likt'iy dill' 10 1'M lor inlt'sti n;a) Ill'mll'ah ilit)· \ti lll nU1'i 1 of that ahSllr!)('1! ha\i nl!:
(It"('ufrt 'fl \\i thill ,Il(' small inlt'slim'. 111t'd n lgs shan:' tli€'t'()1Il1ll0!l pml)('rti('s of I)('ing l'M l!ar
124

and. with tilt' exception of pyri t!oslig milll', IT-Iatin·ly lar~t· (mo](,(.1,lar wt' i~h l ~rt'aft>r than
.too Wmo1d. I'yridustigmi llt· is a quate rnary ammonium ('('lIlpound. which Illil~' explain its
low hioa\~lilabilit)' dt·spilt· its smallmolecular wt'i ~hl ( 18 1 Wlllo!e). ~t ()sl o f the compounds
lislet! in T able 9--1 cannot he ~i\.t" 1l orally for t'lTl'{.1 i\'l' s)ost('mic atti' il)': they mustlx- gh,("11
parenterally.
Finally. the n- an ' small molecular wt' igIJI, 2(X) 10 ;].'j() WIIIO]t' , potu dn l ~s fIJ r wllk !.
ahsorptiou, alt h()ll~h Inco mp lete (50 to ~}% ) , is sumdt'lIl1y hi~h to n-nch-r them useful
~\'l'n o rally. 11Il'S(' include'<:inw titlilll'. ranitkliue-, h)l lmd lOmthiazidt·. and utcnolol. As with
ramtidtne, t h(lll~h . tht· small inf('slillt' is Iikl'1)' to ht' the predonunant sitt' of ab sorptmn.
TIlt' rect um has a small SUrf,K'(' un -a. and a d m~ WH'n ft"d ally is nol al wa~'S n -tatned for
a sufficient Icnl-.rtt. of tlme 10 ensure complete abso rption. :-':0 lillie limitatioll exist s filf a
dm~ injt'<.1('(! into muscle, subcutaneous tissue, and IIII)..st other stte s wirhin tlu- hody; com-
plete absorp tion is anticipated unles s des truct ion 11I.'('Urs 1)(' ,"l ,( ' U silt· o f ad ministm lion ami
S)-'S!l' mie d n 11lulion.
(.'ompt't irag RpCJcl imlll, Any react ion thai ('f lll l p '''tc ' S \\i lh a!Jsc)'ll liulI lllay f{"( IUI'f.' IllI"
oral hiOiI\1ulahili ty of a 11m,!!;. Tahh- 9-2 lists va rious reac tions Ihal 1', 1Il 1J('(llr ",i tlJiu lilt'
~st mi ll i esti nal 11';1l'1 . Hcact tons can he ho tl. t'll~l n;llie and lJUll{'Il ~'ll\at il-, Add hydmlysis
is a com mon nonenzymatic react ion. E nzym es in tilt" in testinal cptthehum and wit hin IllI'
inh'stinal microtloru. wlaieh uormully rt'side in tln- largt' bowel, lllt'tal )(llilJ:' SClIIll' drtlh~ .
TIlt" reaction products an' oftell Inactiw or less potent than til{' pa n 'n t moh-cuh- lun-r-
ac tions "'i lh <.'tmslih wllts o f lilt' ~'lsi roi ll l ('st i nai ll uid.s al.so tll.'('ur ; til{' fes ult may 1)(' low
d n ,,!!; hiull\"ailabi lity. For example, mn- reason why tt"l l';l<"yd iIW is in('ulIlpli't{,ly absc)rl)('f.1
when coadnuntste red with milk and wi th certain antacid s is that this antibiotil' For ms Sp<lf'

'.We 9-1.
P.-r 1....tI_1 P
.~ Dew,. ",_1"1 Lew 0-1 .1....,.11... 111.., 11Hrt I.
III.,-
Owe ..

Amil.ocin Genlomi(:ln
Co,ben,CIII,n Neomyc,n
Ce!omondole Pyricbt'gmine
Ce!orol,n 5rreplOlT¥:: l n
CeIotoxlme T~opIon,n
Ceha.zid,me Voncomycin
...... ~t.:o...

,
c.
11-2. ..p,.._........._tl_.
'- D-. AIt...-ptl_ ........1
wl
_
I...... o......I .....tI ...1T...ct 11Hrt

Comple><ohOfl TetrocycJine

Conl"'9CJlIQll

--"'"
LOM 01 och\/lly: pl'oducllnocti\/e
SuIlocOfllugohOfl
'''''''00''''''
~""
Glucu'Ofl;OOt;on LOM 01 ocrl\/Ily product inoc~ve
toM 01 OCrl\/lly gIven wllh 0 penpbercl dopa deca rboxylo~
Inh,bolOf 10 'educe go$llOmleSllnol rneIOboIl$II'\
Hyd'~$
k~ LO<\$ 01 OC~\/IIy : ptcduc1lnoc;11ve
LOM 01 ocrMIy product iflOC~ve
Prcdccrs (d>g11OX1ool have ecucbe OCf1\/rly
Enzymatic Sol.cylic cod formed, cce-e onrl~nflommotorycompound
Acr,ve ompi<:illin formed pl\/OmplCl\l,n (e~) 1$ IflOC11ve
Lo» 01 ocrl\/IIy: producllnoc 1ive
o.lClorlQll LO$$ 01 ocr,\/,Iy product Ie» ccn-e
~ed uction Imi(:,oiIoml Insended /of cccr (,nresr'nol) on'~mflommolOfy OCIIQll: poreer
drug may have someocr,\/,Iy: ceodcct, 5-omiflO$Qkyli(:
ccd ocnve
Ad loOfplion 10 choieslyfomlne: cdsobed morenol not c bsobed
CHAPTU 9 '25

in.t::ly su!uh l(' ('fllllp!('X('S will. lilt" poljvak-ut cation {e ..t::.• C a 2+, }-'l,3+ and :\.1 1+) conta nu-d
in tlll' st' prepar ation s.
TI lt' eo mp l('xities th at Ol"('ur ill d w prt.dudl' accurate prt'1lictioll of tilt' contri lmt iou of
a ('flmp('tin ~ n ';l{1ion to d''1: r('lL''l'11 bioa\lIi1abi lif)', S omet i mes tilt' problem of Incomplete
absorption rnn h(' l'in'u lIl\'('nll"(1hy physit-ally pron-cnng the d rug from destmctlou in Ihe
slollla{'h (s('t · enteric (Uatill~ di scussion. p , 36 ) or I» ' syn thesta ng a mon- sl;lble deri vati\"(',
which is couwrtcd to tilt' uct ive 1I101(,(11Il' within th e body. Similarly, to euhauce absorpncn,
ilion ' !)('rnll'abl,' deri vath"t"!> an ' made, which are mpidly ("()JIvl'rt('1110 Ill(' adin' molecule.
oftI'll du rin.t:: passa.t::e through the intes tinal wall. For example, absorption of Iht, polar
anti hiot k amp idllill is illl'fllllplt'f(" Its sys temic dd i\l'f)' is Improved substa ntially by ad-
lII in ish'riTl~ a ilion ' lipophilit, and permeable inactive este r prtK1m~, pivampiedliu. Tlu-
h~ 'tlrol ys i s o f tlris ('StN wit hin tht, inn-stmal wall is so rapid that ulll~' ampicillin is t1('h'(1('11
in tht' l'i rt'ulatiun . D r-n vativr-s. such ;l\ pivampicillin. an- ~(,'l('r-dlly refem-d to as 1Jmd",1!. ~ ,
' lS t1l1'y an- ph arnlill'fllc'¢lM dlly inacti ve.
1If'I Kltic Extract ion, Aspirin ( a{1:tyl sal k~..lie add) is om- of till' first Sp ltllt'lk prodrugs.
It was lIlarkl'l ('11 at the tu m o f tlu- ("('lItUl)' to overcome the unpl easant taste and tilt'
gast rotn tes nual irritation ass ociated with lilt' pan-n l d rug, salk ,..lie add. Aspi rin W1l~ o ri¢ -
nally thought to hI' inadin', I)('ing des igned to be rapidly h)"tlmIF '('l1 wi lhi n the hndy to
salit"!i{' add. Only slll)';('(III('ntly was aspirin shown to he pharmacologically adiw, Y(Ot tilt"
ori¢nal dt'sign wor k('11; upon ingt'stioll, aspirin. a labile es te r. is r.tpid l)' h)'tlml)·J'.t'lI, partic-
ularly hy ('.S It' fi N'S in the hw r. Ind(,,( '1I, Ilt'patk lJytl mlysis is so rapid that a siJ".(';lhlt' fraction
of aspirin is {1111\l,rt('11 to salk)'!i{' aoid in a si n~I(' pa~sa!-,:(' th rough th e liver, n's ultill~ in a
substantial "first -p ass d T('('I ,"
1)OII-:S tllat showa suhs tautra l first-pass ('ff£'ct d uo to Ilt'p;ltk elimination art' listed in
T ah lt' 9--.1. Apart [n uu th is feature, tlll'y have httle in common. TIll'" are of d iw I'Sl' chemical
structu re . PI)S"l·s.~ tliffe l't' llt pharmacologic act ivitie s, am i an ' llwtaholiJ".t'l1 via a num ber of
pat hways. \\1 It'l1 tilt' llwlaho lih' (S) formed durr ng tilt' first pas s tIlrtm g:h the lin 'r is les s
po ten t th all the parent t1m~, tile 0 ...a1 dose is la~ef than the i.v. or t.m. dost, n-quln-d to
aclik-ve tilt' ...11111' tlu-rape-uttc effect . 11 1 i.~ occurs for lIlallYof tilt" t1m ~ listed ill Tahlt' 9--3,
In ~ l lll(, instances . t' .~. , i~lp mlen'nol. lu-patic extraction is so hi~h us to ('Sst'lIliall)' precludo
tl\(' o rul m utt', Ih-n-. nn amount of pbunuaceuucal fonllu latioll he lps. Euher till' dnlg mu st
ht· gh '('11 by a parenteral mute, o r it must 1)(· discarded in favor of another drug {'illld icl"tt"
A method of l'stimaling tilt' mlll;imumlikeh· d, '('n'RS(' in oral h ina\"ailahi lit\' due to this first-
p.lSS ('ff('11 is diS{'lI~S('11 in Chap. I I, Elimi;lat ioli. •

, • .,1. 9-3.
.......Iv.· ..n'
..pre H
v. Drve. lltewl~ Lew 0-1 al_v-IJ..,lIlty"'" I. D.e ..
lc Ilf........_·
Alpteoolol Hydrobzllle NaltteXOlle
,Am,'rrptyliroe Imip<amiroe ~mi ne
Chlormeth'ozole 1$Op"~enoI Nico/cI;pine
Chlorpto....o::wroe I$o$orbode d,n'"o'" NiGQI,ne
Cy1o'obine Kelomine N,!ed'p;ne
Desiptom,ne tobelolol Niltogfyce<in
De~ltopropo~ lidoca'ne POpc:M:!<,ne
D,hyd'oe<gotom'ne lorca inide f'henoxet,n
D,ltiozem Me«:aplop,mne PenklZocine
Do.epin ~ida", Pento. ,lylIine
Do.O'vbicin Meloprolol PrOptonolol
Enco jnide Morph ine ScopoIam,roe
EWodioi Nolb..oph ine T"""",,...
5.fluorOUIOCil Naloxone Vero pom,j
Of . 05 ~ "'. on <>-o}O
'''doped<>'''<le ~"","1'or<j 5 M .....ell."... I N f .1l'JIO" .........".", ea... CON.:..... .....eldonocol ~ Cl.-. """'_ _
0 1- 25. 10 8<1
12. CHAPl£ ~ Q

A\'ni di ll~ first P;L~ S t h n l\l~h tilt" liverpnlhallly {"plains mos t (If tilt, ad ivily of lI i t n ~l~l"t'ri li
adrn inislNI,<1 s ll hl i ll~lIally fur all acu n- <In¢ nal attac k. nllll l(I I )( · rfll.s i n~ til(" 1 11ll'(.·ill l"l\it~·
bypasses rhe liver and ente rs di n ·(:t1y inlo tht' supt.·rim vena (';.1\'01. Tlu s <lntian ¢ nal d n l~ is
almost ('o m p ll' tdy nWla!lu ]i7J.'d as it P'L\ st'S Ih mll~1J 111l' her-r, a m ) ;IIIY d nl j,t sw a llo\\l,'11 is
nut svs te-ruicallv il, <tilahlc' , The lI lt'taholih' s M't'll i ll h!ood an ' link weuklv ad in' hut umk-r
t't·rt,;in d n.·l llTl~tmll't~ may n',wh couceutrations hi~h {'l1011~h Ie; l1 J11 l ri i lll lt · III overall ,1(>-
nvt tv.
TIlt' n-ctal mlllt' hils a (I{'fi n ite atl\1U1ta~t ' over lilt' oral mult · for d m j..'S dt-slmyt'(l hy
~'I.' l ric ad tlity or
hy ('1I1)111(, S in tht· illh -stillal wall and m il ' m lill m . I'nh·ntially. rln- rt't1ill
mnte- may illsu pa rtially (t'(ltll,(' first-pas s Ilt'patit, loss. Part o f 111I' n -otal hlund sll pp l~"
Jlilrt il·ular ly Ih,· Iufenor and midd l,· hl'1Il0ITI.oidai vein s, h~ 11;L\st·s tln- Ilt'patil' portal cir-
culnnon amI dUlllp s di (('t11~' into ti lt' inferior vena l'u\,a. " l'h i,·, ill !!: a (('p mdul'ihle biuavuil-
ability, whic h is Imp ortant in dm ~ IIll'mpy. 1I1 i1~' 1)(· d ifTkult . how,'\ "('r, silll'(' h io<lt' lilah ility
slro u!-tly d" lx' mls flll till' sitt· o f absorpti ull wi thiu tilt' rect um.

Absorption from Intramyscvlar ond SuIK"toneous Sites

Tile G ent.'ra l Ca..... III 1,(lIllr.L\1 10 Ihl' small intes tim-, and il\(l(','( 1 to till' ,·Ilti((· !-t<lslm-
intestinaltrurt, abso rp tion of mo st drugs ill solutiou fm m musch- am ! sllhl' ul'I!l,·Ull.S Iissll"
is pl·rfllsinll m!t'-Iim ilt'il; hll'(('ilS" S in hloud flow havn-u ahsorptiou, For ,' s,a mpl,'. conside-r
tln- dat a in Tahl,' 9-4 for lilt' loea1 iUlt'stllt'lic lit!u('ain t'. SllllStl l un rlu- p" ilk pl'l\mil t.UII-
l'('nlm!iulls "hst'rv, '(! when Ihe Sllllll' dost, (If lidocairu- is adminish ,(('(1al difT"(('u t sift's in
tlu- "udy. n,'t~dll , fo r a gi\"('u dose, Ih,· h i~l lt' r tilt' JX'ak couce-nt ratton. III\' fasn-r is c1 m ~
ahsorp tion. I.a tg' · diffcn-nc cs ill speed o f ah sorptmu ure d,·"rl~' l·\1d" II1. 11 ll' sp,'t 'tl d' '('(('il\ -
ill!!: fm lll Inn-rcostal mu scle to s.c. tissue-, ill lin" \ti th a t1 c'(' ((', l\in~ fissu,' perfusion.
111is d"p"nd"lll,(' o f ahso rpli'lIl on rwrfusiull llIay he t'xplailll"li h~' lilt' uatun- of rln-
harriN (the- l'apillary wall) bctwr-en tlu- silt, of injl"l"tillll (inie rslitial llllic! l alit! hluoc!. This
l~lp i ll;II'" \\1111, il uun-h IlIlIrt· I(M )S(' I~' knit snuctun- than 11." " pitl lt' liili l i n i n~ uf till' ~;l-sln t­
illh's tiual lrat.·I, o ffe rs Iitt l,· impt'( lam'(' to till' movement u f , I m~s inln bllMlll. even for po la r
illnil.'.'ll c1 m~~ . Fo r examp h-, ~c 'n lilm id u , a wute-r -soluble, ionize-d, pula I' llit'it' of mok-culur
t\'t" i~llI -Iii WlIlOIt·, !I,ts ~(('ilt c!iffit.·lllty Jlt ' lIt'1 mti n~ tln- ~,tslf'(l i n lt'sl il lill IlIUI'(lSil h UI is m pitlly
lind t.'C IIlIpl" ld y absorbed from an intramuscular site. Thi s ksw illllx 'ilanl'(' by thc' l'ilpillary
\\1111 in llIust·lt' alltl S.l'. lix..\ lIt· ;Ipplit's III dm ~s, im!t'!x 'm!c'nl of IINI, dl"~r, 't· o f io ui...a tinll.
alltl Illoll'('ular sin' III" In llppmximatl'l)' 5(MK} WIllO\t·.
~ I acrumol n:uhlr a nti LJTn p llatic Tnm spo rt, In I"l m l l'll-~ t tu slllall m" I' "l'IlI,'s, si...t·,
l""laril,.. and d la~I' pUst· a pa rt il'ular p mhlt'lIl for adm inistralioll (If prnlt·in. and latgl'
pol)llt'ptitlc' c1m~rs : t1ll'ir lransport across lUauy lllC'mhram 's is him!c,(('tl. Fu rtllC'rlllllrt·, 1...·-

,.It........ 1""__••'
Ce_ _ tr.ti_
Site .. 1.lectI
,.n.wI.. '''lectI_
the P_k v •••• • Ud__I_
1 00-_, 0.. ..
PlAA fV&M
wcx:..o.N: CONCt N'~"" liO"
(""'9/ 1(

Inle<cmlOl 1 46
Po,~1 120
Coudal 1 18
lvrnbor ep;durol 007
Brachial p1eXI.l$ 053
Suborachnoid 0 ••
Svtxutoneov~ 035
"'_""'"c""""" 8e l'In-oo:d........ oIloxd~,;."g.., 1'In-oo:d-.u<J~ EdOO<lb-o C """~ond C C ""':l
fllacl .... SC.-.k~.().Io.d 1Q84 w ~70-m
'000 '"'9fl - .. 3 ......
CHAPTEl! Q 127

(11lN ' IIf t1t,(' llllpOsilioll hy pml t'l,1~1i(' t·1l0'lllt·s ill til(' g'ol.<;tm illh"Stinal tra<:t, the-ir o ral all -
so rp tion h t·\trt ·lIw ly low ami errat ic. ~ l c )S t Hf tilt' Infonnanon on tlww kiml, of tl m /-,'S has
11Il'C'1l ohlailll'li fo ll(lwi ll~ lIOTI" lwu!ar pan-uterul ad minis trat ion. Fu r tlu' s.c., i.m., am! ill-

trapentoneul m utt's. d rug n-acln-s ti lt' s)~lt' m ic t:iR:lIlatioll I') ' Iwu mechanisms: d ifTlISioli
thm uj,tll tilt' Inn- r-, tilial f1l1 itl, alltl ft·!It'stmticlIls ill till.' l illin ~ o f tll(' \':l-"l'1llar (';lpilb rit"S and
by n lllH'(1in' How o f lilt' lnterstittalH u ids through lytll phat il' d.;Ullll'k ~ l oll'(1 Ittr si:l.t., is
of p rim.u) · illlpo rt;\Ill" fo r p. t'Sll~t' acros s the capilla ry eudothcllum . l'olyp{'ptidt'Ji cf II's.,
than appru\i JlJa lt'l~· .)( 11 11 1 wmn1t' p rimaril y p,l'" th rt)ll~h lite ca pillar)' pathway, Those of
~n 'atc' r than allll ilit :2U,lMMI WIIllllt, un- h-ss ah lt, to trnverse tilt' edpi llary wall ; tl1t'Y p rimaril y
1'lItN tIlt' hh lll via tilt' I~lll phat ie path way.
1.~·mJlII IInw is slow ami {'aIlSl'SallSllf]ltion fm m nonvascular pa n-nte-rul sitt·s to l,mtinllC'
for lIIallY hOllrs. a' shown in f ij,t, 9 ....'} for ~1~t.usyl ah.J recombiuaut lnnnan /-,rr;ultll (x.-'~ tt·­
n lil(:OJpha~t ' (Ulolly - sti lllu la l i ll~ f"(1o r (mok -cnlar wC'i~ht .. I S.£MM. to 3 -l,lMII) Wlnoll' ). Tilt'
d nl~ 11;1' a half-lifl' of fl.!; m ill afh'r i.v. .uhninistrution, hilt f()lIo\\i n~ S. {' . ad ministrat ion. tIlt'
plasma l11l1l't'nl ratioll is p mI Oll~t 'l l for at It'a, 1 42 hr . wi th a r ate of tLx 'lim' illdi{"ltin~
(ullt i lll l ill~ input.

'1111" 1I0n \1Isc:llbr pa n-ute-rul m ule's "fT('r lilt' lId\'alll a~t' o f pm"'dill~ pmlnll~c'(l input fur
short Ilalf-lift· peon-ius. Thu s. 1l'"1\11\C:11t lT part'lItt' roll udminlstrution allows fur Il"Ss frt.'l lut'nt
ild rniuisl mlioll than tllC' L\'. routr- ...\ mai n (1111l1'01 Iwr't, relates to tllC' n 'p md ud hility IIf tlu-
rt'1l'<t~t ' int« rln- sysn-rmc l'in'u lalioll fr om the silt.· of ad ministration. .\ IN If]Jtin n li m'li{'S
Irmn IlIlth i.m. •uu ] s.c. ad 1l1 inistr'llticm ltitS hl..·n s1ul\\l1 to hl· lt i ~l. ly dl1x 'ndc'll t on tl.(· silt·
o f injc'C,tioll. It'mpt'mtllTt'. am i c1q~rt '(' of mbbin ~ al tilt" injection sitr-,
Bt'C'a uSl' of t lu - shnrt ha lf-lift' nflt'll UhSC: I'Yl'(l anti d("(11111!'It)Siticm in tilt" ~,t\ l mi nlt."Slir lill
tnn-t. IllC'rt, is d t'arly a IIt'('(1 for tilt' dl '\·j·lllpu wut of 1ln\ 'l,1 t.It'1i\'l'I)' s)'St<'ms for pmt t'ill
t.I m l!:s. Smnlh-r 1'It,I)l'lt'ptidt's Imn ' hl'('n tl'sh'(l in connulled-n-h-use (rnil'n ll'nea ps ulalt'l!l
illjt '(·tahlt· 'ysll' lIls. T hc'y han - alsc l 111'('11 ShCl\\11 to lill' a bsorlx'(l a('rn ss 1Ilt';.al u WIll IJr'OUlC's .
1 1i~l lt' r lIIolt'{'ular wt'i ~h t pol~lll-ptidt's anti proteins may rt'l l"i rt, mu rt· ('rt'iltin ' IIwthcllls to

o 6 12 18 24 30 36 42
Hours
t·ll(. ~'j , 1 1.'l'lIl~ 1......·" I. "Ii< "" " ( ¢:, (, ~L"~ I n·o, ,,,I';,,.lIl l In"'.....' l(r..."'J,"-' 1,·."....·.. 'w...J:' ·nM"n~' .•Ii"'''L.t;nJ:
(...1". ti~J,,"i"J: j , .• • . ">li< IIi ,,,·>..,,.1 U ", t£.. ....,J.... IIi ,..·) I...ol". ill;',1i"" "f .oj IlWl< ~, n M' n~ults. lIhta.ic"..1in
t'o'" ,1,tT"n'lll il.. lr.i.Io~J" ~l>1ry II... Lic,,",K'" ,,( II..· ,Ino~ f,>II<.... i lljt II " ....1<... tl( I....".ntt·r.d ;oo;1",inhlmlit..,.
..... L'I".~1 rnn" 1l' ''Jo:...,nl D , \I " rt.·" ,,·u, It T .. Sodlif" ',. s.. ",,,I Sio n. S ,I.: C\init,.l pll.olmUot.. l.i,..-1it· ~ 'Klit ... ,,(
a ," " ",," Io...·"", ...id k J:n ",ll. (.K1" s, ( ;~ I ·CSF, t:" m. J. eli.. , h.w >t.. ~ :4.""""!:l. 1!:1!i".U
121 CHAPTHQ

('nslln' {'Unsbh' nl and mon- t'UTll p ll·te hina\'ai bhi l i l~' or Illil}' rt'fillin' til(" dl ·\l.·lopnlt'1I1 of
1II0 rt' SPl'1..1 fil' methods for ( Iel i\"t'ri ll~ t1wS(' dnl ~s to tilt' sil t" of act tou.

Absorption From Other Sites

DOl ~S mav hI,' udministe n xl to vtrtnallv unv sih- of til(' bodv. Th is is cr-rtamlv trm- of local
;lIl l'stllt'lk~ . III rt'1.'t'1I1 years then- h'L'> ill"t·.; l'()IJsi<!t'rJ,hle i!lien-st ill ('\plllitill'~ sonn- o f tilt"
les s conwution al . .in-s, suc h 1t'> li lt' 11I1l ~. 11'('>:11 lOil\;I,.. ami bucca l (w
.n i t)" ,t,> a IIw ans of
ddi \'('rill~ dmj.,~ s) ""Slt·lllk-.i.lly. TIlt'
IIt'W P(JI~"Pt·plidt· and pmt r-iu d m~s that an' poo rly mid
(·rr.t.lkully abso rbed when ~h'(' 11 UrdU)' h,,\"(' r('('('i\"('t! parti cular .utent tou. Tr ausdr-rmul all-
pltcauon ha.. become popular for systemic dd i\l.·ry of small. ~(·Ilt ·I1lIl)' !ipoIlI.ilk'. pote llt
molecules that n-qutrelcw Input rates 10 a(.'hie\"t' d Te(.1in ' tln-rupy. In all cases. consider-
arion hit.. to hl' ~H'II to the particular p roperties o f 11Il' sin- and rln- d m ~ . :'\OIlI.'t!I(']t'ss. Iln-
Iactors i n fl uellcill~ abso rpuon fro m IheS(' sites art' li kd~· to ht' till.' same .t.. t!loS(' i n llllt'lll..'in~
ubsorptfon from tilt, oral, Lm., ami s.c. sites.

ABSORPTION FROM SOLIO OOSAGE fORMS

formulation

Ecpmlil)"of d m~ content (lot,S lint ~uar.lll lt't· {'flua lity u f dlk~I{·Y . TIll.' prt'S('IIt1.' u f diff i-n-nt
excipients (iIlWt'tlit'llts in addition to t1 m~) alld lllimll fill1llri ll~ pmf,'l.'SM'S lIlay rt'snlt in
dnsagt· forms l1mtaining rlu- S'Ul1l' dn S(' nf drug hl'1 m\i ll ~ difft' rt'lIlly i" t· it~J . 1I 1'1Il'l.' Iln-
n-ason for It'slin~ for hioe quivu leuce of preparations of a d m~ iutended to bc' switd lilh!('
(p . 45 ). Gt'lll.'mlly, Iht' primary conce-rn is \\illl till.' extent of absorption . Ot:l ot<;ionally,
variations ill ah stl'l'ticlll mit' may h{' impo rta nt. vtucb ofh-n depe-nds 0 11 thr- dl'~rt'(' of
uccumulatlou that O( '(1 Irs un multi ple t1n<;ing (F ig. i--6. p. lSi).
111t' major (·;lIISI.' of dilTl.' rt'IK'('s in abso rp tion o f a t lm~ from various products is <IiSstl-
lut km. Staudanbs exist for content and pu rity o f lilt' mum-reus iniU:IiH' i n ~rc.'(lit'lI ls list'll to
stabili7.t' till.'<Im g; to facihtate ma nufal1un.· and maintain iUkgrity (If rlu- df lsa~t' fonn dllrill~
lJandlill~ and stura~t'; and 10 fatili!;ltt', o r .\o llwlimt's contr ol, n-leuse o f dm ~ foll(l\,i n~
adminislr.llion o f till.' dosage fnn n. I ntended, Of otherwi se-, t'al.:h in~n'l.lit'lJ l (";III illlllll'Il('l.,'
tilt' mit' o f d isstl]lltiOIl o f Iht' d m~, as can the manll faduri ng p n x'l.,'ss. 1111.' n-sult is it largl.'
po le ntial for tliffen 'n('I.'s in drug absorpuon a lllon~ p roduct s. Indeed. a large '~l rit'ly of
df ~l~e forms of d m gs are mark eted in whic h release Illay he.' iuum-dinte. t1elayl.,,(1. pm -
longed. or susnunr-d. n.-ganllt,ss of the phy~il'(x·lll.'lllil·al prope-rties o f ti ll' d m~ ilst,lf. Some-
times , difference s ill absorpuou ( . 111 he.' l1'ITt-lall'(l wit h differences ill dissoilitioll m{',f,'lln"(l
ill all ill rUn' apl" lmllls. 111{,rc.' are dis.';.ollliioll n'( plirl' II\('llfs fOf an illen.'il.sill14 Illlml){'r of
important d m~ pm(llIt'ts. On (X'(·llSioll, 1J(1\'·"V{'f, ill d im d isstllutioll ksts fail 10 t1lITl'Ialt'
\\i th abstl'1Jtioll. At pn.'S('Il!. ,l<;st'SSlllellt in humans ('I.JIltillllt·S 10 ht, thl' p rimal)· nwans of
l'\-a!lIating dm~ p mtlm1s am I di s(:rilllillill i ll~ 1)("tw' ''('11 . ..'t isfadory and un Sillisfaetol)· for-
Illulaliolls.

Dissolution
11ll' ff.'<l.'M1II why d isstl!ulioll is st) impo rtalll lIlay ht' ~aillt 'l. l hy n'al izill~ Ihal ahsorption
fo!lo\\i ng atlministmtinll (If 1I so lid is a tW()ostl'p pn)(1'ss:

Entry into
Drug in Di ~5f)/ution
product
... body

T\\1J siluations 1m ' IInw (1msidt·n'l.l. T Ill.' first. tlt'pit1ed in ri ~. 9--6A. is 0111,' in whid l dis-
(HAP1H Q 129

so lutioll is a llllldl faster p nll't"SS than is t'llIT)' o f drug into the hotly. Ct mSt"(llIt·ntly. mos t
of tilt" t1 m~ is di ssoln'1l la-fon- all appn'dahlt' amount is ab"orht'tl. 1It"n", pe-rnu-ability
rather th an dissolution rate-lunus absorption. An ccunpk- is rlu- ga.s tmin!t'stinal a bs orption
of IIt'tlrnyt'in ¢\"t'll ax a ta h!t.,l. 111is jXJlar .m lih iolic tlissol n.·s rapidly hUI ha.s dim<:ulty P"!"
t·tl":ltill~ tlu- ~,ts tmi lllt' ''l i nal t'pi tlll.' lill lll . So. liult· is absorbed. Difference s in rates of dis-
solutiou of lll.·u lII~~·ill [rom (Iillt'n 'nt tllblt·t" ha\'t' little or llo l·llt'1:"'l 0 11 tlu- spt't'tl of absorp-
tinn of this t1 m ~ .
In tlu- second and much mon- <1I111l11011 situutiou, shown ill Fi~. 9--6B. tliS.SlJ! utiol\ pm-
l't'l.'tls rt·latiwly "low ly', '!lld an y (lisso ln'1! d m~ rt'ild ily traverses tilt' ~a.stmin lt·slillalt·p itllt'­
hmn. ,' ''sorp tion cannot proo-ed ,IllY faster. howeve r. than the rate at whi<;h ti lt' d m !!:
tlissn ln ·s. l1li\t is, absorplion is d is<;o lll!ion rate-limited. III this cast', dm ll~t"S ill dissolution
profoundlyaff ect Ihe rail' . anti sometimes lilt' exten t. o f t1m~ absorption. Evidence sup -
port i ll ~ dissolution ratt·· limilt'l.l absorption cumes fmm the Ilntit't'a hly s It""'t·r ahsOlvtion of
mosl t1 m ~s from so litl t1os<lKl.' fnnll.s than Ir om a sim ple.' ,UIUt'1l11" solution.
Factors (ontromng Dissolvtion
\l allY factors inllllt·nl't· Ihl' dissolution of a dr ug. AlIlon ~ the se an' surface are-a. solubility.
pl l. .uu l s t i r ri n ~ .
Ex palll. l in ~ the- SIln. Il"t· t'xjlC lSt'1l to IllXly fluid s hastens t1iSStllulioll . Ht't l ll lil\~ Iht· sin ' o f
tln- solid p.,rtid t·s is 11ll.' Illost conunnu uu-aus of ach i{'\in~ this ~l.lal. To this l' lTt'l1, for
t·...muplt· , man-rials ( di " i n lt '~ra n t " ) art' tncorporan-d into tablet s thut {·aIlSt· tln-m to SWl.' lI
IltlClll cont.u-t with watr-r an d 11ll.'1I 10 di sint l.'g mlt· into gnmulcs that finally tI{'a~rt-galt' inlo
tilt' tIIiJ.,rillal [itn- d m ~ partick-s.
III t1isso llltiull filtt·-lilllilt't i absllI-plillll, tlu- concentration of t1 nl~ ill solution at thr- abo
s orpttou silt- Is h' pt low ht'1·.IU<;t· t1i <;so t\'l.'t1 dm~ mpidly enters Iln- IMllly. Tln- dri\ ill ~ fort't·
for t1i"Slllutioll is tli rt'l"'l ly n-latr-d to the Stlillhilily of the dnl~ at the surface o f till' disSt)hill~

A. Permeability Rate-limited B. DiSSOlution Bate-limited

Absorption Absorption
100 Absorbed 100 Absorbed
Drug / Solid Drug Drug "
Drug in Solution
"-

50

./ Drug in Solution
_ Solid Drug

o 1 2 2 3 4

t·iK. 9-6. \\ 1"'11 ..1"" '1" ",11 i> 1"·n,,,·..l ,ih ~ r..tt··!i"' i",t1 (c • ,\ ). "....I " f tI..· t1m~ I"" <li. "oI>. ..1(ml,," ..110,..·)
I..·r,,"" "" .'1'1... ..;.." ..• fr...1i"l1 h I....·" .."."..t.... !. In t....,tr t . ",I..." tl.,... .t..li"" nl lt·· !im ih ;d"" rptio" l ((::.-. ii i,
'-"r;. Iilll.· ,tml( i> in ....Iuti,.., ( n..1li"d .tI II..· "h''''l'tic." , il.· '" ..,,~- Ii"..·: ,I",,, i. ;d""..t"..1... "'" ;0.' il
.Ii .", .t,, ~_ X..'i..· thai Ih. · "'..~ ,ri ~ .. r ,1 m:.: n.. ..1... >rI"...1 i. aho.ll~" r'''llltllll till" r.d... linllti"l: .It"!" in ...,Iutio.., in
C,,-,,· .'\ ;11,,1... a ...,h,lm Ca....· H.
130

solid. T his explai ns why tablets. capsules. ,lIltl even sus pen sions of sll;l ri ll~ly soluhle dnl ~s
an' prOlIl' to absorption problems. E\"('II if dissolutiou WN t' 1I0! tln- rate.lilllililll?; ste p and
it s,;ltu ralt't l solnnon at til(' abso rp tion silt' l:ou ld Ix· llI,u lllaillt'<l. tilt' nth- of abso rption IIf
tlU'S(' dmh'" ....u llid sti ll II(' low . o....i nl?; In tln- low <I(III \,O IlS so luh ilit)",
For ....'(·ak adds um] ha."l"S. tilt" mit' of d issolution can "t'
ma rkedly mcn-ased hy mill Ka
salt forrn . TIll" explanatlou hes ln the diffi-n-nt ('lllll 't ' lIl mtiI IIl S ill tln-surface of tilt' di ss(J"in ~
so lid. Tlns conceutratton is mud. lngher for the muchmon- so luhll' salt than for the fn'('
add o r base. Adj usting p H of Ihl' medium also i U{'T('lL\t'S dissolution of we ak adds and
bases, h~' lll' l pi nJt to ma int ain such con dttlous around tln- di ssuhill ~ man-rial. This is ~t·n ·
e rally. however, not as effccn vc as IlSill~ a salt form .
Pt' ristaltil' IIIUn'IIl t'lIts in the sto llmt..h an' ~t' I \{'r.tJly ft't·hlt, alltl \~triahlp. ~l hi ll ~ ill lilt'
ant rum can he Ijui lt' \i~nr()lIs . T he disilltt~r.tt i c)ll rate. tlt'a~Tl1!:ation m it' , locatfon o f til('
dosagt· form in the stomach, food. and tilt' stah' of tilt" p atien t each inllllt ·lll't·s ti lt" st i rri n~
rate am un d til(-' d i s" ;ol\in~ p1ll1idt", Stirrill~ is gt'lwmlly su ffid t'nt to ('IlSIlTl' ('IllItp!t'h" and
rdpid dmg ahsClIlltioll from solid tlosagt' for ms l'l lll tai ll i n~ solu bk- dmgs.
As mentioned previously, littl e d nJg is ~t'll e mlly ahsofhetl from til(' sto lTladl. Xom-the-
les s, di ssol ution in the gas trk fluid is a p n'n'tluisite to ti ll" absorption o f s(lllll" (Inl J.,"", This
point is wel l iIIustmtt'tl hy h'tml')1.·lillt" h)'tln x·hlori dt". Only Iha t which di ss(llvt's in lIlt'
stomach is appa rently absorbed. This 'lI11p!.O!t'ri(' au tibiotic. fn 'dy soluble ill both s lf(lIl~l)'
<ld dk und ,ukalillt· solutions, is mi nimal l, · soluble at p H .'Pi. a p H t~11it,;t1 of till' Iutes nuul
lInid . Perhap s the sp aringly solubll' It't rd(')l.·lillt' prt'('ipilatl's onto 1l1idisS(II\'('(1part icles 1'1\·
tl'ring tilt' illh"Sliul', tlll'n 'hy limiting furt her di ss(liu lion.

Gastric Emptying and Inttsta Transit

Befo n - di S('II.ssillg the nlll' of ga.s lril· 1'lIlpt~i ll g Oil ah s0'1)tion o f d nl gs ¢ \'t' ll us solids, cou-
sider til(-' iufonnalillll pn )',i dl'tl in Fi~. 9- i . Slll)',\tJ <I n ' thl' uu-nu transi t thues in 1111" ~tnlll ;ldl
anti small iutes trm- of small noll\!isintegmling pdlt,ts (diauu-tr-rs h(,t\\"t't'n 0.3 aJl(I I .~ mill )
am i o f latgt" singlt· lIom !isinh~raling umt s k itlw r capsules. :2,7 mm hy 9 I1IIIl or tablets. ~
to 12 mtn ill diameter].
During fa.sling. gas tric l'lIIpl)illg of bUlh small alltl liltge S( ,lill~ is ~'t'1I , 011 ,l\ l' m~I', 10
Ill' mpitl, wit h a mean transtt tilllt' of around l hr, a!t ho u)!;!. then- is luns idt·m hlt· individual
variabihty. In this state, Ihl' stomach d isp lays a compk-s temporal pattern of motor alii\ity
with "ltt' m ating perio ds of'lu it"S("{'nt"{' alltl modr-run- l'{lIItmt1 io ll of \':If)i ng fn 'tlllt'ILl')',
('lIhn illalillg ill an illt£'Ils(' l'lllllnU:iinll, tilt' " h f)II S(·kt'l·pi n ~ \\~ln' : ' th at prnpl'l.s all ~;Lst ril'
l'{JIIIt"n ls, illdllding s(Jli( l~ illmml im'spl'ti h·t' of Si7.(', intn tilt' sma ll inlesti llt". TIlt" I'XlIli
I'jl"liioll time of a S(llid Il;U1id l" Illt'n'fon' lI('IlI'ud.s (III whl'lI lilt' S(llid is lakt'n duri ng tilt'
mot or adi \i ':-' l')'d l' , an un pn'tlkiahle pt.'riod \'a f)i l\~ fnlllt 20 min to a f(,\\, hours .
111t' situalio ll is \'('f)' d iffel"t'1I1 aftt'r t·<ll i ll~. As sht)',n l in Fi~. 9--:, wht'll takl'n Oil a fl'l l
sto m;u:'h, llw g;l\t riC Inlllsil tilll!' of soli(ls is illln"a.'it'li. 111is ine rt' aS(' is ~rt';t tl' r afh' r a Iwa\'y
mt 'i1) ttHm aftl'r ;l li ~ht 0111"anti is mlleh ~n'ah' r for a 11I.rgt, si n~I(' IInit th :w fo r ~ lIlali pl.'lIt'ts.
Fo r ('xa mpll', tbt' mt'an g:lstriC Irdnsi! timl' fOf largl' sing le unit sys!t'llls is 1I0W alultlst "j' h r,
\\i th SOIllI' of t11t'1II still in tilt" sto ma l'll I ) hr af!t'r iugt·stioll . TI II.·S(' I.l!N·I'\·lItions an' I'X'
p lailll.'ti hy tilt' sil'\ i ng ;u:i iou of a fl"(1 Slfllll;l('1.. Tllt' i m;'~ll l.lr "htllISt.'kl't'p illg wan"s" i1n'
1It)',\ . rt'plill't't l h~' n 'gil lar amlmtlfe gl'ntle t,,{llltrae tioIlS. whil'l l('I lIltillllllllsly m ix anti trilu nl!I'
til(" gas tril' l,,{lIIte llts. Furtllt'flll of{', o nly S(llid.. \\ilh t1iall l('lt'ri I I's~ tlmn -: 10 10 111111 an'
allo\\"l'll to fIllSS into Ihl' small illtl'Stilll.' \\i th ~:lst ril· lI l1 i( 1. l .;t~('f fflotl p:trtid t's an' f('l aillt'tl
u ntil f('II"l'I.."ll lu till" rt't juisite Si7'(' hy t rilu r.ltioll alltl ));.trti al tli~l'sl illll . \\'illl l"{lIl\'{'n tifln:11
tllblds, d i si nh~rdlioll and SUhs('t !lll'nt dt'aWt~at ioll into finl' p;utidt.s ad lil'\'l'" 11.(, ..:tnit'
nhjl"li i\"('. As lou ~ llS thl' SlllllllU:'" relll ains ill II fl'll sta lt', thl' l'l llld iliulIS a bo\'{' pn '\ <lil. For
thoS(' !lI'fSl.lIlS who t'a l tlm't· ~lJotl llll'ills:l tla,., this i.s 1II0st of til(' \\~I ki ll)!; hOUri of til(' (lay.
CHAl'YH Q AB5OIIPTION 131

I n routruxt tUl'q 'lIh ill Ilw stomach. I ll(' transit unu- uf sol i t l~ " it hint lll' small inh'sl i l\('
va ries liu ll ' among: sllhjt'{1s, appears 10 1)(' Independent of either tilt' sin' of a su lid or till'
pn'St'Hl't' o f fotltl in t ill' slt ll ll ad i . ,UIJ is n 'lllark;tllly slUII1, app m 'dlllatd )' .1 11r ( F iK 0.--7), a
tiuu- sim ilar to Ihat foun d fo r till' truusit o f liquids. Bo tll solids andhqeids app<>;lr to rnovc
down till' small iuh'slilll' ;tS a p lll~ wi th n-1;tli n ,ly li lt ll' Illi.\i ll ~. As the mouth-to- anus transit
tiUll' h t~vka lly 1 to 2 days. Ihl'S(' llala 0 11 ~,t~ lri l' and small tntesnnal tra nsit ti llll~ indkllh'
that. for tln- majority of this tiuu-. unabsorbcdmatr-nuls an - ineither tht' large Iltl\\'t'l ur
n-cnuu . I'rm i dl '(l with till' ph)'siolt~l' illfu nnation above-, IllI" pos sihle mil' u f g;lSt ri<' ('1111>-
~irl g: an d inn-stiual traus it on tlu- absorpuon of drugs gwen ill so lid dOS<Ig:(' forms can Ill.'
tlm ll' rstol ltl. Constder lilt' fullou illg: situations .
Hapid Di ,.••elut io n in Slo macb . 111h ts tilt' ("'(1I1H1IOIi situation S('l'U with mall)' con-
\'l' lll iunal tablds an d 1' lpSnlt's . D m g: t1is."lJI\l.'s !it) rupi tlly that most is in su iutiu ll IlI.'fun '
nlUd l has r-ute-n-d till' inh ·slilll'. II N I' . ~,ts l ril' t' lll pl~i llg: dt'arly in l1m'Il("t' s the mit! of dmg:
ahsorptiou. lI 'l\h'ning: ~;l\t rit· t'lIlpt~i ll~, for example. quickens drug absorpnou from so-
lutio n.
Hapkl Dissolution in Intest ine . l u tlus situation, d rug dot's 110 1 tlis.\lJI\l.' Iutlu- stom-
ach, wllt'fl';l\ in lilt' illlt'sli lw il r,lpidly hut h disS()Ives anti pa..~S('S across tilt' inlt'slill .tl wall.
( ;;lsl rit' l ' l ll pl~i ll ~ tln-n t1r.ull ati (~llly atTt'ti s tilt' time and perhaps till ' mt l' of t1 nl ~ absorption.
All t'lllt' ril"('(MI('(1 pnltlnl1 is an t' xln'lIlt' t' ~lln p lt, (If thi s snuancu. El)1hnllnyl'i ll a lit! pl' n·

Stomach It Smalllntestine
II
•
10 •• •
•
- •
8 I •

-c-
Eo 6
~
E
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0 •
•
•
•
• •
•
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;=
."
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• • •
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~

"
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Q
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0III-
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t
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2
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lIP
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•• J •
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••
o .. I ... y•• •
Fasted Ught Heavy Fasted Light Heavy
Breakfast Breakfast Breakfast Breakfast

Fi". lJ- 7. F. ~~ 1. ,""rtlt"brJ:.' a I...a,~ ,,,,,ai, i 'lt-n''''''~ lilt· ):",-,Irk>Irall" ll1 ml' "I' .",allp.·lld' (I,Lw." rin·..~ ) alld .
....,." "",n' "... ti..... Uy. " r laru.· ,i"ltl.· n"ih (" ,,,,,,...1ri"·l.~ ). In co"lr...,I. ,,,'ill,,·, r. ~ .. 1,,,,, II..· pI1~,in" .i'.·..( II..·
" ,1,,1"rr.'(1' Ih.· ,,"all i"h·, li,,,· t, all. i1Ii " ..·, 11,,· .1.0.1.. (l",L"kl"aI po >l nl•. I,t... " I' ... ...", ...1n n·"~. al .. 1tI..'i, "" 'a"
:!:. S E.. i" . tic·.d. , 1 10:- tlK' .....1a"I: .1 .. , .... , ~>l;<j, .. ...1 ill '"·,,lt h~· ~," nlf . 1,,1,. ". i"l: .In'I:'(''''' ", " KI"i" h1U"tinlt
"t.>h·riak Th' p"in" will, " n ..m · i,,,lil·..h· tiK' .. IIi<! ...... . till in It..· "'.",....·1, .d tt..· tur..• "r II,,· lasl .Il... •....."h''''.
II .,, ~ . J G.. an,1 Fan•. J.: T n." . il "f l" mn......' ..llicoJ ,1cl'Wt)«' f"mlS
, I,,· till '" ~ i'KI;'"I<... 1. (A,Ll'h ...1r.....", 1);1' 1<. S.S..
132 c-wttec

icdliu G art' mp idly I l~llrul~·/,{'(1 to illadi\1.' Jlr( lt llld ~ i ll tilt' addie envt ronment of thr- stom -
ach. Salil) 1k add is a ~ilst ril' irri tant. A so lution to hoth f)pt·s of pr olih-ms h iLs Ilt'('11 to (,11,,11
these- dm ~s \\; 111 it material n -sistunt to add hul 110 1 In tilt" intestinal Ihuds. ~ lallY slI(..1I
enteric- coated products an' la~(' s i ll~l(' tablets. ami tilt' tillie' taken for an illi ad tabk-t tel
ll<lsS [rom tln- Sl ll lllil(,I. into tln- in t('sli lW \'a ric'S IIl1 p rt't lit1ilh ly Ir mn 20 min til S('\1'ml lio llf'S
when taken Oil all {'Illpty s tll lll ad . alltl ujl til 12 IIr or ('\ '('11 mort ' wln-u taken (Ill it fed
stomach. AI,(~ JRli ll~I>'. slid , r-un-ric-coated product s an' lIlIt til II(' 1ISl.'(! \\'11("11 a rapid am l
n-habh- rate of abso rp tion is required. A p n l(Inl1 {'u lllp'JSt'tlof ('nle!ie-l u illt'(l ~m ll ll l('S is
an impmn.·llwllt lx-cause tilt' run- o f d e!in.·ry of the grauuk-s 10 III(' int est ine is t'Xjlt'l1t'1l
10 Ix' mo n - n ·lialllt·. I lt' i n~ h-ss t1qx ·mle·nl em a s i n~lt ' e-vent am i o n food.
P(MJr D isso)uti o n. SOliI(' d Ol~S , such as tilt' oral an tifun J.:al aK('nl J.:riS('oful\in, an- sp'lr-

in ~ly soluble in both ~,l"l rit- and Iute-sttnul Hukls. \\l len 111('5(' t1m ~s an' adminislt'n'1l us a
sohd. the re llIay aln'ady ht' insufficient limp for compk-te d issolutioll am i 'I h~ lrpt i(l l\ . wtth
a fiwd short tilll(' within tlu- sma ll intes tin e. n-teution in the' slo mae h inen ',l'i('S the tillw
for dnl~ 10 di s....l)"'· h('fo rt' (,llh'rillJ.: tln- iutestnu-, tlu ' n'hy fa\uring inert',l'i('(1hio;w aibbilily.
As !lU'lltiHl\('11. fOCI(I, and fat ill pa rtk-ular , delays ~;lsl ri(' Plll pl~i n~. Th is dday Illily lit· 011('
of tln- explanations for 111(' ohS(,rYt'1l im 'rt'ilS(' in tln- hiua\'aibhilily o f ~ris('ofllhi n whcu
tuken wit h a fatty meal o r \\;111 fats. Sub s("fjll('lItly, us tilt" inh 'stin al fluid and contents 1ll0\t'
inlo tilt" largt' tnte sttue am i \\111('1' is reabsorb ed, tll(· noslllt ill~ I1lmll;.cd ion o f Ihl" so lid
content s lIlay S('\"('rt'ly limit fu rthe r di sso lution ami ht'Ill'(' abso rpl ioll of d mg.
Co n ln)lIed. Release Produc ts. nit' conclusions d rawn for sll;.lringly soluhlr- d m~" ma~'
also apply Itl certain ('(mlmllt'1l-n'lt'ilst, do sal?:(' fon ns. Scum- of tln-se an' tUiltt'(l "'ilk or
contamed .... tt htn. a Il ondi sinh~rdtill~ material throug h w!lid l the n-h-ase r an- of d m g is
indt,pt'nl1t'n t o f IMlih I' ll and a~t'l lioll . In Slid . ( " (.\("S. V;.lslri(· t'lll pl~i nl?: hax litt l(· (,!T('11 011
tilt" rate o f drug ahso rp tion . Evt-n t!loul?:h tln- solid dosal?:c' form Illay lx- rt'la illC'(l ill til('
stomuc h, til(" n ·I(·;lst'1 l drtl ~ is (,(JIltinuuusly PlJlpl i('11 with Ill(' g' lstri<.· fluid into lilt' dU(I(I(·-
nUIIl mid i~ il\'uilahl(· fur allSl'''ltiuli . Any c1c·l.l}' ill the- ,l.!;itstri<.· t'lIlJl t~i lll?: of slld l p r oduct s
p rnloll~s 11\l' totu l period for d rtlg n-leuse and absorption . For n ';lsoIlS diso:'uss('11 alxl\"t',
this dda~' is mo st likc'ly 10 1)(' SI.'1'1I " ; Ih I,I')!;(' singl(· un tts takeu Oil ;l f('11st(lIllilt'!l. It \\lIUld
lit, IIIm;St·. hnwt,\"(·r. to dl·!lt'llll too 11lI1l'h oni llis do:ola)' lo .lellie\"(· a pm lolll?:l'(l ahsurplioll
profil(' gin 'n tilt' wo:oll· "·ll(l\\1l unp n '1lit'lahilil)' o f !l;.ltienls' ('atill~ hahits ami tl wir ~t'l lC'ml
la(·k of tUllip lillll<',,(' ill ta";ng 1ll('(Iit'a lions. fll rtlll'nlluro:' , su mt' <'llll('('m m ll.sl t'xisl Ihal ll llll-
1l;.t<.1ion in Ih(' la~t· intt'stinl' may pro:·dude rt'!iahll' input of d m~ 1"lt'YOlltl I2 10 16 hr. T his
wOlllcl S(·\'t·rdy limit tilt" dt'si~ l of <',(lIllm llt'1l· rdeil'i(' do s;lge for ms o f d m ).,"'S \\ilh sho rt ha lf·
Iiw s inlt'm)('11for oll("('.a.day ad minislr:l!io ll, Th at said , dala fo r SOUlt" d mg·dd i\"(·I)" sysh' llls
indit1lh' th ai rt·liahl(· 1Iml slI_staillt'(l ahsUll ltioll for lip to 22 hr <'1111 1M' a('h i('\"('(I. Fuluro:'
\\llrk in Ihis an 'u is 1ll'1'(!c'(l to IIllclerlitam llhe S(,(lJX' aJl(l limilaticlIls o f th(· appm..cd, . Om'
lim itation m n lit, thc' pmpt,rtit's of Ih(' drtl g itM'l f, ,lS 1I0W dist'lIsS('1I.

Ganging Rate Control

n it' mit' of abso rp tion is ('C llitm lll,(! by a dc·li\"(·ry dt '\i et · RS I OIl~ llS rd t',l\(' fm lll Ill(' c1e'\i l't·
is tilt' mh'.limiting shop in ti ll" ahsu rp tiull pn )(.'('ss, \ Vilh till' I' . SA Ie I'm fCl r drtl ~s d("t.·n·ilsi n~
alm lR tilt" l e'll ~ h o f t!w in lesti nal tm<.1 . Ihe mle limit ution ('(mid dlanl?:(' fmlll tilt' 11(,\;<.1' to
th t· inttoslinallll("mhmll e ,l" Ihe dt'\ i e(' IIlO\"('S0:10\\11Ih(· inlt'slilw ( Fi~. 9-H ). \ Ind l o:IqM'Il(Ls
011 Ihl' n·latiH' impt'1hlll(,\-s for dm~ lllll\"('llleuf ill lilt' dl'\;('\' and ill ti lt" intt'st ina l \\1111. III
tIlt' slllall inh·stil\('. p . SA is at its h i ~I ll'sl ilnd ('olltrtll may t1lt'1l wdl lie \\; Ih Ill(' dc,l in-ry
dc'\ict·. 110\\"(,\·t'r. O il 1lI0\"l'llIt'nt into Ill(' ('(11011, J' . So\ lIlay <Imp (' Ilnu~h so tlmt til(' mlt·-
lim itin g slt·p 1M."t.'(IIll(OS p;l"sa~t' at'rtlss th t- "~III . in whid ll'iN', ('(mtrtl l of dmg inpul is losl.
TIlis silu ation is Il\urt.· likt'ly to ()(.'t.1,r \\; tl l rdati\"dy polar lIlol("t.·ult's. for whit'h 1M.·rllli'ability
 133

may Ill.' a problem. En -II wi th rapkl-rt-h-ase dOSllj,:l" Forms. ah sorption of tllt'st, compounds
is !'''' 'nt ially n 's tridt"tl to t i lt ' small in lt' slillt' (t·.g.• Fig. 9--1 ). Cum-nrly. IIUWt>\"N . it is
difficult to make any quunt itativr - pn-dict iou of tlmst· dnl ~ fur which coutmlled d mg rk--
lin 'I')' run hI' adli,'vl"t1 I )( '~und li lt' small inh'stilw . Rut dea rly. wln-m-u-r n ']l'lN' of t1mg
1)(')1111\ 1 t he stomach ('onti lllll'S for 4 hr or ilion', some of th e d m g is likt'ly to he TI'II',l'it'11
i ll tlu- Ia~(· iu!t'sti rw ( F ig. U- 7 ), Mon- needs to he k 1lU\\11 abo ut the rdation sh ip h d W t ' t' 1i
tilt' pllysit( ldll'lIl it',,1 pnlpNtit·s of a mok-cuk- and Intestinal pe r nwalnfuy. C urrently. tilt'
Ollly "'('OliN' is 10 ('\"a lualt· Ilw dm g tlt·lin -r)' s-yslt'l1I ill r ;I:(J.

j_ 0.8

a'"
8
~ 0.6
~
~ c
a.
iii 04
!i.
aw 0.2 o
&
o L-----+--=:::====...:::::
o 6 12 18 24
Hours
Fi ~. 9--1\. TI,,· rall' nf 4h"'''l'linll " 'Ldino In 11K· ral,· of \~ "" I;",t n·It~.... ., fmm .IIl nr.ol 24-lor ~"~I;u,,,..I ·n·"·a...·
,10·1;" '1)' ' i" · ",ri," . . , 1I, Ii " ,,· .... ~ ..·n u..",·"..." l ... ·n.... 1I" . uM'ml.r. .".. Il f 11M· ~q n>i"Io~ill;tltr....1 . noll,,·, Ih.m
n·I,·a-'.o'. I ~"", ... ral,' li ""linl:. TI,,· d,an)(,' i " ral,· \~",In~ fnm, n·.......... 10 ""·,,,hr..,... '''-'n,n fnr IIJm)(" ill. "M'
" "'hr..'..· I..·' '' ..·..hi hl~" TI..· r.II., "",In.l i"'I..", ,,,1 loy I"·n,,, "ilil~'l. " "1 in II..· (~II (6 1,r i. , I "
..' II,,· hIt '"~ fltT Ih.· , ",,'i<~' In It,,,,,· 111,· 'I''''''.. ~, a,.. 1 Ira,,";l tI,,· . "...11 i"I, hfM·. ,k.ho..l \. ·rti<...t Ii,,,·) I ...
1"·m..." I,,hly " m"d, I<"" 'r Ihan tI' 41 III II..• ~",al l 1n" .. I""·. TI,,· Sl" "'L<IIr" " l. "" h..1,..1wilh ,h. · n ·!

d.~,;tll • R ~....:.~o\ ... _ 1< ' .0\,.

'Ii " ,1.,;<."..1f l'l"'''l-:o
,;tit· ..
dm i(
' nf Kalo' .. f
n ·...,....
\ '<1

Roll' nf
in 1"""' 11 ah•.,rpti<>u

....1,,·1'· .-\" i\ a" ..",,,1nf 1'·1.-;<." ..1tin ,!!: " ...i<I"'1( in tI,,· l(a.,l ruinlnlinal lr.1. \ 'a i~ tI,,· \1.1" 11'" of 100min.ol!l"..1 iul..
" t, kh 11... n-" ·a" ..1,11"1( i • •h ~l nIJt'I'''1. "",II, i. tiM' rod.. ("<"I"lalll li>r I.... ' ....Tl·a.... ill p . .\0\1\'" will, tnr..•. A. lit('
...111,,1 dl" n~. ·. iu r. s.\. .1.,,,1 \ '" willt ti ",.. an ' unk",,,,,,,, an ... p' .... ·nlilJ (h..aI f·lif,· " f3 1,r) ,"·d i,,,· ill lI"·'''''''I''''il.·
i. " " .. I. TI,,· f"I.....,,,1: '..".. IiI;..... an' ~; " "' Ltl ' .." A. r · s.o\I\'" i•• "m':;'·"l!).' I.ito:i, ("1'1,,, _ 01,,.. "'J III ,."."... tI..d
lilt" r""'-(''' 'ln.l li ,,~ .lol' i. alw"~,, in 1I ,Io"'i<~' ",11, ,al.· of ah.. 'rpti"" makhin~ rat.. of n'''~''''''' . R. p • •0;.0\1\'" b
IUlor - ' . a \ ..1,,,, fnr .... I.kl , dnlll: ;~ ;o.1"'.rI 1virtllally.., ' I"i<-kl~ .., it is " ·It ~ 1 .. ~,i ..· ill lI"· I"" lil1..J sll",11 iUIo-M i,t<'
1>"1 ,,,,, ..., f" " I"'r ' ~"'1' 11.,· l("'l ruil1l lilwl lr...1 ....f,, ·n· nth' (. " ,1" .1 I" ,tI Jo.... k ..· I. 1.. , 1. C . p . S.o\I\·" is II,r - ' .
TI..· r41.· , of ,,1"""111;'''' ' ...... ·r lIull'l II..· ral,· .. f n'It·....•. Thel'nlllll':1 fail. In (..,In ,j a1""'1J1itIlL D. r · s.o\I\'Q
_ n.1 I,r- I. I\;'h - ",,,' n.l !i, ~ al" .." , "nlin*,' "'tl. II..• Il..·mhr '.... of tI... t.... ln linl... hna! 1""'1 III .011 lim..... In
,-a,,'" Il ,,, I). ,Inl\: ",.. " ""lal in II... I"" n ..f 11M· ;n l,'\I i", The Iln'1l "",It'r .."..I, C'l '''''''' n·L,I" ... t" II,,· Iln~'"
'''I< It'r li lt· n·I.·..,,· mr... (' " , . i. tI,,· fr :t ;'m ..f ".",_..1 ,In,s:thaI i~ IlI",>ri"..!
' 34 CHAPT[ i Q

Precipitation and Redinol,tio.

Absorption is llo n nally l11Illptd (' within I Of 2 h r u f i.llI. or s.c. uduuuistrunnn of au ' U l lll "iJ II.S
s olution of a d m ~. Then- an- {·u1· pfiollS. il \ S1't'1l wi th p rutr-iu d m j..ts ( Fi ~. 9-.5) alld when
ill~"(..t illg a solutton uf a ~t1t of (' i tl lt' f a spariugly snillbll' add ur ha.'O(', For t·\l.lI nplt" illt lluugh.
d llortli,\7.('lxlxidt· hydrochloride. in sohr tion , is {'wlltually (,(Illlplt·tt'ly ahso rlx'(l. ubso rpnon
is slnw from til(" l.m. sin-. II llwl'\l·r. largt· do st·s somennu-s appc'ilr til Ix' ponrly (·ITt"(1i\l'
or im,ITt"<.1h"t,. Indeed. ahsmp lion is I"\"{'II slosH'r limn Irom ,hI' gastmin lt·sti nill tnIl1 . when
{·a psll)t·s of d llllrtli'l7.q )oxitll' h)l ln)(.'lJIoridt· a n - adnnmsn-n-d (Fig. H- Oj, TI lt' cxplauatton
involves cousldr-mnonof pi I, snlubilitY. lwrfusioll, <llld stirri ll~,
III the st udy refN t'II('('t1 ill Fi ~. 9-9, th e sann- dose . 50 111 ~ of chlo n li:v.('IXlXidt· !lyti m.
ehlo ridt ,. was adminb tNt'tl bv hot!l rll uh's, 111(' t.m. do",,' \\1lS d issol\'l'tl ill I TIll. u f all
allUt'tllls vehicle. Chlonliiv.t.~ )xitlt. is sparill~I~' so illblt' ; its a111lt't IllS sol uh ility is appmxi-
llliltdy 2 IIlWm l.. To a('!lit·\,"(· t his hi ~h concent runou of 50 m~ of e hlortl i,v.(·pox idt· lwd ro-
chlonchvm l .. till' \"{,IIk-It· contaius 21)ll p m pylt'IJ(' ,glyl'ul am l 4lk polp orbatt· .'In. hot h wat er-
lIlisdh lt· ma terials tlml peruut a gn'atl' r soillbilily o f tln- d m j!;. Bein.l: lIlt· Sill! o f a s l m n~
add a nd a wt'ak lli(s(' (,l& 4.5 ). IIIl" filial p I! is low . app n n;imaldy 3.n. Upo n illjt't.'linll. til('
huff er ca p acuy of bo th tilt' tissue and tilt' blood pt·rfusillg it j!;ratlua lly n-ston-s lilt' p ll al
the- injt d ioll silt· to 'A.lliis riM' ill p ll a mi lilt' ah so rpt ioll u f illt" injt't1:('t1 wa ter a mi w ate-r-
misdhlt· materials (.... 1st. d l!l,nlia7..1 ·!'lt lxidl· llilSf.· to prt't·ipifillt· o uil if SlIJUIiOIl. As 11111\'('111('111
a nd lu-ne- sprt·ad in.l:is minim al. a b r,gt· m:lSS u f tl m g is depos ih 't l amullll tllt' iujt't1:iu lJ sln-.
1111' raft>of a bsorp tio n IJ(J\\' he{'tllll es lim ilt't l by di sSlJllItiem of Il.t· p n.'t·ipilah'tl d m g. IIIIw-
('W I'. till' sllla ll surface un-a. IfJ\\' so luhilit)'. limited perfu sion. am l m inim al sti rri ng n-ml 10
keep tln- ra il' o f tlis.'iulut ioll deJ\\ll . The result is p m t ral1:I't! ah Slllll lioll 11\'1 '1' mall)' h01l1'5 or
even days . In contrast, «leorpuon follfJ\\i ng ural ad mi ni'itra tioll is rt·la!i\l·ly rap id . For
reas ons aln ·ad y d ilit.·lIsSt, I. a ",rrt'a h' r t1t'gn 't' of a",rilalioll, a (,lrl-:t'r volunn- of fluid at tlu- site,
am i a hil{llt'T nih' ofhluot l ll' l\\' til tilt' Wlsl nl inh 'sti nal lrad pnllno h ' uu m - rapid t1isSlllution
uud ahSllrp lioll fulleJ\\i ng ingl'slio n of d llnrtli,v.(·j'ltlsitll· "~'ti mf:l l le lrid(· . AIIIlll ll'f (·sa mple is
diazepam . a dnl ~ tlrat is spe r mgly soluble a nd slowly ah smhl 'tl when injl't'!I't! lnt ramus-
t'ulady. 111is t'sSt'nlially m-utra] d m ~ is kept ill Slliulioll wi th lilt' ait! of Pnlpyll·l\t· glyt, ,1.
Precipitation at tilt' injt't.1:ion site 1)('{'l11'5 wtth Ililutiun a m i abSlI'lltiun of t his wa l(·f -Illilit.ihlt·
solve nt .

nl(. 9-9. A <Io'I..~...1 al,,1 10......., I'.·..k I"' KKI 2

" "K' '''llr..I ~ ", n{ d ,Io",lia.rll"Ki<l••• wh. -u 1(i\1'n
in lram ll"" ' ["~' cO--OJ. ....l . ll nl);l 1to "~M'U
I(i....n "nrJl~.. le - e). ;,M lir;"".... . t. , al",1f]'"
I~Ml fn MII II,,· ;nlr..mU'I' lla, "; 1.· Ihan {min III<'
nr..J .,1...O n I"llh ,K'("lI.. kM.. ,'Sl l 1tIf( " f t"'t.mh.
v l, ,,ni<.1.. h~,l n "..,t.IritIo· "...,.. ;lOh";n;",,,",,1( I
niWl . - ,1.3 1i ~U. I R...lr.....ll fnlln <:", ·nt.latl.
1lJ-. SI~Io" . R I.. ;u,,1 t;"d " W,'M" , J.: s t.....-..h·
d ,t.onli""'1"».ltIo-, :,,_
"'fl>l kM. .. f ;1>11";1.111"'1<."1....
En!:!.). M,..1.. 291 : 1 1 1 A- l l l~.1 9j-l H'1Irinl...1 •
.~
1~·I"'nni ..i"".) o •
o 20 40 60
Hours
 STUD YPROBllMS
(Answers to Study Prob lems ore in Appendix II.)
I. List OIl It ";lSI three reasons for rt'tlul't"tlo ral bio'l\'uilahility of a d m~.
2. 11\{1il'a lt· tjn- ilel't1r.1t, · o f til(' fullo",i ll~ state ments:
a. \ \ 'ln-n ati mi nislt ' rt'(l o rally ill so lu tio n. Wlslrit> ('lIlp l)in ~ mW-Jjlllils th e absorptiou of
srnall lil)lJpllilil' t1m~'S .
h. Fur rapidly t1hsoh;ll ~ pr oducts of a d m g. llifTl'rt'1lt't.'5 in rates nf d issointioll lllarkt'tlly
afTI'd tln- p h sm<l t"lllJ('l:'lltmtion- lilllP p rofile. Wll(,11 in te stin al pt·T1Ilt·ahility is tilt'
rat {'-l i lll it i ll ~ sleJl.
c. Polar d rugs an.' p rilll ari l~' ahsorlwtl Imm tilt' small intt'stin(' via lIlt' rranse-llnlar
route.
d . A substantial Fract ion o f hio<\\';.tilab!e dnlg enters the syslt' l1lit: d rt.'\ltltioll via tlu-
lymphatic m lllt' for Iargt· ( ~ I , \\'. ~rt'iltt'r than 100,000 WllIole> protein d mw; admln-
istl'rt 't l lntranu rscularlv.
I ' , Lou ).:t· lIt1l1disilltl').:rati;lg coutrolled-n-lc ase dosa~e fo rms ('IlIllllu nly n-maln ill tilt'
stomach for 6 hr wlu-n takt'll ju st ufh-r a Iwit\) , 1Il('i\1.
,1. U st six <I m ).:s for which oral hioi\\'ailah ility is low <111(' to a suhstautial first-pass lU'pat k
loss.
.t. U sl four factors that can illllul'Ul'(' tilt' rate of di.~sol \l t ioll of a dmg fr om a solid d os,agl'
form .
S. (; 01l1 1111'nt Oil Ihe stah'llll'lIt: D m gs udnunisten-d ill so lution ,m ' more slowly ahso rllt.,1
Imm 1ll1l <;(,I" [i.m. admillistmtion ) than fmm tilt' small intestim- (ura l administrat ion].
6. U slt'tl ill Tah lt, 9-.'5 art ' four dr ugs tng:dllt'r with some of tln-ir ph poit':ll prope-rties .

,.1t'.9-5.
ce eeoc ceco ooo
1'tQl'f 11l'Y
C~ "C If I1lS"C """
• • C o
oYoIe<:ulo ' _g~ r Ig/molel 327 273 315 378
pI(o 8'
[Acid)
78
(Aminel
_0' Oucle<nc'Yammon ium
coepcced
PoIa"j, 01 UIl1Qflil ed form Nee polo, Neepolo, Pd,,,
SoIub< 'Iy 01 UIl1Ol'\'l ed !OIm
Img/U 13 ISO

(;in'n tlla! rlu- conven tional sing!l' doS(' uf hoth Dm g A and D m ~ H is IOn 1lI~ and
thai IM Il h drugs an' slah l" ill 11U' gastromtesnn al fluids. circle the IIImt appropriate
tim ).:, wo rd . or phr.l'it' (in Italtes ] that completes the foll'J\\i n~ statements.
a. The su d ium salt of Dmg A di sso h't's milch [aster. milch slow er, (It rs.~'" ti(llJy thl'
n il//(' m t" , in a so lution o f p ll 3.0 tha n (as) dot's tilt' fn." add ill a solution of p H
,'j .U. (O the r factors, such ax surfal" an'a and su mng. an- tln- same.]
h. Tln- I.ytln x:hlorid(' ~1 1t of Drug 8 should d issolve muc1. fint..r, milch ., Ioflx ", (It
,'_"w'lItitllly the .wH/1I' mt,'. in the stomach of a patient with acblorhydrie [uo ~ll'it riC
illid ~"l,rt,t ioll ) than ( il~) in it pa li('nt \\i th normal ~a.~tri l' funct ion.
c. I)m~ A is poo rly absorbed wln-n taken orally as the fn -e add \,illl lUI) mL o f water.
111t' hioa\"ai lahit i~' of thi s drug should 1M.' siK'lifieantly incn ·il'K.,1 hy taki n~ tilt' dmg
Id O. 2(XJ ml. of untrr. in diddn l llm rs dllrill~ the ,Iay , on an empty .~tomllc!"
d. Abso rp lioll pr oldcn» an' Ii kt'I~' to be grea ter witli [)m~ A. B , whe n adm inislt'n"l:j
intr.ullust.11Iitrly il'i un a{IU("l:)us solution of the .~f)di lml, " yd mclllmide salt.
r. In T nbh- 9-6 1It,Iow art, !islt.,! tIlt' Aue ,·alm's of dpmRoxadll, a d m g \\itll a hm:atl
ill\timil' m hial al1i\ity, foJloy,ing its ddh"l'lJ' ( 100 mg) in solution to vari OliS region s o f
136 CHAPTf &Q

the ~~ l'f nJi ll h-,;fi nill l m(·I . Cipru flu Xild ll aplll'ars In ht· stahle.' i n all (lOlrt !'i of thl" ~,l-, lm­
inte-stinal t ract .

, ..... 9-6. AU(' Vl;Iluel of CiproRoJlacin after Delivery of 180 "'9 to Va rio... Regions of
the Gash'otnte.tinal Tract'"

AUC(mg-{/h'l 1 48 03 8 0 2.4 008 0 ,05

~A,booooc 1Od. "", _ _ ~, f ";' , v, "",-,--,, 0 _ s-b, "H cop<;lb.o:.. ~ ... dIIoo.to~ cJ" ......,.., ~ OQCI

~ _ *- ~ 9</ On JItooowxol JO))-30 IQQO

a. From w!Jit..h silt' of the ~ll' l mi ll t t's li na' trac-t, stomach, smal l ililt -stint', o r large.· in -
tesnne is lilt' Illajo rit) ' o f lipmlluxatin likely 10 Ill' ubsorht'< l follu\\ill~ o m) udmin -
tstrauon of t ilt" d m~?
h . Bil-"t'<I IIJI ti l(' diffen-uce- ill ..\ UG values follo\\i ll ~ dt·liH·l)· inlo lht' stomach ami
jt·jUIlIIIIl. SIlAAI'sl 11 JXIs-, ih 't · pri lllill)' ...ill- of .1h.·lo q )lio ll o f dpmflo xadll.
e. For d m l?:s tha i l'xhihi! a bsClllltioll palkms sim ilar to that of d p m Rux.ad ll. co m ment
o n tilt' d ..iIIct·s o f SIIC(-'( 'ssfull)' ad l it."\i n~ a constant syste mic inp ut for u p III 12 hr
follo\\'ill~ admi nistr ation uf an oral dnl~-( II ·Ii\l.·I")· sysh· m .
 DISTRIBUTION

OBJECTIVES
The leader w ill be able to:
1 Define the Ioibw ing lefm~ :
a Perfusion limilork>n in dish'iburion
b . Permeability limilolion in distributiOn
c . Ifssoe-obood equilibl'ium distribution ratio
d Fraction unbound
e Pbsmo pt'OIein binding
2 Deenmre lhe plasma co-ceenonoo. the a mount 01 drug in the body. and the o~fenl
volume of dislTibvrion when any I'wo 01 these volU8$ ole known.
3 . Describe the efIecl3 01 perfUSion lim'lOtion. pe!"meobility limitation, and the li~
equilibrium distribution Iorio on the lime required 101' dr ug dislribulion 10 the nssoes.
4 . k.certoin whelhef , /Of a given omounl 01 drug in the body, the unbound plasmacoocenno
lion is lilety 10 be sensitive to vorialoon in pcseo prolei n binding when the volume of
dislfibulion is known ,
5 . Cokokne the fraction of drug in the body rho! is:
a unbound
b In the eXlroceilulor flUids
c. outside the e erocellokn fkJids
d bound to plasma proteins
e bocod to plasma proleins in the eKlroceilubr fluids
I. bound inlfocellulorly (in Of on tissue cellsl
from knowledge 01 the volume 01 disrrib"riOn a nd the fraction unbound in plmmo
6 . Anl'cipole!he effOCl 01 cseed pkwno prOlein binding on the half-life 01 0 dn.'9, bccod 10
albumin and with a volume 01 di$lliburion leu Ihon 0.2 l/kg

fJj ,U1/JIIlj"ll rd; 'r; 10 tlu- n ·\l·r,ihl, ·I r.ill,f, ·r of dOll!: from OIW location 10 unotln-r \d lhill
l ilt' I... ... I~ . Dl'fillilin ' illllJrlrlalioll 011 l ilt' c1i' lrilllllioll of a dOll!: n-qmn- i" I1IC ' ,~'lln'lIl"1l1 ill
vartou-, li"lI' ·' . Slieh c1"la 11,1\\' 1"''1'11 "hlaillt'(! in animals. hill an' .·' ...-ut inllv bd,inl!; ill
huruauv. \ Iud l uv -ful information Oil rail ' alll lc"1l'1l1 of di ,trihulion in 111111'1 ,111 ' can l x-
de'rill 'd . 1I0 \\I 'Q ·r . from oIN'I"\'"lion' ill hle... )(1 or pla, ma. 'I11i, ('hapl('r l"plon', t1i,l rihlllioll
and its applil'al iuu , ill dirlkal plla rllla("okindil.... It hl'~in , \\1111 kim·lit· u lll,i d,·r. lliollS ;1m!
c'lId, \\ill. I'e!"ilihrillll i 1'(1111'('1''''

RATE Of DISTRIBUTION
Di, t rihlllioll of tlnlg, te l anti From blood .uu l otlu-r tissm" "{'('urs al \ a rium mil's am ! to
\'ariOIl' c·,Io-I1". S('\t'ral fador' dl'll'rllli ,w l ilt' d i'trihlliioll IMI Il'm of a dOlI!; \\1111 tiuu-.

137
 131 CHAPIU 10

IlIdlll ll'(l an- 1I1·lin ·l} of d Ol ~ tn th \Ii('S by hlo od, ability to ('ross tis-an- uu-mb ram-s. hi lldi ll~
\\11I1i ll hlood am i tissur-s. alJ(l l );'trtil ioll i ll~ Iuto fat. T issue uptake, 11l1ll1llo nJ,.. <''11Ilt",1 extra-
!"tHtl tjOIl . 11 1l1lilllU'S towurd equilibrium of li lt , d iITusihll' (lin n hl."tw ( '('11 ttssuc ilml h lllOc:l
l"lI;' rfll ,i ll ~ it.

Perfusion Limitation
Di!ol rihuti ou . likt· ahsorp tio n ( ~'f.' C hap. 9 ), ca n l)t· mtt·-limilt'(l hy dtllt'r Iwrfusiou o r 1)('1'-
Ilw<lhilily. A pn jiu jOlI-mtf' limil (/t/ l m prevail s when tilt' tissue- membranes pn' M' nl (,SM"n -
lia ll)' lUI h arrier 10 dist ribution. As " x(M'(1('tL t l.is condition is likt'1y III 1M:' IIlt'1 I",· smal l
lipllp llilk dm~s di lTlIsi ll ~ across most membranes o f till' hod )" ami. hy almos t all dmj..,Ts,
('\('('p l ll1;l{'rulllo lt'('u lt'S di ffllSi l1 ~ across loo s«."l)" kmt membrum-s, slI('h <IS (';.'pill'il)' walls of
IIu,,,d t· ;tml "uhl'u talll'i IU" th "\ll' ( 'it '( . C hap, ~ ),
I't'ffm io ll ts u"ually (' xp rt'S'it'(1 in units of milhliters of h lootl p N min ute P " vnlnun- o f
fi'i"ut·, :\" 'it'('11 in Tahlt· 10- 1. tilt' p(·rfu"illll rate IIf ti"'~lll'S \'lIn l'" [rmn appnl'\;inmtdy III
1Il l ilnilvml. fur lu n~ tlO\\11 to values of only 0 .1)'2'5 m l J milvrnL fur n...till~ lllll'it:I(· o r fat.
:\Il ntlw r f"l'fllr-. n 'lIl aill i lJ~ equal. wt·lI-rM.·rfu'it'( 1 t i_~ "lI t ·S take III" a tl nI~ much more ra pidly
li mn tlo poo rly pt'rfu'it'(1 tissue-s. ~ l o n,( J\l· r. a... tilt" "llhst"'-IIlt'"1 all"I~'S i " shows . lI11'n ' is a
t1irt'('flllrn ,lalion hd w('('11 ti ssue Ill;'rfusio!l rate and the lilll(' n-qutred to tlistri huh' a tl nr ~
10 a tis'illt·.

T.lal. 10-1 . ale.tllflew. PMt..I_ 1"'",. SI_ .. D 0Pw-"

..... T1_. u__ .._I c..MlIltI_ I 70-k. M_ _-

om 25 02 I2
7 15COJr , H)Q
'0 250 5 0 .02
20 700 1.: 0 .5
20 200 0 ,03
0" 200 4 0 .6
05 >'00 22
•
08
"
i 71Gvlj
350
050
13001
"":6
'6 15= ,'00 10
43 750 15 0 .025
300 6 0 .""
" 03 77 '5 0'
OO} 50 I 2.
'00 500') 100 0 .071
.., ,~,,""r""" ,. ~ l~,t~,.I",""J<: ,....,. J. ·"ldF'>"""",.~"."~<",,,_ ?~, :; ....-
.. I . ~..... II < 't h"-1. l<JB ...-j().... . , . , .... j ..... ' .... ~,.,""...._ , d.>- ""',...-_
Of'd--. ~ ~'" 101093-1095.1 QllJ
ox- Qtp• • \I _~ , _ ~ Of'd """"'..". Qt. net "'Cl..dod
' h:ldoo "" ...... ~ "'1P'"

l>OIIo: i. po ·..I....1 In .. Ii-.".· ..I ..to .. r- a \ a

Bit, 10- 1.
IN l.o.I "'...1 t~ .. ln ·"'r.cl " ,,{ <.'., ..... 1.., .. ...." . ....I" ..t
In III<' rn"t"'1 "r I,Ie..I II" Q. ,",,,.1 C A _ TI l<' .1011(
(0:::::::::l
(C A
Tissue
V,. C, (C, (
Ie·..." .. Ih, ' I" " M· ..I .. \1·' M '~M" ..."lr..h"tl o( C" ..,,,I
" I .. r..h· ' ~ I ' '''' In V ' C,., TI l<' II• • ,..• '~ ""..."Ir..ho n , \ )
C r, i'K"'·........ .. I..·" rdl" "( 1'0....·111;'1" ... ru~ ...... I, r..,,·
,,(Ie·;o>; ,,1o: ill ,I..• w ,,,.,,. I.Ie ..I, "'KI IIK' '~"''''"''' , TI K'
.."".. " ,1 ill ,1M' h u,... i. tI" 'l'n >t hK1 II{ \ .r . , ,,, . .. ~ " ''''.
"r II I<' h.."w. alKI III<' 1i' ''M' tlml: ,~ ..>t"'·lIl....l itlll _
CHAPTER 10
"9
FiWlrt" 10- 1 shows 111011(1 perfustug a lisslie ill which disl rih l1tio n is perfusion rate-lhmn-d
amino elnninanon Ol'ClI l'5 . 1111' rate of prt'S('lllal ion 10 til(" tissue is t ill' product of hloud
11m\', Q, ami art erial blood concentrutton, Gk i.e..

Role of pre$entolio n - Q , C A

111l' Ill'! ra te o f ex travasation is l ilt" <!ilTc'rt'lU'c' 1)('lwI '('1I m hos o f p rt"St'nlatioll and I('a\i llp;,
Q ' C\ -, when- C" is tl. e t'Ill(' ~I 'nt \'(' 1I0 U S comx-nt ratton. Then-fore,

Net rote of uptok.e - Q , ICA - C~ 2

The maximum initial r ate of upt ake is tilt" rate of pn-sen tancn. Q ' C A ' Further, with no
d ft-"(1 i\'(' im pedance to 1II000'(' II1("nl into thetissue, hl l)(1(1 and tissue (,",10 IK' "'; ('\1,'("<1 killt"lk ally
;L'IDill' l"Ol1lp;l rt llll'llt , ";tll the ccncentrunou i n l'IlIt"~t'nl n-II011S blood (C",) ill l"<!uilihriulIl
wnh that in Ihl' 1i_'ISIl t' , C r ,
Al a ny time -, then-Ion-

Amount of drug in ' iuue - V, · Kp ' C.... 3

when- \'r is Illl' tiSSlIl' volume ;IIJ(I K,. is Ill(' (-"(llIilih riu lIl d ist rilm lioll ratlo (C,IC\,). Fur-
therruore , Ill(-" fm l1ioll a l rate- of exit, k r , is ¢\1' 1I h)'

It _ Role of e xil Q , Cy
r Amoun t in Iiuue V, · Kp ' Cv

whe n' QI\'r is lilt' perfuslou rate of th e tissue. TIll" pa J'itllll"tt'tkr- a distributio ll rat e n nls l;lul
with unit s of n-ciprocal tim e, may he ft-ganll'1! us a measure of how rapidly d nl~ would
leave the tissut' if till' arterial concentration wen- sud den l), to drop 10 7.NO , It is analogous
10 the I'liminalio ll m tl' constant for loss uf dmv; [n un the who lt, body and. ltkc ehminanou,
Iht, kinetics (If tisSllt, rhst n button can 1)(' characte-rize-d hv a tissue d istribution half- lire for
which •

H IfH .. 0 .693 _ 0,693 Kp

5
o le " IQ/VrJ

Thus, drug leaves slov. ly From tisSllt's Ihal han ' a Il i ~h affini ty (KI') fo , it an d that an.' puu rly
pc'rfUst'1l.
Suppose no w, tha t tilt" urte rial conceut ra tkm is mainla ilic,,<I ('o llstaul "it l. thm-. Then
tissue uptake co nnuues. hut at a dl'l·l"('a."i ll~ rate ;LS tissut' concentrauou rises . until ('(llIi-
hb rtum is achieved. when the uet mit:' of uprekc- is zero, C,. =0 Cit and C r .. K,. · C A Tlus <

stt uatio u is a nillogolls 10 events tX'l'urri ll/;t dll rin~ a constant-rate infusi o n of t1 ntg into ti ll"
h' l(l)' (C ha p . 6, p . 7 1), with the e-quation dl 'finill~ till" rist' nf tissue corx -entmtkru lu its
plateau h('ill~ g1n'Jl II)'

Iissue ccncenncncn w Kp ' CAl l - e - h . ,) 6

Thus. th e approach 10 plat eau is ddt'rlllilll'(l sul,'I)' hy lIlt" liss\lt' distributkm ha lf-lift" In
 .40 DlSTiIBUTlON CHAPTf l11Q

01)(' half-hf.." ti lt' tiSSllt' conrent rution is 50% of ils plateau va hn-; in two half-hvcs. it is 75%;
and !i() 0 11.

To app reciate tilt· f()rt~oi n~, conslder ,11(' events dep uted in Fi~. 10- 2. Slltl\\1I art' plots
of coneentrution in various ttssues \\1111 time d llrill~ tilt' maiun-nauee of it constant art erial
concentration of I mWL. First l'tJllsid N plIl\t'l:\ in whit-I. tilt, K r vahu -s of a d m~ in ki<!llt';o'S .
hruin . and fat a rt" tln- sanu- and equal to Ollt'. Gin'lI that till' p..-rfustou rates 10 t]w S('!isSut' S
an' .I , n.5, and 0 .03 m l Jmin/mL o f tissru-, (t·sI1l.,<1i\"l'ly (Tabl..• 10.. 1), it follows that till'
l'urn-:ipolldj ll~ ha lf-li\'t's for d istributioll art' n . 1i . l A, and 2.1 111ill. TIllis. by I min (IIIm t·
than -I half· lin'S), d m~ in li lt' kid ll('p has reached ('/lllilihriulIl wit h Ihat ill blood. wlnh- it
takes closer to 5 and 75 min for 9Ull of l"(luilibriulll to IN.' n ';K: hc"(! ill brai n am i fat. tiSSUl'S
of low e r perfusion . X ext consider pauel B. in whk-h events ill fat are sIJ{l\\1l for dm ~s with
dim'n'n t 10:,. val ue-s. nanl('l y I. 2, and 5. 1I('n ' tln- l'o rn'spo nd inl: half-liws an ' 2.'3,-16, ami
115 min. Now, not only is tlu- time taken for dnlg in tissue to n 'adll'flui lih riulIl difTc'n 'ut.
hilt sn an' thl' equilibruuu tissue concentrations .
These simple examples illust rate two l>ilsi<-· principles . ~m llt' ly. hot ll ihe approach towan]
equillbruun and tin- loss of dm~ frorn a tiSSUl' take lon gl' r tilt' IXlo n ' r lilt' 1N.,rtusioll and
Ilw grt'atN lilt' p<lrt i ti{Jn i ll~ of drug into a tissue . T he latt e r is contrary to what 0I1l" Illi ~ht
iutu iti\1'ly antjcipate. !I (l\\"{,",,'N . rln- ~rt'all'r thl' It'mll' lIe)" to conceutrate in a tissue, til('
Iml~l'r it tak(,s 10 deliver to that tlssm- tilt' amount 1J("(111'(l to n -uch distrihutiou equilibrtum
am i til(' 1 ()Il~N it takes to n "(lisl riblltl' d m g ou l of th'lt tissue. Slatl't l diffNl·llt ly. all Incn-ased
affin ity for a tissllt' accentuat es an ('Kisling limitation illlpt:Is(1! hy perfusion.

Permeability Umitation
A pl:nJleahility-rdtl' limitation arise s particularly for polar dru gs diffll si n~ am ISs li~lltly knit
lilXli{llJ memhram-s. as demonstrated in Fi~. 10-3 for 111(' p;.lssa~l· u f compounds into till"
ce re brosp inal fluid . In th is study, till>couceutration of (';u:1J d m ~ was un-asun-d in ce re-
h mspinal iluid . n-latl vr - to that in plasma wate-r (unbound], wuh tillll' roll(J\\i ll~ attaiurucut
and maintenance o f a constau t p lasma conccutrarion. Diffl'n.'l1l'(·S in (',lS(' of ('niT)' an' a

A aN, B
(mUminlmlj K,
Kidneys 4
5
~ 5
S 05 ~
c
0
S 4
c
~ 0

E Brain ~ 3
g 0,5
0
<.>
Q
'"
~
u
c
0
<.>
2
2

~ Q
~

0 Fat 0.03 ~
~
~ 0
~
~
~
~ 0 0
0 2 3 4 5 6 0 1 2 3 4 5 6
Minutes Hours

t'l lt , 10....2. Ir .li,tnl.Illio" i. l"'n',-,it.u nl h·-limil... 1. tilt.' lin... til lI,at,l, . 'C! "i lih riu ,n ill Ih <u.·, ... 1."11 tiM' """ ' rial
<'OIM't.. ,lnltWM' .. (~MI<t.. "t (1 mKfLl • • 1.,...·
6 00 pt' rf'L<i" " "'MI ''<llIi lihrilllll .h, l rillllh.", r..IW•. ,-t. Ctll " l'·" lr.ati" m
will. Iin M' in kid"•.,... hM Il, "'MI rid Ii"', will, dilT.·II.. ,1 1..,n "'it M' rut ... rllr .. tim " .. ~II ii., _ I ill all lli"","
1i ~"M". 8. C. M>t1'·n lr.llW"" wuh hil l(' ill r..l o( ti m ... JrnJ:' "~Ih ,lilT"n'1I1 ii., ,-;oh M" "f I . Z 1 5, n .. p' 'C1i.... ~·.
S oh' II..• ,lilT.-n -IKl" in li"M' x .,.]... IIf A (min ) ;I.IKI 8 1llr l,
CHAPTE ~ 10 ,.,
fund ioll of holh lipid-to- water p artition t'()(,[fjcit' nt and deg rt'(· of kmlzatkm (Tah l(' 10-2).
s ll~est i llg; that only tln- un-ionized dm~ penetrates brain. For example, till' pa rtit ion In-
('ffidl'nts of salicylie add allli pt'nt uha rhital arc similar, )1." the time rt"flu irt't! to n-ach
d istri lmliou ('qu ilih ritlnl is far shorter for pentoharbital thau fnr ~tlkyd k uctd bcc ause.
Ill.'in,gllll' w('aker ad d , a ~rt'il t l'r frotl1juu of pentobarbital is un-ionized in plasma, pi I i A .
\\"ith ]arj!t' di!Tt'rt'nl1.·s ill pe -rtusion and permeability of va rious ttssues . it wo uld apl)('a r
III ht.' impossihlt' to pn-dlct t i s.~IIl· distnbunon of <I d rug. However, either of the se two
fadors llIay limit till' roth ' of 1'..,tr,n'l'>Oltioll , tllt'n·hy si lll pli ~\i n~ the situa tion and allov,in!!:
souu- (:Olld llSion to 1)(' drawn. Conskk-r. for examp le. the follo\\ill Jt question : -\ \ 1IY, Oil
IIIt'a.~lIrillg tolal ttssru- ronce-ut ratiun. dOI'Sthe gl'llt'ml anl'stllt"tic thiope-ntal enter the brain
much mort ' m pid ly than it d()('s IllIlst,lt' lissut' ; ~1.·I, for Ill.·nk illill tlll' op posilt' is rrue?" 111l'
explanation lit's in th e propertk-s u f tll('S{' dmgs and of tissue membranes.
Thiopental is nonpolur, lipop hilit, and , hd nJt a \~1.·ak add (p Ka 7,6), only part ially lontzed
at ph\llIa p l l . A\ sudl . its t'lltr)"inlo both brain ami muscle UtX.... I TS l1.·;uli!y and is perfusion
r ate-limited. 5 ill('(' pt'rfusiu ll n f Iht' brain , particularly ~rdY matter, is om- or t,~u orders n f

.111:' 10-3. F..tuilih....lio" of .Iml:: in II..· {'('n,I,,....

Thiopental
. pinal Auid "ill, II.... in pt..<I"a i. ofh 'n p' ·I1I.....hili~·
1.0 Nt....li"'i" ,J. 11.., r..lio .. f .Jm jt "o' ll"",t r..li.." . (ce n -,
Pentobarbital h,.... pit..,] AlIitt' llUho'll..lin pI..." na);' . hc""T1 for , ar·
i..... MIlt' in ...10'1(. n,.. pt..\ I1111 n ..llTtll r..IiIl" " 1llo
0.8 k'1>ln-LoIi".ry, m ...l""llh" ..'I::I.... '1 tI..· .hK~" (R.~
,lr;r\OoTl fmln tho- ,Lota of H,.. " li.., R-'L 10:" "1, 11., ..,.. I
Barbital s<'-n:lllk.. r. L S.' n ... i"'p'>rt..,,,.....f .b.. .. " i;tli<'" ..... ,-
0.6 .I ;""t """I hpMl .. ~ or hihty in inf!''''lK'inl::tI... pa.. >;<g<'
of .l ml:' inl.. II..· ....... ,...fm:.. pinal Auid. J ' ·!tann.... ">l.
E.p. n...r., 1':»'20-2.'S , 19fil1. C.<op:.Tij(lrt 1000. T he
0.4 Willi.lm. &: Wilkin. Co .. Bidlin"'n' ,)

SalicyliC Acid
02
Sulfaguanidine
0.0 j<2==--_ _ -_~

o 20 40 60 80
Minutes

T.It •• 10-2. Physlc_ ....lc.1.....perti_.1MI TI•• fe, Cere..... I. .....I..

c._.IttnrtI... to a_ch so,," ef 1".lIllN1u. V.I_ ' - hlectotll Atltlle c..IN>. .......
of FI,. • 0 .3·
PH1TO'j
"" 10

' . .. ' 1; "

' .. ,,;W
Of" "1' ."
)I ,',ICU;!~
'0,"
~ II!'" ".
p~r ~
cosuc ,N'
'
"'CH

"'"
........
C<

""""'"
.,,!p'''-~

""-G " :
~. ,~ ~
,"'.0'1' '" '''''' ,\

Thiope<1):J1 70 06 33 20 1.4 d
PenlOborbi):J1 8 I 08 005 0 042 4
BarbilCl r5 06 0002 00012 27
Solqic acid 30 0004 0 12 00005 115
SuIIogvanidine .> 10 10 0001 <000 1 23 1
-S-'" c....-,._loo..,..,~
'Ooo;,,,,,,,, . . . ,,,,,,,.,,,F'9 I()'-JG"d~.C "' M 1<xe<>,OJ . !l<odo.. B B G"d ~ .I S o.""' ~d-o ~ d
'*"9' J ~ I .., n... 11j21~ -2U IQ~ Q
"I_.....,..l'<'d<?pH l 4 ' __ ~"""'""_,J,*,""""....,jb1o
"P-., ~ .-........,
"2 CHAPTER 10

lIIa~J1itU(lt · ~n'<ltl'r than t hat of musch- [T ahh- In - I), ('1111)"of thiope ntal int o till' l uuiu is
til(" uu m- rapid p mc..'('ss.
Pt'u id llin. a rdatiwly b~l' pillar compound. tlOt 'S 1101 ((.,,<Ii1y p il-SS thr ough nn-mbranos.
The [,(SiN r.l!t · of (' utry of peuieilliu Into IIIIISt-I" than into bratu urises From till' /.tn -aie l'
(lo rn sil)' o f IIH1 M: lt · l~d pi llari("S . Hecall Irom C ha p . U (p. 126 ) for mauy tiSSIII'S. t· .~ .. lllll·;dt "
('Hp ilb ry 1II('mlJrilllPS a p p Ol·ar to 1)(· \'( '1)" pomus and Im'1.' littl t' iullllt'lIl'\' 0 11 tjn- (' 111'1)' (If
d m gs of us ual moh-cular Wt' i ~l l f ( lOCI h I -HM) Wmo11') illi n til(' int erstitiul lIuitis. n -ganll('ss
of tlu- d n lg's physi<'odwllIieal propert k-s. Then- lIlay he a pt'Ollt'ability Iimitatioll at , I1t,
tiSSUl' ("(,II uu-mbrune. hut in terms of nn-asun-meut of dOl ~ ill Ill(' u:/IO/e tissu e , tl lNt'
wu uld appt'a r to h... u nly a partial impt"tlalll't· to thr- t'nll)' uf vi tln-r lonlzcd or polar <" 1111-
Iltlllm k or- borh. Other ttssues. for t'.l(amplt' , much of the- ce nt ral m -rvous system. aua tom-
imlly han ' <I pNllIt'ahility limitation at the (;'Ip iltu)" 1t'\'('1 Ihn t illl llt"tit's movement of dnt~
illto the - liSSllt' :IS a .....!lolt" as OhSl''''t'il with IX'llidllin , 11lis llhSl'fyation , t'Slx"(.'i,llIy wi th a
nlllllh..-r o f polar n~allie t l~'t's , k-d to t jn- ('oll("pl (If Mo.. It/-' o- IJrlli" alltllJlood -t o-{'('n'b m -
~1 ,i mlJ jI,lid barriers.
TIlt' t' lTt"(.'1o f a h i ~h t'lju ilihri mll di sl rihu tion ra tio (1\,.) Oil lilt' tlnu- to :Id lil'\'(' distribunon
r-quilihruuu, t1ist.'USSl't1 prt'\ iollsly for a I)('rfllsiou-Tilh' Hnunnion. applies t'tlually wel l 10 a
Ilt'nl lt'" hil ity-fiIft> liuut atiou. A pe -ruu-ability-rute limitation simp ly t1t'('f(':l-Sl'S till' rate of
t' 1l11) am i ht'III'i' tucn-ascs tilt' ttnu - 10 f('adl di stribution t't lllilih rim ll over tluu of Ill.,rfusioll,
W!L.. -ri- tilt' t'lJuilihrium lit'S is ludependent. howr-ver, of whi ch P",(:('5S is rak·lilllil i n~.
If the - urterial t'tllln'utraliol\ is mainl aillt"tl lnl\~ t '1l0l1 ~h. lilt' uubound eoucentruri.. J1l iu
tisSllt' IM'('tllllt'S till' sauu- as tluu in plasma. Scnn-tum-s. however, Ihis t't lmllily is uol 01..
....."nl. HI'.I-SOIlS for lack of t'q ua lity indudt, lIlaill!t'mll\('t'of sink (,mtlilio ns hy IIwlalMllislIl,
atii\'(, tran sport , hulk How o f Interstttial Hutds tlmlll~h both I~lnphalk dllullwls am i ducts.
ant i pi 1 ~ratl i t 'llts acros s e-ll nu-mbmm-s. I nt"' lll al i t~· munbound eonce-nt rutjon is frt't !llt'ntly
nhst'rvt 'tl in till' t" f1'h rnsp inal fluid ft' lati\'{' 10 plasma for laTKt'llt,lar molecules. (" ~" lllallY
an libin lil'S. TIlt' most likely explanation here is th at thr- mit' or fluid forma liun is sllffid t'lIll)'
f,!-si am i lilt, mit- uf di ffusioll slllli<.'i('ni ly slow so that tilt' n -sultiug eouce-n tra tion. t'\ '1 '1\ 011
slt'ady stan-. remains hell J\\' that of lilt' di rrusihle unbound d m g in plasma. Another example
is Ihal uf till' d istribu tion nf alhumin ill Ihl:' IltM.ly (Tabh- Hh 1 ), Albumin sllJ\\'ly diffu ses
a('mss ti lt' t'ntlulllt'lial linillh'S !If lilt' ca pillaries . 11\(' hulk IIm\' n f \\~lkf in the inlef!ililiill
II llitl.s alltl lym phati(' \'{'sst,ls pn)\idt,s a IIlt'a ns n f rl'lI11 J\ill~ alb um in frnlll Ihe tiSS\lt's. 11l1'
rt 'slllti n ~ tisSIlt' ('tlnt 't'lIlmtiun is m u<.·h IM·ltM' Ihal of p l.l-~Illa. Alhu min also d ilTusc s inlo I!le
{'t'n' hrn spi nai llu itl , hul tht, r.lft' is so sltM' ('(Impan'tl to Iht' mit· o f prntlll<.iiun of tilt' fluid
tha t thl' t'tlll('('nt ralin ll is \i rt uallv illllllt';l-,>u rahlt" \\111:'11 thNt' is a hn 'akdm\'tl in llit' blulM.l-
('i' ft'hrns pillal llllid barriN, as t~'('Ilr.i for t' xamplt' in nlt' nillglt is, alhumin is fo und in tilt'
lIuitl a..s a n 'sllit n f an ill('f('aSl't1 ra lt' of t·nt"!)·.

'.ltl. 10-3. DI.trlltwtI_ ef AII__I. I..... ~

InllOVOXuio,
F',, ~ ' 40 43
E.1Iovox u!a,
23
"'~'"
50
Skin 40 7.7
'MO
Go' 8
2
5
'4
Ot+>e< I, MUe ~ 110 3
,,,,,,I 210
lOlaI body 350
~~""""~<l <bcJ <JP-. 1 s....... ~ " Iho ~ "'- 2"ClEd Vei l f'"'-:ji:'l'I W ........... Noo,o, v(ri ~
~ l Ql~ p 10]
CHAPTEI! 10 ,.3
EXTENT OF OISTRIBUTION
M ulnph- I'lluilibria rxvu r within plasma when' t1n l~ (, III hind 10 carious proteins. I'Xiullp lt,S
uf which an ' Ih h-t1 ill Table- ll ~ . Add k dmgs (,(lllIllllJllly hind 10 alhulllin, till' most
ahundant pl,l'1I1a protein, B;lSi(' d m j.,"> oftt'n hind to a i-add gl~'l'op mlt'i n and to lipop ml t'ins.
I'mll'illS, '1I('1i ;l" y-glolmlill, transcortin, fibrillogt'n , and Ihyrnid-hillliing glohulin. bintl
~ p. 'd rit· tn nllllllllllk n ; ~Irihllliflu \\ithin ,'a("11 ti S~I W al"':l iU\'llln ... 1I1l1!tip ll' l'(lllilihria Ti ~ slll'
tlislrih lltiHll cau ill\'lll\"(' both him!;ng 10 " \\i dt' \"Irit'~' of subs tances and 1~l rt i l io ll ; lIg into
fal .

Apporen. Volume of Distn"bution

TIll' t'tJ!lt't'nlrJ.l ion ill plll\llla udl;t,\t"tl after distrtbutfon is complet e is a n -sult of till' dust,
"d minisl t-rI"t1 alld IIIl' t', It' l1t of I;SSIl" di stnlnuiou. Hecall [rom Chap. 3 that. al equilibrium ,
lilt' extent of dislrihulioll is dt'fillt"t! by 1II 1 apl~lrt'llt volume of disirilllliioll (\'):

v _ A mount in body at equilibrium '" ~ 7

Pla sma drug conc entration C

111is Ililmmt·It'r is IIs,'flll ; 11 rt'!aling amount in hod y 10 plasma conce-ntration, and tltt'
( ,(lIIn'I"\I ' . Hccull, also. that volumes of dislribulion varv wtdclv, \\i lh iII11slra lin .' \ 11I u " s
mn¢ng From :) I J':11 kg hody wt'ighl 10 ~l),OlJ() 1}70 kg 1~)(ly wl:ighl , a \1111lt, far in l'X('('SS
of lulal hutl\' si:t.t'.
Kllo\\i ug ptl\ l1la \11111111('. \ 'r. and volnuu- u f distribution. \ ', til,' Iraction uf drug in h.)(ly
ill am i unlsidt' ph sma ('an 1)(> eslimah't l. The amount in plasma is \'r ' C: tl.t' amount in
till' 1)( )(ly Is \ ' . C . Therefore.

V
fraction of drug in body in plasma .. ~ 8

It is ,'\idt"lIll hal thl" la~t' f tilt' volume of tlislrihulioll . tilt' smallt.'f is tln- fradiull in pI.L\ma.
Fur .',amplt,. fur a IlrtI!-': with It \11111111(' of d istribution of )(X) L.. only 3% n-sldcs in plasma.
The n 'm ainin!-,: fmditJII , ~ H'II I~'

Froction 01drug in body outside plasma -

IV -V V~ 9

lnchnh-s tlnlg ill the- hlut)(! o -Ils. For lilt' ex nmph- considered aho\"(', 9i 'J, is uulsidt' plasma.
:\ltl u lll~hthis fmdillll run 1)(' n 'adily dceenmncd. tln- act ual dislrihution of dmg oUlside
p!.L\ lIla cannot .
Tle- n ',NIII why tln- \1l111111t'of distribution is an appa rent volume an ti wby its value differs
alltlJ1lg d nl ~s lIlay 1)(' appn-ctan-d by (,o l1s i tl ('ri n~ the simple model showu in Fi~. (().... . .

Al bum,n 67.000 35-50 500-700

u , Ao::.d gfycopoo!e,n 42.000 0 4- 1.0 '>-23
L ,popoQl(>ln~ 200,000- 2.400,000 VO'lObie
CortIsol bond,'"'9
globulm (~on~ortml 53.000 003-007 0 ~1 4
 '44 CHAf lH 10

In thi s mo d el, dm~ ill tilt-' hexl)' is enti n'I)-' aC"(11111lIc'(l for in plasma. o f \U]lI I1W \',.. ami Oil('
liSSlI(' com partment, o r volume \ .T' AI distrib ution ('tluilihriulII . th e amount of d rug in e ach
location can ht· expressed in terms of plasma concentration. C. volumes of plasmu aud
tissue and distribution rat io, as folluws :

A. Vp ' C + Vr ' Kp' C

Amount Amount 10
in pla sma in tiuue

And sinn' A = \' . G ( Ell. 7). it follows, Oil d i\i tli ll,l!; the equation abow Ii)-' C, that

v- V, + Vr · Kp 11

l11t" pr oduct \ 'T ' Kp is the appa rent vulunn- of a tisslle ,;ew('(1 fmm measun-ment of <1m,!!;
in plasma. 11111s, h)' ('lpandin ~ , ht, Illodt'l ln ('mbmn' all tissues of th e hod)'. it is M"('l1 th'll
th(· volume of distri hution of a drug is till' \'U I U lIll' of plasma plus the Slim of tlu- apl);lfCnl
\ l , I IIIII('S of distribulion of ('IK, 1i tissue. For SOIll(" lisSIl(>s til(' vahn- of 1\,. is laf'KI'. which

explains why tilt' volume of d istribution of some- dnl/-.'S ca n hI' much ~rt'at N than total hody
slzc . Fat, for ('xampl(" occupies appmximall'l)' 20% o £lM Mly \11111 111(". If tln- K,. \"i.IIIt, ill fal
is .'), t11(' 11 this tiSSIW alnll/;" has lin app<ln' nt \'O h l lll( ' of distrihution ('(pml 10 thai of I MMI~'
vulunn-. Heme-mlx-r, however, even when a pl'rfusiull rate limital ion ap plies, it take-s ap-
pm ximatd)' i h rs for distrihution ('(luilihriulll 10 occur in fat ( Fi~. 1O-2U),
The \UIIIIlI(' of distn bunon of II spt'dfk ' d nl ~ ran vary \\idd)' a lllnl1~ p atients. n it'
n-asous fur such d ifT(,rt'lll't'S art' now explored. I~' f{) f(' doill~ so . how('\ '{'f, a ~('Il Nal po int
is conside red .
Bin din~ WUhin Blood, Within blo od, d rug can bint! to umn)' componen ts indlld ill ~
blood cells ami plasma proteins. As a ('O!lS(-'l IU('Il('t· o f btudtng. tl.(· l'OIlt't'lltmtiulI o f d nt~
ill whole blood (C h ), ill plasma (C ) aut! unbound in pillsmil wate-r (C II) ( ',III dilTl"f grt·atl),.
Fo r ease of chemical aualys is, plasma is tilt" most ('OIllIllUU fl uid analp ,{'(1. Jn man)' n-spe-ets
this cho iet' is unfortunate. Oue of til(" p rilllllr), ~o.llls o f ml'a.s urillg (1)ll('t'ntnttiou is to n-lan-
tilt' meas un-menr to phanmwulugit: f('S!'lllll5t' and toxkil),. 1I0w(,,\'(' r, UIlI}' unbound dnl~
can Plt"S Ih ru\l ~" most rellmcmbrancs, til(' p rotet n-bouud form hdll}o1; 11M) Iargl'. Accord-
ingl)', til(' unbound dmg concentration is IImll)uhl('(lly uum- doS('ly related to till' adhily
of Ihe IIm}o1; limn is the total plasma conccntranon. \, (,t III1IMlllln! coueentrution is ollly
occasionally measured, p rima rily hl'l'alls(' tln- 1II('III(MIs for doill ~ S( ) an' ofh-u tedious. lack

Plasma Tissue

Amount Vp'C Vr' Kp'C

Volume V, V,

. ·IJlt. 10-1, n ... ..If...i " f !i"".. h; ", I;"" " " "m" .L\l rih"hnll i\ , lIu'lr.tl.~I I~· .. ,In'l: Iha' .Ii'l ri lo",.~ 1..1Vo'~'"
rl....m;o ;o,,,I;/' ti,,,,,,,n,,· r'l~..i" lt l(i<' ..J1" ",,~ ;on' \',. ;tI1t1l·r- rMl.odi"'~'. At "'I" ihhri" m !I... oIl1 ltltltli " f .In,,, in
....1-11 Inulh' Kl liryM·,,,I. 011 II", '~I"; lil ,ri,,,n .lislnl" 'I;"" (p;o.rtitinn) rolli<•• " ,.. II,,· pia,,,,....,ItI tI", Ii ..",· ,"l" ",,~,
. n" Ii", pla. m.. ('>IIl""Ir.di,," ,
CI-W'TE Il to 14'
an.,mK.) ' and precision. uud an- l"oslly. ~U11l't1lt'less . it is helprul to dc·fine an unbound
\l llu II W ur d i~ lrihll l i(Jn . ,",fl.

Amount in body 01 equilibrium • A

Vo - 12
Unbound p1osmo concentrolion Co

whk" permits 11ll' amount or d m ~ in lilt' hod y 10 he n-latcd to 111l' unbound dnl~ roucen-
tr arion.
S ometimes whole hloocl l'lJlIl"t'lItralio ll is nn-as un-d, ()m1 ' again au appmpriall' \Ullllllt'
u-nu. \'" . run 1)(' dd im"tl. :\alllt'I~·.

Amount in body 01 equilibrium A

13
Concentrotion in whole blood - C b

A~ till' amount o r drug ill hody is i1ltIl'IIC'mlt'nt or till' ~ i lt , or uu-asun-nn-nt . it rollows from
Ect~ . 7, 12, anti 13 thai

lA

111t' values or tIW!it· volunn- n-nn v l'1" 1 d ilTt'r markc"tlly ror a ~\·t 'li drug. 111(' u-nu must
Ortt" 11 q uotl'tl in the lite-...a ture is ba.\l,,1O il 1II1'1l.'lm 'lIlc·nl or dOl~ in p la..mm [i.e .• V). Examples
or t1 0l gs with di lTc'ring value-s or \' an' ~'1.'n in Fi ~. 3-2 (p. 22 ),
P fas ma Protein BindinJ;l:_11l(' prtucipal eont-eru \\il h plasma protein hincling is n -latt1.1
to its ' -dria hility \\i lhin and alllllll ~ plllic'lllS ill vario us Ill('m pc'lIlk ~ 'ttillg'i . 11](' d('~rt't, n r
hi ll di ll ~ is rn'tIIlt'lIl ly t'xp n'sSl't 1 as the
bound-to-total coru-entrution ....lIio . 111is mlio h;Ls
Iimil ill ~ ,miles o r 0 and 1.0 . Dmgs with
m llll's l-,1Jl.'alt'r than 0.9 an' sa id 10 ht' hi ~h l~· IIC IUIIt!.
As stated previou ~ ly. unbound, rather tha n bound. l'(lIll'C'nlration is rn" IIIt'ntly IIInn'
important in Ilw mpeulit·s .11w n· rnn ·, Ihe [ruct ion o r dm~ ill plasma u nho u nd . j u ,

15

is or gn'alt-r utili ly tha n rrat1iUll hnlind . Oh\i ou "ly. onl)" ir j ll is l'tlll.stani Is total plll-~llI;1
conceutrunon a ~nod mensun- or e ha" ~t·s ill unbound dm~ cnucentration. Appn»-
unate values o r [u usually lLS~K'iah'tl with Iht'mpy rur repre-se-ntative dmgs un- show u in
Fig. ro.s.
8 i nd i ll ~ is a run l1inll of tln- affinil), or tln- p rotein Ior tht' d m~. The affinit)· is c:ha rat··
h·ri7J.,,1 bv un ussociut iou constant , K.". nt '<."ltll ~· tilt' 1lI1ll,!)('r or hindin~ silt'S on a protein is
lim ite'll. hindi uJ!; al....) depends on tht' molar t'()llt'{'utmlio ns or bot h dru g and prou-tu. Fo r
a single bi lltli n~ silt· O il the pron-tu. the a.ssoc;jatiull i ~ s i lll pl~' suuuuurized by Iht· foll......iu!-t
n -act ion:

Drug + Prote in ~ Drug-prolei n complex 16

Equilibrium lila)" lie e ithl' r 10 tjn- ri ~h t o r 10 Iht·lert. lI i ~h a lfinity, or course, im plk-s thut
{"Illilihrilllll lh-s fur In Ihc' ri~ht . This is a n-latiw statemvut. however. as tlil' ~fl'al l'r tilt'
p rotein concentration for a ~v('n dm~ couceru ranon. lIlt' ~n'ltl l' r the bound dnl~ t,(IIIl'C'n·
tration am i lilt' l'tmn'r.'\(·. From 1II1L~ S law conshlc rations, tht' equilibrium is ('xp n'sSt"t1 in
terms o r ti lt· coucent rattons or 1I1lIICIlIIltl-tlm~. Cu . llIlo{'{:up it't! pmlt'i n, P. aud hUlltltl d m~,
CINI , th us
 ,.. OlSTlI1BUTION CHAPTH 10

Percent Drug
Unbound (100 fu)
100 Ateoolol.lIltlium
Protamamide. gentamiCin
Digoxin
50 PeniC~ttn G
TheoPhyiltne
Phenobarbllal
Carbamazepine
20 QUinidine
Verap.am,1
A1tenlanit
10 PhenytOin

I
Tolbutamide. Dwo.1de
PfoprallOlol
t "l l!:. re-s. TI N' {r;M1i1I1',,{ . lnll( i ll pia,,,,,, r><~ IU ll.. 1 5 Nrttd eplIle
t.. I'rutd" . "n. ~ ..;...·l~ ""''''''1': t1 n,1t' Armodarone
OlOlloxm
Chlorpromazine
2 Owepam
FUlOsemlde
Keloprolen
o..m"m
Tolmelm
0.5 Wanann, lbcproten
Ptlenylbuta:zooe

0.2 Naproxen

0.1 Flurbtprolen

17

'nil" ull( l(-'(.·upit'1 ! prote-in conce nr rut tou depends ClII the tot al protein conceut n mon. 1',_
TIIt·S(· h\1I l'UIlI't' n lm liur ls an' n-lated h'j"fil , = PIP,. when- jup is ti lt' Irac tton of lilt' lol al
1II111l1)(' r o f bindi ng sill 's lI1lc)(.·(: Upil'( l. FurtlwrllloH' , l ilt' unbound roncentratfon is I II . C
am i l ilt' hOllnd conce-ntration is (I - fill ' C . Appmpriatt'ly su hstit uting mto E ll_ Ii. it
tln-n-fen- folhlw" 111)lm rt'arnUl!{{'m{'llt thitt

18

From thi.. n -lations hip rlu- value of f ll is ~'l' 1I to depe-nd Oil lilt' tot al protein concent r a-
tiOll, it.. illllsi rall'l i ill Fi~. 10....6 fur lilt" hi lldill~ o f pr opranolol to u l, add ~1>l.1 Jpmft>i n . \\ 11t'1i
frl is ..mall « U. O. Ell- IS is a ppm' illla td y Il l1\" ·fil,,· P,), Bv laki ll ~ tilt' ra tio o f th is
{"( Illatioll for lI on ll al allli ulten-dt."IJ11 t1ilio ll". tilt" vahn- (If f ll ifr/ l wln-n tln- concent ra tkm
IJf bi ll( li ll~ p m lt>in is aln- n -d (P,') is,

L ' P, L
19
,. ~ ? .
, ,.
CHAPTER10
'"
Conskk-r, for exa rnple the change illIII expec ted fur ilmpmf('11 ifll ::: O.()().') , it dmg IMJllnd
primarily to albu min, wlwll llll' albunuu ceuce-nt runou is t1t'(·rt'l.LSt"l1 fmm 43 W I. to 2S w L
nit" [ruc tion IInlMlIIlIl1 is expecn-d to ill(:n 'a\t' to n .l)l);"; ,
Usually, o nl,. a small Iractron (If the llvailah lt, s ilt'!' 011 h inding pron-ius is occuptod (f " I'
"" I ) at tjn- t1lt'rllp('ulic t'Ont'C'nt ra tiullS o f most d nJ ~s; the Frac t ion unbound Is tln-n rd ativd ,.
consta nt at a ¢ \'(.'n prot vin concoutr atton ami imlt' I:M'm!t'lll of <! n l ~ concentranou. O('l'<l-
siollally, th erape uti c co nccut rattons a n ' slIffieit," t1y h i ~h St l that most of the availah l(· h ind -
in ~ silt'S are- occupied. Then hot h )i, ami )i l,. an' t.·o ll("t 'ntr.t1ilJll-tlt·I:M'm le nl (we C ha p . 22,
DoS(' and Time Dt'lx·mlt·" eit's).
In suhst'q U('llt chapters. it " i ll 1)(, helpfulto n-membcr thai phanuiK.'Ulngic at.1hit )· n -
late-s to tln- unbound concentrat ion. Plasma pmteiu h ill(lin~, then, is o ftt'lJ o n l)' of Inten-s t
I :M"('<I II ~ Ihl:" total pla.sm a conce-ntration is uu-asu n-d . 11 l(' tota l plasma t'l lII('C'nt ralioli til"
p -nds Oil IMllh lilt' extent o f protein hi fl{lin ~ nnd r!n- unbound concentranou, i.c-.•

C . Cv/ Iv 20

\\11('11 c(lIlt"t'ph lill i7j ll~ d t.· pt'udt·IIt'), and flllll'tin nalily. th ili equation should no t hI' n-a r-
r.Ul~I ,(1.
Tbeue Rindin~. The fract ion o f t1 m~ ill botly IUt.·al t'l1 ill pla.\ ma depe-nds 0 11 its hi ll( lill ~
10 both plusma a nd ti.'iSIl I' t'lllllpOIlt'llts . us !'IUI\\11 St.·ht·mltlk l.llly in Fi ~. 10..7. A t1 rt1 ~ lIlay
hlt\'l' a ~n'al affiuily for plastnn p rote-in s, bUI lIIay ... tillll(· lut'<lh"ll primartly ill tissul' if Iht,

0.20 • Control .-'It. 10-6. 11..· frd<1'"'' u" I. .. "K! " f pn 'lmu...lo>l
0 Renal ,-a lii." "itl, ,I.., pi..., ,,,,, t . ..... ... I"" ji' ''1 "f ,, 1.......,1 ~Iy .
('('1",.h'; n ill 7loi p.d io-llll III;lh ,-.uir.. ,~ ,li"'·..."'''' ;oJ .. 1in
.. Arthritis I..·..hhy' ,, >l uuto...·n . n ... Ii, d r- , thru,,):J, II..· ,1..,..
6 Crohn's
"1 '..... ·nh tI..· n·I"lio ,,,,hip 1'"-1 1f" ,", 1-:'1 III. 11' _
0.15 • Cirrhosis i"~ .. \llI, ,,· or l l I JIit ( " .~ X HJ"! / ",,,J,·) f,,r ".. ,11n,
~
c " ·I;<lioll"lir "f'I"...n 10 "("CU" " 1 rolf "..Pot "f ,I..· .....
~
0 "'·f\''1I'lIn.Jli h~' in It... f.....'lioo " "",.." 1. In ..II C-"-"''''.
B
c • III., r "".';n i~ 11[" \il'ur~h'(t til<' mill t ·tllr.•'io",

....
0
::>
c
0.10
• • of 1'" '1w" 'M>I" I I, I. ·..... lII.ot uI' l,l 1· ..,1 e:~ t.. '1"'''dll
(Imw'J , - 22.7 ",\I ). m"'1 lnr.oll f"'tll To...-r. T.S .:
~ Implk-..tio:II,. III" "",..Il'd pI.o..tllll p rol..i" 'li,...li" :;: ill <li, _
~
~
o. •...... ~I .. I.. ~. I n : 1' I"o.rm ,"'Olthll' ti o: Il.a ~ i . fur D n ' lt
0.05 T n ·all,..·" I. E.lth..1 loy 1. :1_ Bt·, S , \1 ..".II.t.1. ;oJ .. 1
s 06 0
1(:, C;" ml"·I1' 'lI:[itl. R~ , P",". S · \·"rL. 1 ~1. Pr'
173- 1\1.1. Ot1¢n.J tLt .. f ", l r.lty. ,",,\I .. Bt>flo:4. ( I .
( ), Lar·( :t'<,,·.... or.i..
J"h.m Il. C 1Sjo"I" ,t . F.: I " .
o .\--~ __ ~_~
,·n·.....1 pLo." 'liI p IMn I>lt.. t."" .or
p"'l' r..t .. .lo ~ ;oJ .. 1
.·hl.. rl,",u...nt... n li..'. '11 ",. •li.. -a ;,..I0..... 1..10.... ·
o 1.0 2.0 3.0 Ii",,, " r pl..,t".. a r lldd Iit])·."t''' f.·in , S . En I:I, J

u 1·Acid Glycoprotein (gil) \ 1...1.• 29!J:I 4.n- I ~. IWo!!. Ro1'""Io K... I .....ill. I..·•·
mi" ;.-,,, ..f tu<'..l 1,,"-•.)

Plasma Tissue "·IM;. 10-1. .>.I " \"ihl,num_ II... ,Ii" rih" ,io:,,, "r ..
d nll: IIIit hill tI..· , I)' ,J,,,...-ML, "n hi",lh'l: In I" ot l,
Bound Bound pt..., ,,,,, I'"" ,.;tt lliu '... ('(>lnl""" ·III\. In ,I... "" . ~ -I.
."""",.c.·o.or
j r _~
""Iy unl""" ..1" n'le i, .·nl,·riltlt ..n.l l.·.." "..:
1l , I,,· I't..'tllil ..t,,1 1i"" M' cnmI"'I1"..-nl' .

Unbound ~ l- Unbound
 D1STPI!llITlON
'" CHAPTER 10

tiss\lt"has an affinit)"{...vn ~n·ah- r than thut of plasma. Unlike ptl~lll a h i lld i ll ~. tisSIlt' hilltli ll~
o f a d m~ cann ot 1)(' II lt'a~Il H'( 1 dj rt'(11~" Tlu- tiSSllt· must II(' disrupted. rt's ll lt in~ in Ill(' loss
(If its inh'Krily. EW II !MI, tissue hi lld ill ~ is impm t an t ill dm~ di si rih uliu ll.
T tssue hilltlill~ ma)' II(' inft'm'(! (n JlIl uwasun-nn-ut of d n l~ hi ndill~ in plas ma. {;o llsidN.
t·.~. , tilt' fnllo\\ing mass-balance- n-lutinuship.

V· c - Vp ' C + Vrw ' CT\IV

A mount Amount Amou nt 21
in body in plo sma oo tside plasma

ill whi<:h \ '1W is til(' aClllt'()I!S \1)111111(" o ulside (If p loLslIla into which l ilt' d m ~ drstn bun-s alltl
C rw is tln- t:om 'spo nd illg IO!;11 d m g concent rat ion.
Di \'idiTl ~ hy C.

v Vp + Vrw · fI»:
c 22
Appa rent Volume Appar ent
volume of 01 volume of
d islTibu tio n plasma tiu ue

Ih'(~.Jllhat ffl= Cu/C. Snuilarly. fo r Ibe li ~~\ll', fiI T "" C"J /C nl"" Gi\'l' u lha l di ~ lri"llt i on
tlu- un bo und couceutra tions in ph~Ill;l . e", und in 1 i.~MI{·S .
{~ llIi l i b ri m n is adlit"\"{'(1 whr-n
Gil.,. are equal. dll..' 11

23

whid l Oil ~ ll h~ ti l ll t i n~ int o Eq. 22 yields

v_ V + V ' -Iv 24
p rw lv,

I-"Ilt. 10-li. n ..· ,..Il" ...· " f di"rih"h , "f ( of- )'1'" "
I'ra,..01011 , <triM with II,,· fr.•d i"n u"I u..1 n ..· ,II..
800 0
.. ·,Yah..., "''''' ma,lo· In 6 .~"'I n ll . " I>jo'(10 Ie, .....1 in
15 pal;"'nh (01 "'~l " clln ln it' hq-.alit' ,Ii..·......· af" 'f""
Lv. 1.. >1". (40 "'R) .1 ( of- ).p"''I'r..'......1. (I>ala fn " " 600 0
Br.u.. ~' . B.A.. J......... J.. and Brill!. ,' E.: A 'h " ~' ,I
0
fad..", '"H,,,·,rinR .1011: ,1i,!",..iI;",n itt . ....n .. 'it· Ii...., 0
di.. ·....•• ,, \ittl: II..• " ...It·l dnll: ( of- ).1'" '1 ,1'1.. .....". 1'Ir. 0 0
400 <P
J. Clin. 11"'n n..... .I.. 3 :U1-249, 11176.) 0
. 00
.0
\
200 0
•
0
0 0.1 0.2 0.3
Fraction Unbound
CH.APTf ~ 10 ,..
From this relat ionship it is wen that tilt" uppan-nt volume (If distri but ion Increases when
l u is in('n'aM't1 am i t1 t'(·n·;L....'s \\1Ienjilr is lncn-ased.
To appr('dall' tilt' n·lat iollsh ip in EII_ 22-24, cous hh-r the data for p ropranolol show n in
Fi~. I( )......"i.
TIlt' linear n-lat kmship be-tween \' and jil 1I0t only Indicates thai "nt/jilT is
('flllsiant, hilt also that d ilTert'n('('s in hin d ing o f pr opranolol in plasma acco un t for most of
ti lt' variation oh""'I"\'('t1 in us volunu- of dlst rlbut rou.
Tlu- relationship t'xpn 'sS{'t1iu Ell. 2.1 exp lains why, h{'<.~IlN' o f p];l-sm<l and tissue binding:.
\ ' ran-lv corresponds to a n 'al volume, snd l as plasma volume (3 L), extrue -llular SI); I('('
( IS I.). or tota l hot ly water (.12 1.), Even if \ . co rresponds to tilt' valut· o f a physiolo¢ l'
spal't·, o ne rauuot l'tJlld ntle \l Jla lll "i~ lolls ly thai tilt' drug distrihllft's ou!y into that \UIU11It'.
Bimling: of t1 n1g:s in hot l. p lasma and tissues complicates the situation and often p n."wnls
making: allYconclusion alMllIt lhe actual volume into wluch tlt(· drug dist ributes. An ('X{'('p-
Hu n is when d m g: is n-stncted to plasrua: the \""IUllIt'S of distrthutiou, appart'nt and n-al,
uretlu-u tilt' same. aiMlul 3 L in an adult. Th is last situation is expected for smullmok-cular
\\'t'ig:ht d m g:s tlml ,ITt· hi~hly bound to plasma prot ein s hut not hOlllld in the tiSS Il{ ·S. How-
eve r, thi s apl);lT!'nt \u lulIit' cannot 1M' all equilibrmru value . lx-cause plasma p roteins {'(Illil.
ihrate slowly IwtWt·1."n plasma and ot her extracellular fluids.l1lt' appan' nl Vn llllllt' of plasma
p rotein s. illM lllt 7.5 I, for alhumiu, is perhap s a 1M-Iter est imate o f tht· nununum value for
such t1 m~s .
Fur d m~s I)f h i~' l molecnlur wl'i~h t (g:n ',d er th an ap p rtl'illlatt'ly 70 .000 WllIoll' ). extra-
\w.t.'ular distribution is wry slnw tn nonexistent . For sUl'h dm~, III(" volume o f diatrihunon
t1W Il It'nd s to apprtlxilllalt· that of plasma . 3 L, A ll excepnou ca n occ... 1T if tilt' mac romoh-c
ular drug hin ds to l·m lllt ht· l i al linin ~s wit hin tilt' vascular syste lll.
Fur d m j.(s rhat an-b ound in m-ither tlssiu- uor plasma. till' volunu- of d ist rihuti on varies
IM'tW('t'll tilt" t·,l ran ·lllilur fluid vnlunu - ( 16 I.) :lllt l tilt' lotill l)fltl)' water (42 1.). d{'IM'fl( li ll ~
on lilt' d{1-:n't· In which the d m~ g:ains acces s to 11ll' iut r.l('t·!Iular 1I11itk Exampl{'s of dm h'S
that t1i strihlllt· in total lMMly wah-r are caffctm- and alcohol . IMJth sma ll molec... rh-s that p< l-SS
frt't·ly t hml l~h nn-mbnuu-s.

SMALL VOLUME OF DISTRIBUTION

Mod.1
T Ilt' m(MI!'! exprt'sst'tl hy Eel. 2.1 is con ceptually useful. hilt it does not take in to al'('1Jtlnt
that pl,l-slIla p n m-ins distnbun- th rtlllg:holli extracellular fluids, ,LS slltl\\1I for alhumin in
Tah lt· 10-.1. A IlI(Mll'I is th erefore Il{'('tlt'tl 10 d istin g:u idl, ill tissues , 1){'t'.\l"{·11 billl lill ~ to
p l'l-sllla protein ami billdin~ to otln-r constituents. 11lis nr-ed is pa r1it'II"r1y Wt'at for dm~
that hind to a ph sma p rtl!t'in and that have smal l (less than 0.2 [ Jk~: 14 1/70 k~) volumes
of t1islrihlltioll. \ 1uch o f tilt' d m~ in lilt' I)fMly is t11t' 1i IMlIIlld II) tilt" phl-~ll\a pm lt'ill and lilly
dlang:t· in biuding: or in the distrihutioll of til(' prolein ("an substa ntially inllm·lIl't.· Iht' dis·
trihuliollllf ulllMllIlll1d m g: \\i lhi n illt' IMltl)·.:\. ll1odt'l lo dt'serihe sud l d istri huti nn is dt'rin 'tl
in :\ pl'M 'mli>.: I- F.
For a d m~ IMuIlld tu alhlllllill, th(' app m'l:imat{· rt'latiousllip !wt'.\l,"{·n \ ' and hi Tl(l i n ~ to
alhurn in ,lilt! utI1t'r silt's is

V :o 7.5 + (7.5 + ~) Iv 25

wllt'rt'/lI is till' fmd ion llnlMlIllld. \ '11 is tilt' illlllt'OUS \Ull1llll' of Ihe illtnK't'lIular fluids into
whidl d m~ distrihutes (tolal a\'ailahll' \XJItIIlll" "" 27 L ), alltl jil tl is the apll;ITt'nl fmd ie)ll
unl)fllllld in Ill{' intr'K'I·II 11tlr fluids. TIlt' , i rtm' of this lIleMIt>l is that il p ro\; dt's a m(',IIlS of
150 CHAPTH 10

'lIIaly.{j Il~ Ihl" dislrihution of hul l. d m~ and tilt' pl.l~lI1a pr otein 10 wllkh i t hil\(k Bl'p rt··
S('1l1a!iv(' d", ~s \\; 111 volulIles of d i<.l ril m tiuli It·ss th.mll.2 JA:,g und 10 w h id . this mudt'l is
Spt·t.i fil-ally applk'ahlt· an.' ~WII ill Tah1(· 10....5.
To Illust rate tln- ulilit}"llf tln- pmpo S('t! mudd . ('(l llsillt' f ti ll" tlal" ill Fi,g. 10-9. s ho\\ll is
a lillt'ar n -lation ship hdwl't'1\ \ . ami fll for a sem-s of ce-phulo s porius. T his dq )('mlt·lIl't·
lI1 i~ht 11ll\"t· IIl-'(·lI l·xplaillt'tl hy tilt' ~(' I J(' ral l11 ()( lt-l, \' ::: \ '" + " n t, -f ulfilr. as sllllli ng filt
dill'S lint var), ,1Il1nng tlw (, ·plmlospn rim . A major pmhlt'lII \\1l1l1d haq , lll'('n noticcdln-n-,
ho\\'t'\ "l'f. 111( ' o!Jst'T\'('(! H I l lin it' in n-rcept w ht'Il}it appmadll's lJ.·rn is "j 1170 k,g(n. l l IAgl,
a \~III1t· 111111"11 larger th an thl" ptl\lIIa volume, \ '". u f:3 I.. T Ilt"u!Jst'fYaliollSart ' much hdtt'l'
('xplail\('(1 b~' tilt' p m poS('(1 1I11111d . T1lt' d ist:rt'P'Ull'y hdwt'('n tln- 1\\11 nllll ld ~ l il'~ in 111l'
distnbunon o f tilt" plasm a protein . T ilt" pmpl)S('(I IllIII)I,1MlAAl'sls that ulluuniu is till' major
hilldi ll ~ pron-iu for tht,S!;, ant ibiutil'S ill Ihat Ihl)s(' 1"l'ph a.lo~pori llS Illat ure t i ~b l ly IlIlIlllti
han ' distnbunon dm ral1l' ristil'S ill 1'\I1II1I10n with alhunun.
111t' volumes of distrih llliOll (If tilt' 1't'p hal(l~ rN l rillS al h i ~I l( ' r fmd icllIs 1I111111ll1ld , h lJ\\ '( '\"!'r,
imlnut e that till' t1m j.. 'S mu st parti ally e-nt er 1't' II ~ or III' INJU nd til S!; )lJlI' 1'\ lmv,l' I'ular st n u-
tun-s . Tilt, extent uf Ihis dis trihunon outside tilt' extracellular fluids. rm <t\ ('fit!.:(' , 1Il 1l ~1 hI'
n 'I'ltiH'ly smal l ill Iha t hy t' xtm po latio u tn I II = 1. t,,( lrrt'SI )( J lII li n~ III a t"l'phalm ))()rill wn h
no hindi n,g: 10 pla.\llIa albumin. the mlu lIlt' is U.29 I A:~ (21l l lill k ~ ) , a vahn- ~rt'ah ' r than

,.ltl. 10-'. ....-_........ Drw•• W .... V.I. . . . . . DI.trlltutl.1I

.. O.2L/k._ .....•
Calotet:Jn [).clox.oc,U,n P'peo'ac,lI,n
CeIIlio_one o,lIuniloOl P"o~icem
CelUfOllime Flu,bprolen Prccerecd
Chlo<OIhiozide f u,~ide $cllcyl><; acid
CMorpn;lf,Xlm' Oe Ibvprolen SvKiloO_ezole
CloM)llc acid KelOproien TolbrtJmide
C1OJ<ocill,n Nopro.<erl Totmeltn
Didolenoc OKyphenbutozOlle volproc cod
Dobutom",e Pheny!bvto.zone W e,lo" n

. '11/;. 10-9. n; \1I1" "M""r ,1;.l rthuli" " "r a .. .. 0.3 ,

-, ,,

.
rit... "r ' '(1,1..1.'''1'' ''';'' ..ulil ...oI i1.. It ..:,,·..." '· ",i t I. !IN'
rr..1i,," " Uh"OIl Nllu 1'1...",.. p" >I.; u•. 11... ' '',,,.
..r II h,,,' " r 1" '\1 fil (••• J Ii<.. INi "'....·" ,I,,· •.•.
,.,• B
• , .,,""' 'I 11
io

,.'
1"...1 1 n.Ld.. " " I,i f" r dnll:' 11t.tl .1" IM>I "",,"r ,,~ "'~~
Ii..u. ·,,·ll•. \ '/t - O ",l lIM",·lh.d tI... \ '11 _ Z7 L -v 6 7 " 9
(E' I' 2.~ ). 1".1 ,I" IMoI 1>i". II" Ii.",,· "''''1''""..'1.
(f"" - I I. n N' " 1'1,"'....I" ,ri,,, .IN...... an ' ; I -
0.2
• 4 •" '
",.
t,· f.."id. 1. 2 - ,.·r_ ~ i ". :) - "·Ii,r..,,....·. 4 _ •• / . 5
\j II "" ()
u·r..ulOll.. I.>Io.·. oS - ....· r"t:~ll ill. n • " 1",.J.0I1.;" .
7 - I' M.....I..1"'tn." - " ·f'>I",,II1..·. !j - .,·fl.ui ·
. liuM'. III - " ·pl.",J.·\ ill. "'IMI I I - ..1".,.....I;,N·.
(Dr. "'... fn"" .1.1.. .."t1I>iI. 1 I>:> I), NII.-,'. \ 1.:\.•
0.1 2
;(lNl :\ iltlrti"li:aJ.·. C II ,; Err 1. " r 1'' ''1<1'' "f"'"
.. 1i,il~' "r "-pl,,,I." I,,"';t1" :\ ' h' i il·Lor.1..", ...,,11·
hi" b ,,", " ""i,,,,.. r",", d ...tn i'I ~· I" dinil<ll ,·rn·
t ·...,., ..I' tI,,· '''.... ''''T''...I.''IM''';'". t:.lil.... II ':', II C.
:\ ,·u. 11.i1...It·lpl,la, Fr.uw;;. cL."" W.u ll".lilult '
o +--~-~_~_~
r..r l l N' IIi>" .",' "r \! ....Ii<.i".,. ( ;.~], ,,, . "r 11,,,it-ia,,.
ur 11'il. It·]I". I;l. ree. PI' , 227_2.19,) . o 0.25 0.50 0.75 1.0
Fraction Unbound
CHAPTER 10 lSI

the- e\tr,ll't,1I1 1Iar \-(IIIl IIl(' ( 1.5 1}70 k~ ) . hilt (:ullsil!('mhly I(·~.. than total htlll~' water (-12 Ij';(J
k~).
T ilt' 11ll1 1l1111ld \UIUlIll'S o f distribution within the series of cephalosporins ri ~. IC}... IO ill
conr rust ((I tilt' tot al volunu- u f dtst ributfun. t1 r,u natie..lII\· dcen-....'i.t.' us the (ral ,tim l 1I1111l 1U II(!
is illl'n·'l'>('t i. Fo r t1IUS(' ('t'phalosporins thai an- hi~hly l~lIIlld (low jid , tilt' billtli n~ pmh'in
t'ITt'l'Ii\('ly tit ,s lip tilt' dnl~. 11 It' (111l'it'tlnelll't· o ( plasma pmlt'in hi lldin~ lu-n- is tilat a 1I11lcil
I.uw ·r amount of tim)!: mllsl ht, in lilt' 1Illlly In ¢ \'(' lilt' sanu- aut imicrohial t·fTt'l1 for IIIO'it·
dm ~s with tilt' sanlt' minimum inhibitory IInlMJ1l1ld concentration.

location in Body
TIlt' fral-lions of dnl~ in the IMllly that an' in plasma (1lllu ml andunbound ), ill or outside
t"d ral'd lular lIuitls, am i ho uutl i ll pl,.....I!l <l or t1mlll~l lOlit extracellular fluids ( ' 1.11 II(' 1I'\('flll
pit'l't's of information , pilrtielllarly with IhoS(' conditions. examples Hsted in Tah l(' 10..-6, in

e, n~, 10- 10, TIM' ""IMMI1MI ,,,I" " M" of ,Ih tri .
IM'lk,,, o( 11 11... n 'f'l..,j,"IM.rill ' .1M"''' in Fij{.

1.5 1(5.5) In..i j , .. '(Tl' • dram..lintJh· "ith;la' iI KTl·..... • in 11K'

fr.-1i<M' '11l1"MIlM!. Fur 11M·....· ('(,"..Jo"I" 'ri '" "il ll
-a lllllMMltKI '~~ ll ll"" nll Kt , II:n·..I" r lha ll 11M' 1.'\1ra-
:5 e2 (~,lI llL.r 'p.o<~' ( \'f. - o.:!2 IAli:l "I' II..· t"t ..l l ....~
water (ti n I A Ii:I, himhll ( I n r t u ma I, mlt'in _
c
.2 (.J."... ~. n ..I'M..... II <~ ..M " r..Ii"" ..f ti M' ao:1n..
;; 1.0 for'lll fur a (h" 11 ,1. _1St f'1( 10..9 fflr i<1.~ 'h·
D
'C e3 fi,,;,.Ii<Ml ,,( 11M, n,""'I."I'''"''' "'MI ,1M' " ..,n~· ..I'
;;; Ii..· i" f" nrlo4li<M\.)
C
"0 4
~
E e e6
~
"0 0.5 _5 _ 7
> e8
~
c
~
0
e9 I\q
D
C
=>
0
0 0.25 0.50 0.75 1.0
Fraction Unbound

r.lltle 10..6. " •• ple, ef c.IHIltI_,I. 'NIIld.... PI_•• e..cellflwtl_

ef the Twe Meier PI•••• PTe...., .. WIIlell D-.. allMll Are AJt.M411

HepohC cirrhosis Decrease

Burns Decrease
NephrOlIC syndrome Dec-sese
Erd-sIoge rercl drsecse Decrease
P'egr'Mlr'lCy Decrease
Nlyoco,dtOl info,chOn Increase

~~d'soose
Increase
l-c-ecse
Trauma Increase
Rf>eumalC:lld o,fh"l.s Increase
 OOSTRI8lJTlQN cI-tAJ'1( R IO

wh id, rlu-n- an ' d l ,lIl~l'S in tht' di stribution o f p l,L"ma p r oteins. Ht·lat i uJl sh i p~ to t'akulatt'
these Iractton s an ' Kin'JI ill T ahlt' 10--; . Tl n-ir dt'rivatiuns an - Kin' n in Appt'lld ix I- F.
\ \ 11('11 rlu- app.lrt·nt volume u f dis tributlon of 11 ( I m ~ i... largt· ( ~n'al er than 50 to !lX) L ),
Eq . 2.'> appm xilll<llt·ly rt"tlll(., ·s to

26

whkh is \irt ually tilt' ~1I 1\t' a." tlmt p n -dten -d h, · Ell' 2·1. Tlu- major p rat:tk al app lil'iltioll of
Etl. 2.'i. h owt·n·r. is for dm~s wi th small \ Ullllllt'S of dis tribution . i.e., \\i th \~a lues «pproach-
i ll~ 7..'i IJ';"O k~ (tI. I I I Jl~ ) fur a tlm ~ hound to albumin.

AJtered Binding and loading Dose

IAllUliJl/ot do....·" an' /oth" 11 10 rapidly uchir-ve ;l the-rapeutic n -sptm...-, p lltatin ·ly hy rapidly
p rtJdlld ll~ <I tlt'sirt'll unbound concem r atlon. \ \'ith variations in both p lll-'ima anti ti."SIlt'
hilltlinv;. Iht· ttut's tio ll ari ses wln-tln-r o r not thr- It lll(li n ~ dost' 1It ...... ls tn 1)(· adjusted .
Fur llla llYd m v:s voluun- o f tiistrihutiull ts hrn-ater than 50 1.. l.e .• much greater than tilt'
" ppart'nt \Ulunlt' o f tilt' him linv: p rot ein , impl,inv: that o nly a small fr.1l1 io n o f druV; in hntly
n 'sitlt's tIll tilt' pl.lsma p rotetnTl e-refore. iv:no rill/ot till' first twr terms in Ell. 2.5uud rt"aliziJlV;
that [u . C = Cu. it follows that

. V
Amoun t In body - ~ . Cv 27

111is t'tlua titlll indica tes tl litt CII is indt'I)('ntlt' nl of plusma h indinv; and thu s no adj llstuwTlt
in Itllid inv; t10 st' is needed. l 11t' tota l plasma t'ollt"t'nlratitlll do es, of course, c.·h.UI!?:t· \\;th
uln-n-d p h \ ma hinding, h ut th is is o f no tlu-rapeutn- con...."t lllt'lIl't· with res pect 10 It l;l<!i n~
tlO\(' n 'tl uin'lIlt'Jlls. If. h("" ' ''·N . tissue "ind i u ~ ifll ft ) Wt'T(' to d l;lIlV;t-', so would lilt' initial
'~I I II t'( s ) flf c" (and G), fl('('t'ssitutiuV; a tlt'li sillll tn c.'han,t::t· t l.t· lt llltli n ~ I!tlS« ' .

,."10 10-7. App__ I. . . . . . Iatlon..hlp.. . .r Analysln, DlatrU.4ftI_.,. Drv, 11Mrt

altHls .. AI.....I... 1t4II DI..trlbut. .. Throu,hout T.tal .ody W.ter

3/V
V-3
V
42 . lu
Unbound on body wale,
V
15 . fu
Unbound .n edrocellukl, Auid~
V
7S11+fu1
In e~"ocellulo, Au,ds
V
V-75t1+1ut
V
3/1 - M
V
Bound 10 e~"ocellulo, pl'olEtins
75(1 - lui
V
V-35·fu-75
V
CHAPTf R 10 1S3

STUD Y PROBLEM S

lAnswers 10 Study Problems ore in Appendi;J( 11.1

l. Dt'fi nt' rlu- h'nns a pp an'n l vnlunn- o f distribution . frdl1ion unbound. lissl1{,· tll-h loIKI
\'llui libri uJII distribution rutin, and jlt·rtusion -ml t· ami pl'nm'ahili ty-mtt' limltations in
dm ~ disrribntion .
2. TIll' volume of dis tribut ion of qutuacrtne. a dnl~ IKllIllI1 to albu m in in plasma, is about
-to.OOO 1.. 111l' Iracuon unb ound in plasma LS o.ns .
a. TI lt' plasma concen tration when I ~ of d m ~ is in til(" !Kllly would therefore he
= IIlWL.
h. T ilt, amount of tlnlg in tilt' IKKly when IIII' plasma cone-entratton is 0 .0 15 mgl L is
= 1Il~ .

c. TI lt' pe n.'('nl agl' of dnl~ ill l ilt" hody that is:

I. oulsidl' Ilu- phslll;t
2. in extn«....llular fluids,
3. IKlllm l outside extnll'.:-llub r fluids
3. TIlt' \"UlllllW nf t1ist rilllltioll of a t1 m g {molecular \\'('ig hl = 3S 1 Wmold ill a ';'O-kK
suhjt'("\ is " !l,,,·n ·t'll to Ill' s L. Ind ie ,lt e which IlIIt' (or mo re) (If th e follo\\i n ~ stat ements
is (an.') l"tllls islt' nt \\i l h thi s ob",'n ·a!ioll. 111t· t1m~ is:
a. IIi gh ly hound 10 plasma p r oteins.
b. Hound 10 1,()lIlj)(llit'nts outside plasma and is h igh ly ho u nd 10 pron-ius ill plaxma.
c. :'\01 bo und I" plasma proteins .
-to T Ilt' lo la l (ll'ft ) andunbound (righl) coucenr ruuons of D m g A folllJ\\ing si ll ~l l' is . doses
ure SIlIl\\11 in tilt-' Fi ~ . 10-1 1 and 10-1 2. Sketc h on each of tilt" sa me fiW IRT'S th e
,1Iltid palt-'l1ul rn 's l)(lIldillg concent rations of tilt" d m g whe n a dnuuistcrt-d:
a. In l ilt' p n '",'m "l' of D n l ~ B. whkh sigll ifil'O m tly (two-fold l'han~t' ) d isplat","" DOlI!: A
(.5n O-m g dnse) fmm tiSSllt' hinding sill'S only.

3 6 9 12
Hours

h. AI a SUhSl'"(IIII'llt tiun- ( 1 I M M ). Il1 ~ d ust·) whe n the jl;l!it' III's serum alhumtn, l ilt' pmlt·in
10 whidl the dmJ.: hind s. is reduced [mm ·12 til 2 1 WL ( (, . ~. , wh en the 1l;llit'nl
dt... 't,!ops nephrotic- svnd ronu-). ni lldi n ~ In other constituents in th e IxKly is unaf-
It'l·!t·d ,
.,. CH .I1'T E ~ 10

o 3 6 9 12 o 3 6 9 12
Hours Hours
nc.. 10- 12:.

.'i . Brit·lly l'tJIIlIllt"1I1 011 1I't' \'cl1idit)' of eech (If I".' fnllcMill1l: ..tatenwnts.
it. TIle' t"lu ilihrillllJ tli,tri buhnn rdtio for a dru g h,'t\101''''"11 li\l"T "lid pla...ma i... 50; tlwn....
fun.', ih \1I 1U1Ilt, u f tlistrihlltitm IIIl1st be at least 75 1. in it man wt·iw. i n~
h. .\ elm!: t1ul rceches dtstnbunon equthbnum within 30 min. )"(" ,,110M' ,..111111lt" of
kR. ,0
tlistrih utio ll in it ';"O-k~ 1Il<U1 i\ 2f)(I I.. must tlistribUlt· primarily illtn hi~bJy I)(·rfu...-d
n~a lls .

6. U ", i ,,~ tilt' ill(n nlldtion i n Tahle l()..b. ~e&lcllla lt· tlK' tilllt' n '(luin-c1 fur tilt" aIlK MUl t.. in
(",K:II o f tilt" tiSMICOS Ih h-t110 n-at:h 5(Yl o f ti ll' equilihruun vahn- fllr a dn,~ \\.;111 p 'rfusin n
r.t1 t'·lilllilt..1 di..l ril ml io ll whe'lI l ilt' art e-rial h lood ("o nl"t' lIl r ,tl i u li is kt-pl constant wit h
hill!" t l ~' J:i\;,, ~ a !tOIUli and an appropriate infll,inu). Rank til(' t illl'~ and tI... (...rn··
"pollllillj;l; us..IIt-s.

1"'9' I '0

-"
,...
I(tdoey~ 4 4
3 0.0
15 08
5' ," 12 0 0 24

, . DiWlndn !I;l' a \'01111111" uf t1istril mlillll of $ "1 I. in ;I 70 -kj;l; man lind i, 97 % huu nd in
p l;l\lIla. ( ;i\'l'n tluu tl u- 1I1lhUlllld dnl~ di..tri butes ....'t"n l~' t1m lll~lloul total hnd,.. water.
" lliIt fr.u1inn "f dm~ is unbound in Ihl;'" in!t· n.,·llliLir flui d s?
.1;. D i ~(l\ i n h'l' a \Ullllllt" (If d i, lrihulin n of ahout 5S0 1. in ;I 7n-k~ slIhj.'t.1 <llltl Is 23 %
h"und ill pl.l\m" . U..illJ.:, lIlt' infnnll<lliull pnl'\itl."(1 ill proble-m 7, d. ·!t'nllirlt" if di~nl.in
i .. II KJrt · or Ie..... t,\!t'lIsin·l,..hou nd in int r.l('dllllar tllliel.. than d i¢tudn?
g , (;am'\'all"f ;J. \llIdil"(1 tilt· phannac:ukblt'li<:s (If warfarin ill I I ll<di,'IlIS \\it h l ilt" Ill--
phmlil- \~ mlnllllC' lt Ltil)' uri nal)' jlnJl ein e1.('T.-linll = 10.2 : 4 .5 ~; se rum (·n·u linint.·
"" UL') ~ 32 ~ ~ I ) \'I'n,I' II nllllmls (n" pmh 'illuria; lIf" n u u ('n 'ati nim' - Y6 : 2U
JI \ 11. Talii., IU-9 i!lmt r.th'" tI... difft'rt'IK't~ in wa rfarin kindil.,. in th.· h~u l'lt lpllialitlll'ii.
~ n tllla n il cliffe'n 'nn'S in w.·i~hl h..-tw"...-n til(' rnu ~1I1f" wert- ¢wn. For t1.i'i pA.hl.·m .
l'ltltl. ~nlll p" a\l' r'(~I "( 1 7U k~.
CHAPTH 10 ISS

, ...Itt 10-9. M . . . PIMI kl tlc Pw,. 1HI1enJ. . . . . . . 1.

c..e _.I. 11 C 11 Neph c After 0-1
A...I.I I• •,Ief W rI.·
VILI Q 4 :!:. 2.7 137 :!: 66
CI!VI-IlI 020 :!" 0,07 058 :!: 0 26
', / (hI) 36 :!: 14 18 :!: 11
se1um elbum,n Igill 43 • 5 125 • 65
'f..,...~, o f ,,,,,",,,, AM e-.j ,P.....,..., N ~MO ~,p .""""-,G ~~rJ""'""-' ........ ~
'........... """'"""=. "" ...,...., r~ <.,."'9la<"'"' a.. NoPwcl 1$18-80,1080

a. C iwll a fml1ion unbo und of O.lln3 ill tile control J!;nmp , es ti mate th e n J ul' expec t e-d
in l ilt' llt'p h rulil' ~rn J1lp .
h. \\';trfa rill h ;l~ a sma ll vnlnnu- o f di st rib ution. Cak'ulatt' l he expected vnluun - of di s-
trilmlioll if fi' is inl·rt'a.~ 'll to tlu- val ue calculated in "a.~ Hin t: den -n utm- till' \111111'
of filft ill tilt' contr ol ~n m p, and a.~SIIllW it is tln- same ill tilt' Iwph m tic patient s.
c. I t u I tilt" h.llf-lifl' data 1101 Ilt'l'Jl ¢ \"l' U. could )'011 ha\'t· predict ed till' o!)S('I'\ 't'l l sho rt-
I ' lli ll~ o f till' vulur- ill till' Ilt'pl ln llit- pi lt it'II IS? 111is condmon usually S Il~t'St s indue-
linn of 1lll'l aho lislIl.
 Eli MI NAT IO N

OBJECTIVIS
The leader will be able to :
I . Define the loIlo-Nil'l9 USii'l9 boIh 'NOfd~ond eqcctcos: clearance, blood clearance. unOOund
clearance. hepatic clearance, biliary clec-crce. and renal clearance
2. Colculate the exnocnoe rene ocross on eliminating organ given blood clearance and blood
flow in rholOfgon .
3 Ascerto,n Irom the volve of it$ e:d rocliOfl rene wnerhefme clearance 01 a drug by on agon
is perfusion me-lunued Of is dependent on ilS binding to plasma proleins
4 Cakulalethe IT"IO)(imum 04'01 bioavailobili tyof a d,ug given either .15 bepotc eorocrco rene
01 the appropriate infotmolion 10esnece this vclce.
S. Dereemre the biliaryclearance 01 c drugfrom il$ b,le-to-piosmo cceceoeonce reno and the
bile flow.
6. Descnbe the role thor biliary secrenon con ploy in drug dispc»'hon ,
7. Descnbe where 'iltratiOn. secerce. and -ecbsopeco 01 drugs occur w,min the nephron
8 Sene the ovefoge value 01 glomerular filtration rote.
Q Given renol clearanceand binding dolo. delefmine if c drug is predom'nonrly recbsorbed
from Of secreted into the 'enol tvbJle,
10 . Anliclpale rhose drugs for which a change in e,rhef unne pH Of uline flow may alter The
volve cJ the;, renol clearance
1I ~toin the relahve cantribJlian cJ the renal and exeoreocl roces to toIel elimination from
!heir -especnve clearance yol~
12, Explain the ~totemen t , " HoI I~ile ceceods upon clearance and volume of di~'ribulion "

Tlli' ('hill'k r i' tUII('t'n ll~1 \\; 11. c,lilllilliltioll pnl('t" 'l " allli p ilr1it'lIbrly wil l. li lt' l't lllt'ppi o f
d c·ar,trI{'t· . III ( :l lap. :1. I). allt l -;. I] It · IIll·l lul(l, .,f, I ' Ml l l i l~ 'i l l ~ t "l.·ara lu 't· wr-n- pre-o-uu-c l. Lh-n-
ih p lr~ .... iul()t:k Il W,l1lillt: h t:iwlI.

ELIMINATION
Elilllillalioll t l('('lIr, I " r-wn-tion .1IIt! II wl ahul i'''I . SO" ... drllt:' an' "\(Td .~l d<l li lt" luh-.
Otlll'N, I l; Ht i ("ll la r l~ m lalil,' \1I",laun·,. an- c·,ndl 'd ill IIII' lm-ath. Fur lrImt d ru g, . lmw-
r-v e-r, r-wn-tion 11t't" UI' pn ·du1l1iuilull." ,"ia 1111" kidll l'~ ' .
\ 11"1..1Mlli 'lIl i' t l n- lll'tju r Illt,d',llli' lII f. Ir elimiu••tiunof t1n lC:' fflllll t In- 1MM I~ , Snun- t1 n't:'
an- " 1i'" il lilh"tl alluml ' ·l1tirl'l~ IIlldMII\:p d b~ II ... k id rlt ,~ " bul 11.1".· dru~, an- n ' lali\ t ·l~
ft 'W ,

".
CHAP!H 11 157

TIll' II1mt l1I1lIIllH lI m utt'S o f dnl ~ rm-tabohsm an' oxida tion. reduction, hytlmlysis, ami
{'()nj ll~illion , Frequently. a drug .\ illlultallt'1l11sly undergoes IUt'taholislll 1';0' s('I."l'mll.'UIIII)('t-
tng l)ll t hwa~ ..., 111t' fmd inll goi ng 10 each IlIl'1aholitl" dept-'mls 011 tlu- rdath"l' r ates of eac h
of till' pamllt'! pathways . ~ I d ahol i les lIlay Ilndt'rgo furt lll'r lIwtaholislll. Fo r example, oxi-
dation , n-ductiuu, allli hydml~...is an' ofh-n follo\\"''1I I';o' a co njuRation reaction. 1111:'S(' re--
adiollS IK'l'U f in seri es O f an' s aid to II(' ,n 'q llt"l,tinl. Becausethey ofh-n (K'l1 If first, oxidati nu,
n-duction ami hydml~'!ii s are {,()lnmonly referred to a.s Phase I reactions. ami t' lIIjuF;ations
,tS a II reactions.
I'h ,N '
(~:Il(" rd"y, the lin 'r is the major and sometimes (lilly, sin- of drug metabolism. Occa-
siouatly, ho weve-r , 11 d m ~ is l'xtf'lIsiw ly IIlt'laholi7.f"11 ill one Of mo re other ttssucs . such itS
tile kithwp , ski n. IUII/-."' , hl(l(l(l. ami F;ilsl mi ntt'slinal wall, ~it~l)'t,t'ri ll is such all example.
Tahlt, I I-I Illusrrau-s 1l1llh' m s of hiot mllsfon natioll (nwtabolislll) of representative
drugs. Tht' l )llt hwa~ ... of IIwtabulislll an ' d ,t\..s if!t'1II';o· chemical alteration. Several of rln-
trunsfo rmatlons oc x-ur ill the endoplasmio re-ticulum of tilt' lin 'r and o f certain other tissues .
011 h CllJl( ~t-ni zi n ~ t1wst' tissue-s. the e-ndoplasmic reticulum is disrupted " ; tI1the fo rmation
of small \"(·sid t·s ('allt'1l mic n A'lI JtIU',Y, For th is n-ason. lIletabolizing l'IIZPJ){'S o f til(' r-ndo-
plasunc n-tn-nlum an' l'llllt'1l mk n A'lI)JJ1f1l l'fI Z!lll U'S. Dr ug metabolism, therefore, may be
d ,tssif!('11 RS mlcrosomal a nd noumicmsomal.

IHI
ICi
101

10 1 leI
G1vlelh,mode .. ~ro.>:yglvlelhimide ~ Hydfo><yglule!tl'mide glUCVfQllide

1' 1
P,ed",iSOtle ---------; .
~ P,ed"'i5Olone

IHI
Svccirtylcholir'le -----------1.~ Svccir¥monochoI,ne

101

"Clm>..l<a<>" tOI. <>o ~ 1~1.~.fHl~.lCl .~

,,"' ..,.... ohg>",.., _f'IOOOOb:>I,C ~ _ odo:cted
~ '" c""" _. ~ Jok,,.,,rq '" ~ ",*""","",,,,,,d "'1lO'''<loug
lSI CHAPTER II

111t' majo r (' 111.)11]("5 n-spousibk- fur tilt" o:dtLltiull ami f('(lm1iuli of d nl ~s ht'lon,g 10 tht'
superfamily of cyt ochrome P4.50 l'1I1.)1IU'S . Tilt' tsozymcs of this family displaY;l n·!alin ·ly
h i ~h dt1!:n >t· of structural Spt'<.ifi(:ity; a cl m~ is ofh-n a ~oud suhslmft · for mn- ('ll ZY'Ilt' hili
nol a nother (M'l' also Chap. ) .1) .
111t, l1 J!l!i.('l:IIIt'Ilt'l'S or dnJ~ llwtaho lislll an ' man ifold. Billt nUl sf u n u <lti oli pm\, dt'S a
1ll1,"(-hanis m for ridd iu!!: tilt, hody of Illld l·simhlt· fort'i~1l 11l1lll'MlUIltls ali(I d m~s; it also p m -
vtdes <I I1l I ' IIllS of p n ll.)ud u/t acttw compounds. :'I:U lllt'W IlS (" 11111(111'5 an' nuw rt"t-'('!-rni:t..t·d in
whit:h l ilt' ad minislt·rt "'t ) d ml{ is n ·ally a n inil(:tiv(' pmd m~. whid l is 11 I11H' r1t-t l inlo a plrar-
lI\al'lJlo~kall)' aliin' spt·dt·5. oftl'n !loth ,III' d mg: alit! its 111l'laIMllitd sl an' active. 11ll"
d uration am i inte-nsity of till' n*spOIIMOS \"al')' "ith till" tune- courses uf tlWM' suhsla ll<.'*s in
tilt' hody. 111l' pbarmacoktncucs o f ati in' metabohn-s. us well as tllllt of t jn- com pound
adnnntsn-red, is then-fore of tla-rape nnc concern. 11 1e <.'( ) III I1U lI\ plltllways uf hiotm nsfor-
mat ion and the kiuencs of uu-ta bohtes are pn-senn-d in C hap. :2 1. ~It't a"ol i h' Kinet ics . TIlt'
l'Iiminat iun pnJl."l'so;<.' s a n' (' m ph'L~i7..t'lI I lt"rt"

CONCEPT OF ClEARANCE
of till' t'()II("l'P!S in plm nna('(J~illetit"S. cI.'nnlllct' Il ll~ tilt' ~f( 'a tt's l putt 'lltial for d ink-a l al).
pbcauons. It is also tln- 1II0!\t IIst'ful pamllll'tt-r for ti lt' evaluation of un t'!imin,ltiull IIIt '(,..II·
anism,

10.. Au..... Organ of IIiooIoatIoo

Ht"<.'1t11 From C hap, 3 that clearance is dt·filll'll ll~ till' p rupo rtiollality Iactor rl'lat ill ~ ran- of
dnlg elinrination to tilt' pl.l~1lJa (d m gl conceutratfonThat is. run- o f t'limination "" C/• . C,
Clearance may II{' \iew("t! in another way. namely fmm lilt, loss of t1 m ~ ac r oss an 0'l'all of
clumnancu. 111is lat ter physi(Jl~e approa ch has a num ber of atl\'alltll~t'S , partil'llarl~' in
prt"(!itiinJt and ill l'\1tluatinJ.( the elTt't.i s o f dlallJtt'S in blood How, plasma p mtt 'ill hi lll l i ll ~.
('f1Z)lllt' ,It:.1h i t)'. or M"<.·f('tUI)· acu vtty 0 11 till' d iminution of a d m Jt. FiJt. 11-1 summarizes
tilt' \"ariolls way~ of \it"\\inK IUllSS hal,U1l'C:' across all e1iminatiuJt0'l',m. I II this scheme, d m ~
in the el imill1ltinJtul)!;all is llSSUIllt-'t1to have n'ad lt'll distribution t>(!uilibriulll; thus, tln- so le
n-ason for auv tlilTt'n'lIl"l' bt,tw("('u tilt:' artt'rial and ' ·t'lIllIIS l'()lJl'l.'n tmt iu IlS is e1i minat iun.
For all but tI~t' earlit'st monu -nts. thi s assumpt ion is n 'a.'iun;lblt, for the kidllt:;."S and tll(,
livt-r, which an' a monJt til(' most hi ~ltly perfused and ht,III.'I.· most mpid ly 1.'tluilihratinJt
orgam ill tln- body.
TIlt' r an- of prescntanen of a drug to an u'l',m (If elmunanou is the product of hlto.!
How, Q. and l,(J!lt'('ntrdtiun ill blood t'nte rillJttill' urterial sitlt" C." Ibat is, Q ' C." . SilllilOlfly,
tilt.' r ate at whic h d nl ~ lea\"('s Oil tilt' venous side is Q ' C \., whe n ' C \ , is thl' concentranon
in tilt' n ·tunl inJt H ' IIHUS hlood. 11l(' d ilTt.'rt'llet' 1)(,twt"('11 tl l('S(' rates is tilt:' r an- of d m~
extract ion (t'liminalion) hy thr- 0l)!;,m,

Role of extraction - Q{C.... - C~

If tlu- ran- of tl nl~ extraction is related to tilt' rate at whidl it is p n-seun-d to tilt:' o rga n,
Q ' C A , a IIst'ful P;lf1UIlt'tt'f, til(' l.'XtmrliOl' mt/II, E. is tlt'rin'll:

f Role of extraction
- Rate of pre WJntotion -
2

T he t'\tm l1inll ndio lit's !)(*t\\'t"('n 7..t·m , wtwn' lin t1mJt is t:'Ii minalt,<l,lImll , wtwn' IU ) dnlK
t'st'1IIX'S pOlSt tht, (J~an .
CHAPIn 11 ElVV\NATI()N
".
If tilt' n Ih ' of dmg t'xtral1iolJ is n-lan-d to tilt' ill(·tllllill ~ concentratiun ill blood. nn e
o htain s, h.' lh '/lllitillll . lilt' \ ;a] Ill' IIr dt'a r,lIlu ' (CIl<tp. :31,

Clearance ,. 3

in l hb instance. bloot! d t'a nu Il't', CI'I,. ",illl't, tilt' ('tJ!ll't'lltmtio ll in hlood is llU"il"'Uf('(1. O n
slIh",lit tltill!! Ell :2 into E'I :1, dn ' 1'll1o\\in!! impurtaul rt·lalioll,hip is IIhlai lll'(l:

CL b o f
Blood Blood b troctia n 4
clearance flow ratio

TI Mt i"" hlolKI d l';lriUI('(' IIHI.'· IH.' rt'~al't lt'(l it-'" till' \'Ulllnl(' of blulKI Froin wIJil'h all tilt' d m~
wOllld a ppt';1f to l K' n-uum-d pt'r unit tune. For t'xa mplt-, if tilt' t'\lmdiun ratio (If a drug
;I('n "", all o f),tall is n.s and of),t;m hl'KKl l1nw is II / min, 111t'1l all d m~ ill 0.5 L nf lh t, ill(.,( )lIIi ll~
blutKI is l' ffl'(,tiw ly f('IIl(J\I'(1t'"d l minute as hIIKH.I p<l'S(" th rnu ~h tl u- n~;II I , Furthermore,
if tilt' artl'rial ('t)Il('('lllnll ioll is I mWJ.. tlu-n Ihl' mit' nf elimination is n .5 IJ rnin tunes I
lllWI.. or II.S Illwmi n,
nIIKK! d l'a riUlt't' (·<tllllot 1)(, allYvailit' , Exot1l1inaliull of Ell' .. shows Ih"t if rln- extraction
r.lti" apprnadlt's 1.11. 1111'1l bll KKI dt'ar.l1I(,(' a pp rnad't'S a maxunuru. organ hltKH.l lItl\\'. Fur

1 Mass Balance . ·i!l:. I I -I . 11M' ....I r.'di..n ..f" , lnll1 l~' a"
.· Iilllinaliul': "'1t"" tlIKlo'r ,It,~· .•t"h' ''OIkl; .
I;' " .. u"'y 1M' (~" ,.;'Io·n·d frulll tiM' fu)MLouM....•
1..1UMI('t'p!'''( II I..J",II...., I. ll M· .... lr....1;.MI
of ,lnllo: n..... 1M' "' ,,"'11.. 1fill" frum it> r"I,.. in
~ .IlKI ' MIl .. Ih,' ..'1t"'I. 2. ~ ' '"'w1U:inl1l .. 11M'
i
Rate 01Ent ry Rate of Leaving r"h- " f .·nll)' ro " i<Io.. " IIK';,.n' "f ,101''nnitm'l1
• ~ 11K' (""'1;'.., ....I ""'1 ''t1. II..• ..'lr 1im' r..tio, 3.
o-tc.c) ~ "n,w1 i7.inll: I.. II .., t"1'I1·"; n~ ( n ll ....I ;.,,' ..J.
10"". ' '' M' 1<1 ....·u ""'1 for 11K' ,Imll:in 1" n,1' of
Rate 01Extraction
(·Io'ar"'K't' ..".1loIo ul It<,.... n..· '~lllIM .t. an' ,Io~
2. Mass Balance Normalized to Rate of Entry litK..1in E'I" I II,o .,, ¢ , -I,

• ~
E
Extraction Ratio
3. Mass Balance Normalized to Entering Concentration

, ~
(JoE
Clearance
 160 CHAPIH 11

kitlllt')"!' ,mil lro -r. tilt" ;1\l· r.I~(· ur~a ll hloud flOWl; an" 1.1 alltl J.~ Il min (Tahll' 10- 0 ,
rt·Slk"'l.1in-ly.
I ~ · flln · ('t)n si{ I( 'ri n~ dt'anUll' -'(If {I n l ~ I,:,' Spl"'l., fil· o~all s . seve-ral l1UIllllt' n b an' ill nnk-r.

Description of Oearonc, by Organ, Process, Of Sitt 01 Meosuremel'

( :It'ar.uI<.'t' (~ III hI.' tlt'..cnbed in terms of the d i llli llatill~ o~an , ('.~ .. Il t 'l l; llk clearance. n-nal
dt'<lra nn.', (I I' pullllo na r)" clearance-. It can a!!I() hI.' tlt')(:ri ht'(l by lilt" dirrt 'n'lll 'l' IX~l'('1I
n -nal r-wretiou .md e-limiua hou hy all otlje- r pnx'l"S....-s, l· .~ n -na! .. d"a"'' I""'- and ('\tr.IR.' llal
(:!t'ar.ul<'(', How all n~all d c·an. tilt' blt:llJl:J uf (I nJ~ mav at..., ht' IIt"!O(.Tiht'tl h,.. tilt' nahan- of
ti lt' (·Iimi llitli n ll pnll,("!>." , t o.~ •• 11\(1aholic ck~d. ...a IK,:or ('~l'WIOf)o' d t·arllJ)c., ', F l;rthc·nJMln ·. the-
d t'a r.mn.' "al llt, tlt' pl'nds u n tlK' n ' f" n' II("I:' Buid . 11l1ls. to lit· "pl"l;f}l" lilt" d t·drdIK'l.· o f if.
dm ~ t·lilllilla fl..1., .,!t.. I" , lut'I"lw,lism in 1!K·lin ·f, t1S in~ pla...ma concentration nu-ar..u n-na -nts
",u nit! then 1M' Il«'flitliC mt'fahnlic plasma clearance. Similarly', ··d t'a r,u K,'l.· I,,· ewn-uon of
d m !.: " in the- kitllll'p would lit, n -nal ('«ni 0I)' pla,,"l.J clearance. III p rdl1in ·. tilt' te rm
I" II-"'Ul is tln 'l ~""l:1. a.. pla..ma is Iht· common sitt· of lIwa..u re nx-ut . In atklitioll. n Ut' o fll-n
drop-, "u1tJJt"ic Of n:cn101"J wl lt'u d t'StTih iul!: clearance I,,· ti lt' li\"t'f ami kKlnt.,." . n "Spt"l'·
tin,I) . I",'eall \(' tilt.,..· pnw:t"Sst"S ~(' nt'rd ll)' occur in tilt.,.., rt"Spt"l1i\1' 0TRans . lI owt,,\"(' r, 1I1t"-
lal-oul i..m tk","S Ut'Ctlr in ti M' kidnt"\'S, a mi e xcn-non (i llio hilt ' ) IItW"S 1"""lf in tI.., li\l 'r . 11M'W-
fu n ', till' ",',,,u lllpliun.. 1IIldl'rl)in~ tla- d t'a rdlK't' IlUIllt"lll-iatu n ' fUf a spt ·d fit· Ilm~ ..ho nld
alw1l)' hl:' flut ...tiollt.. J.

P10sma Versus Bktod OtarOlK1

FUf IIl;1n) ••p p lk<ttium ill plt .tnllat"lJkinl'lk s, it matte rs htt h- wllt'tllt'f d ('a nm t't' n a-asure-
IIIt'lIh an' l);,l\l..1 0 11 dm~ in pla...ma Of in blood. TIll:' l:'\(l-ptiull i.. wlu-n a dt,<trdllt't· value
i.. 11\(.. 1 tn l:·..tirnah' ('\ I mdinll rano. 11l1:'u till:' h ltnd ck-arance \11Iul:' IIIl1st II(' 11\( .. 1. 11lII"l,.ul\('
It i.. thi.. POlr.l lllt"tC'f Ihat dm-ctly n ,IOIft'S to 0 TR:m h!untl flu\\" anti (' \ l nK1itm mho (st...•
Ell ' . n
ph...,u, dl: 'amlln ' is llIun' fn'fllwlIl l)" n 'port,..1Ihdll hk lllli d l';IroUJn'.11ms, if em- ";!>llt's
til t'stilllalt' t'\Iml1inll ratio, om- 1It "t.. L.. to l"OI1 \1:"rt t hi.. dc'ar.lItl't' \ 1J m ' lJ;l'i.t..10 11 dm!/: ('t ill ·
l't ' nl ml ioll ill p l'l""''' tn 1II1t,I);'l'i.t"t:1u n III(' ll l1ll't·lItr.ttiu n in bInIIll. ll1i.. l"lUi\"l:'rsin n i.. a('('IJIlI-
pH, llc.. II ))' C'\11lII'""\(,lItall)' dl 'h' nllilli ll~ tilt' hl'Il",I-ftt-pl,t.."", t."lJlll't·" tra lio ll rollio. S inl'1', I,)"
dl:·fillitio ll. tilt' prtllllll1S of tilt' f('!ipt'l1in' dl:·ar.tIIt.'t' an d {"lJlll't' IItralioll It'n ns, h .l'it"t:1 011
IIW;tSlIrt'lIIt'lIls in h lntlll a nd pl;lsllla . a rt' ("tilial to lilt' ralt' of l:'lilllillalion. it follows tlrat :

Plasma clearance Blood concentrotion (C,J

5
Blood clearance Plasma coocen ITotion fC)

11 lc' (lI l1('I'lIt m tio n mt iu is a fum1inll o f tilt' IWlllatot.-rit alll i of tht, hill(lin~ o f dnl ~ 10 IIlJt"
ph"lIlit pmtt'ill.. ami h llIlJtIt.'t,IIt."lJlllpolll'nh. 111t' n ·l;ttio mhill is tlt'ri \t ..1 in App,·ndi\ 1-(:.
St nm~ hill(l in~ tn p l;l\llIa p m h-ins p n lllu('t'S a mlio 1l:'Ss t1..m 1.0 " it " :1 IOWN lim it o f
( l -hl:' rnalnl'rit ), wllt'll dnJ~ is n~trit.11 ..1to p la,,,,,,_\\1M'n h;lIdill ~ tn h lllllli t't'll.. i.. ('\h'ns;\l',
till:' rotlin IJldy ht, mud l Jl;n 'alt.' r tlra n l.fl,

Additivity of OeorOIKI

111t' all aturn~' nf till:' IU"'I ,UI I w Jt ~· Ilil1ah-s th at till:' dt'ar.Ull'1' of a dn l~ I,)' UlIt' 0TRall at ltL,
tn d ,·ar-uK't· o f ;tun tlWf. Thi.. is a t"l1ll'it'fjllt'IK't" of th t' dmlLatioll. ('Alllsidc'r, for ('ump ll', a
ll nllt Ih al i.. d imi ll;llt...1 I,, · lJolh n 'n;tl ('x(n 'l in n dlltl hl:"P',til' lIll:ialll, lism . 111t'n
CHAPTER 11 16 1

Rate of Rare of Rare of

elimination = reno! excretion + nepatic metaboli sm
6

Di\itlillg, tlu- mh' of n-mcval a...so<-iall-t l "'ilia ('m,.-II p mc't:'ss hy the illl"llll1ing, dnJ~ coucen-
tration (hlood nr plasma ], whidl for hot h orga ns is tilt" same (C ), gin 'S tilt" clearance a.s-
sotiah-t1 with that pro{"l'ss:

Rate 01 Role of Rare of

elimination renal excretion hepatic metabol ism
C
=,,-,;:,==
c + C
7
T0101 Renal Hepatic
clearance - clearance + clearance

Thus. total ch-arance is the Slllll of tilt' clearance s hy each of tilt" diminating organs,
" ('{'all"!' of lilt' atltlithi t)' o f d earalll,(', tilt' n 'lath":' contnbuuon of an~' o~an to drug
cluninunon is readily m l{'ulah'll. Fo r ('.'(;Impl(', tln- Fract ion of drug exert-ted unchanged
(t!esig,nah-t1./i', SI.'1' Chap. 3 ), "l'i n~ tilt' frd{1inn of total elimination that 1M."l.' ur; via n-nal
cxcreuon . is jus t renal clearance d i\idt'(l hy total clearance.
Dill' exceptiou to lilt" addithit)' of d eard ll{1:' is pUlmOllil!)' clearance. This is din- ill part
to til(' blulxl sllpply to tin' IUIIg,s Ix-iug in series. r ather than in parallel. with ot her o~ans
of r-lunnuuion ;tlld in part to tilt' total cardiac output p'Lo;sing thron gll tjn- lun gs lx-Fon-
n·adling till' sill' of 1l\1"lO;Un'I!Wnt, usually h lolXI in a peripheral vein. TIlt' ccucentranou
m(';t\ tlH'{l is that It'a\i tl ~, rat her than ('ntl'rillg, til(-' lungs. TIlt' lise of thi s concent ration to
( H,Ill-lI lah' d l'alallt1 · is in("l)llsish'llt wit h its ddinition {see E'I ' 3 ), Indeed, if thl' pulmowl!)·
extructi ou mtio is h i ~h , cleurancc vahlt's {';l lclllat('d in tlw usualmanner lIlay ("'l:'11 ('xl1't'{1
ca rdiac output. Illakill~ interpretation problematic.
Cll'ar..l1ll"l's of dmgs by the- her-r am i till' kid lll")'S an' now cx armned. Each o~all has
SIIl"l.1a1 auatonuc <t!ul physiolo¢ c fea tun-s that req nin- its st'pa mte consideration .

HEPATIC ClIARANC!
Althou gh dm~ lIwtal Mllism ( H,I 1l takt, plal"l' in lIlany 0 'l!:.IIlS , till' lin 'r fn '(lllt"utly II<L\ tilt'
~n'all-sl mdalMllil' (~olll<l{'i ty and {,(lIlS('q lle lltly lias lx-en Ihe most t h Oroll ~hJy studie-d. 11 1('
most di n -ct <pmntitat in' Ill('a..u n - of the liver's abil ity to d iminat(' a dnl~ is hepatic d ear-
unce-. l k-patt c ck-arauce Includes bili<l!)' eXl'rt' tOI)' clearance, whlcl r is subSt'(!tll'n tly d is-
l'''\SI.''l1. ant! !tt'p'lti{' 111l'Ialxllj(' dl'ar..l1ll,('.
As \\i th orln-r o r~<ln_s of elilliinatioll, IIII' rl'IIlIJ\';11of dm~ by till' lin'r lIlay Ill' nlllsidt,rt'{l
[mm 1ll<L\ S ha lam'(' n '!.ltio m hips. Th ai is,

Hepat ic blood clearance '" 0H ' EH

Hepatic Hepatic
8
blood extraction
Row ratio

II N ( ' VII is tilt' sum nf hepatic portal and h('Il<ltk arterial blond fl ows , for which a\"t' m~1'
vuhws an ' 10.')0 and 300 lU I/mill, n' spt'{1iwly.
Perfusion, Protein Binding, ami Enzyme Activity
T ill' fol1 U\\in ~ priuciples, rt'l ati n~ ehall~('s in clearance- and extruetion ratio to llltemtinm
ill j'lI'rfllsioll, ploLSIlI<l protein hilltlill~, or lnhen-ut elimination charact eri stics. appl y in ~('I1 ·
r-ml to all 0T"WIIlS of elimination . TIlt'S(, principles aIT'exemplified here with ln-patic cxtrac-
non.
'.2 ' ' ' ' 'OON CHAPTU 11

P..· rfu..ion. At I,·,t>;l fi,,· pnll'l'SSt's.;I.>; shos vu in Fi ~. 11-2, lIIay afTt·c:1 tht' ahility of th t·
hver In ext ract dnl ~ fmm blood . I! uwt"vt' r. wlu-u ti lt" Iwpal k c·.\ tmetjnn ratio app ruad ll's
1.0, tilt' drug must haw !lild suflicit' nl tune whilc' in the her-r to partilioll out o f tilt" blood
{'(·II. di sso d .lh · fmmillt' pl,lSlIlil pmll'i n. !liLSS I hm ll ~ l til(' h l'Il;ltic meuibnnu-s. a mi lit, dllier
metabolized by a ll ('1l Z)1 11t' or transported into the hill'. or beth. AI...o hluod dC'afiUl l'l'
a ppn);ll·h,·s it s madmum value, hll );ll i<-' h lo ud flow. U nder t his co nd itio n . dim illa tio ll ts
rate-limited by pe-rfusion and 110t by the spl't"tl o f any of tln- p n ll'( ' Sst' S dr-pict ed in Fi ~.
11- 2. C h:mg:,'S in blo od How pmd lll't· co rn-spondtug d lanp;t·<; i ll l'!l';lralll, ' and nih- o f
elimination. hut llil' ext raction ratio is virtual! v unaffected . III cont rast. elimi natio n o f a
t1nl~ \\i t" a Inw ('.'<!ml1ioll ra tjo (ilppn);l(:t.i ll~ ;A,"m ) mu st ht, r.ltt"· lilllitt'll l>l llllt'w !ll'n' t"IS(,
in ti lt· on-mil Sd lClIlt" (Fi ~. 11- 2).
\\11('11 the t'x1md ioll rat in of It d m R is low, Illl' \'('1I0US d m K comvntra nou is \i rt llall~'
id,'ntil';al "illl lilt' artertalconc-ntranou. hy defin ition. Therefore. dla ll~l'S in hloo,1 f10....-
should produce 110 d l,lUKl' in lilt' dnlKcoucentratton \\ithill tltt' u!"K" II, ill mh" o f (,limillatioll

nil:. 11- 2. Dn 'l: ill hIo••1 i. IU II..l tn Ill<ul

....11.
11); I"M
(1"
(1"""'." <I) Illld to pLa' '' ''' I' " ot.-in. (p" ,,~ ....
W . it i. II... lInl" "n"I .lnll: It.;,d <!i!Tu..-li
t"l lnlo II..· ""1""'1'''"" ", WiThin tI,,· I..··
p"'I<ot)'''. II ""l ot..,r,,1c1n lj{i. "110;..1 1" Tt·lic'n
Blood
Q a Unbound b Bound
~ .=;:- 0r~cg -=== Drug )
inlo hi!.. (1"" tI ) o:r In ''''''TJ... li(- llitot " . fnr·
'I
m..lic", (1m ). n ..· ""-1;d.,hh·Io.·.,~ .. " ..· 1.,. Hepatocyte Unbound ~ Metabolite
Drug ..
pal' . ')' .. . i.IIl,j, u l ... hilt· ur il l• •UI>jt..1....II" Iur-
11. ·r 1....m. rOn llahon ,
Bile

15 Lidocaine
Colloidal
'2 Chromic
~ 10 •
Phosphate
§.
~
u
c
e
1 5
u

0
--- . • • Antipyrine

0 10 20
Hepatic PerfusateFlow (mLJmin)
. '11/:. 11-3. ( :m" I.." il.. .J..III .a.." ,i"l/; Ih..1 II. · .. ·,,';t,, ;t~· "r II..· <·Io.·;or..r.. ~· "r .. l"" u," M" .. l t" d ,..r,!t,,,, In h~ ••1110 ,
.~. \\, ,,.,, M.t n.d i".. r.d i" h u, n wid, 1I" lil'yri ll" i.'. d.-anu .. o· ' ' lU.. 1i, .. I., " ·lI<lt·" , or 1o~ l ll ·.
CI.- ...-it.. I.. <li n"" pn,.. lrt i..n 10 110...., r..,,· r,.. l it~ ..-..i'''· I. ). Ii <In.!t .., 111 a,n .. "lr...1itM' r..lit, d' · I.. I ,O.
8f-to,o ·n tI · .·"1",,,,," i'l<ut" litld d lro mit · pI....pI...t.. Ca.). TI..• ('Io.·....,.r • or.. h it'" II" "''' ,"",'.~' fn 'IIl " I rf",.jcon -
"'h· li",ilalit.n '" hi¢ r fl,...." . ., " ,L.I... " l ot;oi,.. ~1 ill lUI i."t.t...l. j..-rfu I ..t 1I"·r. I.."" I,,,,·1O nlln ll,t1m lln a 11).1/:
Ii"",. 11M. Ii..... " ft" d n j~. •.,..... IOala "1.. 1......1. ...1 rn ....: :\ Illil~ri' ..• a,,,l litltr.i,.. ' - l" lTll'- ":.S. iII..1 " ·Lar..1. \ 1.:
lI '1"'ti<- <~a",,,,,,,,,, "f til'llit' I. J. 11, ,""-"oId". 8 i" p' ...n " " SJ'.'i.U ...o. 1117':', C.. ~ ~oi< W d ln ""it· pIM ""W'.&l,, -li r.,,,·r.
fI.\\'.• 1..",,,1'- G,.... \kEl",~' Jr.. R a,..I II , ~ kJWay. fl. J.: C ln "bh "') l"'I I".;o~.. ill tI..· r.d Ii"", ... n...·. "... I I~· :1;/1'
d1l't 'mk 1'1. "1'",",1" <",Ik-,itl "I't. t.r h, II... i." I...."I. 1"·rf".. "I I;",,, 1'1I'.........icM' ., "'. j . 11'~"i< " . 11> ' 511'l~')!)'j. 1\;l.'l6.)
(l-WTEP 1 1 ELlfI.',lNATlON 163

or hy d(,fjnilioll in dl'ar ,lIIl,(', From Ell_S, hm\'t'w r, it is M't'll tha t th(' he ll;l!ie ext raction
ratio vu ru-s illH'rM" ly \\i lh hlood UIl\\' wlu-n l'!('a nlll{'(' is constant. 111t' S(' expect attons 1"1' -
~an li ll~ jll'r fusioll for d nl j,ts of hij,th ami low ext raction ra tios lift' iIIustmtt'tl ill F i~. 11 """,,1 .
Bl'p n 'S('ntatiw d nl ~s and 1I1daholih' s \\i lh low (It'SS thun 0.3 ), illtt'nllt'tlhlt(· (0 .3 10 0 ,7 ),
and h i ~h (!-:n 'a!t' r Iha n n.7 ) ('\lnu.1 ioll ratios in tilt' llvcr an ' lislt'tl in T nbk- 11- 2,
:\ wenl of cautiou is T1t't'tlt'tl hen ', :\hh()u ~" mass-bala nce pnlldplt's sta tt' Ihat d l;U1~t'S
in blood lIuw an ' !lut expect ed to alft'r lilt' l'!('amn('(' o f dr ugs of low extraction rat io, t111'n'
art' ph~-si llll ~~k lIlt,(..l.anisllls thai llIay St,(1 )l\(laril~' p roduce such an ('fT('(i:. Examples ,m '
thl ' pn ',"'ll(1' of hmTlt'tJstatie cont r olmec hanisms and a IlI'rfllsion .lillli h'tl supply u f cofac-
tors such as O\) "J,!;t'lI or sulfate.
Bindi ng WUhin Olond , For a d nt~ with a lugh t'xlm<1ioll rat io, lilt" li\"t'r is d t"llrly
(~Ipahlt' of fl'lIlminl: ,JI tilt' tlntg Pfl-st'IlIt'l1to it ill spite of hilltlillj,t to blood cells ami 10
ph..nM proteins. Haft' of t'li lllilla!ioll de-pends Oil tot al concentratiuu in hloud , Ct' rtainly, a
dt'l·nw.t ' in binding aids in n 'll1o\ing a dmg; hut ill this <'a.\I.' , it is cSM'lltia lly all n-mocr-d
auvwav. T hen-Ion- Ilt'itllt'r t'xtmli:ioll ratio nor dt'a nUil't' is man-ria llv afTt"l1('t! hv d l;lIIgt'S
in 'h i ll~l i ll g. • .
Fur a d mg \\i th a low extracti on r atio, clearance tlt'llI'ml s Oil plasma prote-in hilltlill,i:
hl't.·all"l' only unlllJIIlld d mg 1'II ' I ]('t ralt'~ membranes and is available fo r elimination and
111.'1',11 1"1' 1111' limp iii t1 m g ('tllll't'lllmtioll ,K' n JOiS tht' [ivr-r is small. The 1I1llll.JIIlHi coucent rution
ill plasma Il'a\ill j,t 111I' liver is almos t Idr-ntfca l to that ill the ein1 11ating p la...mn. Cu . Then
the mit' o f d rug t'li minatioll ill tht' !iw'r is tlin'l1ly n-lated to tilt' concentra tion of dmg
1l 1l1II. llluti ill 111I' ctrculatillg plasma. ,'\(-u m lill!-:Iy,

Role 01 elimination - CLu Cu

Clearance Unbound
bcsed on concentration. 9
unbound
concentration

T.It•• 11.2. Hepetlc _1 b:tr.ctI_ epre _ 0-, ...

M . .....n....

~O" i "
O~,,,od ne
C~"<!
N!~,o'r~
No<':llpl'J!,roe

Amol<iciMin Am,!o<orl<>
Cvrenove
"""'*'
Cefa1:oI.1'l Cephak:>tr.,,,
C,proI\o>cOCll'l ~o" 'od''>e

""""'"
FUI'~de
Genlomi(;in
Llmi.",..
Tel!ocyd,ne
 ' 64 Cl-W'Tt R 11

E\lm· , ..ill~ till' rail' IIf Ilt' p"ll k- t'limillOlholl n·laliw· In till" plasma ("1I11('t' nlmfillll. it h il.p.
pan'ut lll,,1 tl.t' IW!'J;lti l' p la\IIl<l de,mllK'" '\ 1Iri('0; p ropo rtiona.l!} with dl;U1~I"S in till' fr.u.1ioll
1I111)( IU lld .

Hepatic: cleara nce - CLu fu

Clearance Frodioo
bc sed on in plasma 10
unbouod unbound
concentrotion

For ('\ampl,,, if/II \'aril"S l:\\ufll ili . '\01:) d Ol'S h(' I);Il ic {:k-arann '; tiM' IIII,"OUIIII d l'arAIK"I' n.·IlWII.'i
1IIll :llallJ,:I't1.
TIll ' ~ 1.lt;1 in Fi ~. 11-1 oh l ailH.'c.I in tht' isolalt'tl. pt ,rfu\l:"(1 rat lin'r. iIIu"'rah' ,lit' points
liMIt.:· "ho w . In ,I.i.. preparat jou . prrxein hilJ(lin~ can l)t° n'adi~' alIN\'(II",· dl.an~n~ liM'
(ull('1'n l ml ic lIl uf tl tt· hil KLn ~ pml t"in. and pt·rfU.'iioll can be Ilt"kl (·(In..tanl . \A IIl"itlt' r fin!
lolhul.nlJitk ', a d nl~ o f kM' ( '\tr M1ioll ( "\ 1.'11 ill tIlt.' al"" 'IK'l.' o r hillllill ~ ifll - 1.0 ). As l "·
pt 'til"ll. tht' (·\tr.K1icm mHo (ClIKI d.-ar.ll K"t") o f tolhutami(k- is di rt't.11~· p mportimliJ to Ill.

Propranolol
1.0

Diazepam
o
~ Phenytoin
is 0.5

J
Tolbutamide
o
o 0.5 1.0
Fraction Unbound
.'ll;. 11-4 . ( ;'''''1.'''''''' m.·...',b llt. • 4ot;li'lt..1ill ," , I"' ..ItI....l. llt·rf" ......I .... IIi -.. , . " .......; "lt ll...lll... "'·n.il "1 1~· ..f llt-patic'
..... r;ll1;.." . ..u" t.. d ,,\CI" In frood ' "f (Ino~ un l " ..1';Inc .. , Ell r;ll1M"'I'lIIM. I'I'" '1".r1M,md I" fr;M1i.." .. "1 ,,..1
""I~' .. ....." Ih.· 1...' ....u" , 11.. , 1' ''''r tl..· " nhn' n"",,· "f t.ir..I"' J: fur 1,.11..,1,"" "", (T f 1..11 ~'
,"'.• It 1i""I,...1 "",,,. fll' ,Ii""' ,,,,,,, I.: .." ,I 1 ·"~1l1in (.'. \\1..." tI,,· .·'1.....11<'" r"'i" i. " ,"',. _ ,.., .. ,n .. ,.t.
1>I "'''~1' ''" ..,,<I ,11_"..,,, Itt .....' loi,..1i1l1( ,I wrth pn'f'O""'&<l1 (0) '"' ..II ,I.1I:n..... ,,{1",.. Ii"J: ~'I<""1. 1_1i" "
r..lI" i. n ·I..I1...ly ' n" '" 'I''' '' In d","~", in f 1" ..1 " nlu"od. S lllir.... t1..t in tlu' p "1>.lr..h' '', . In ,,-hod, ' fr;ll1I<'"
""lu"..1,. ,·..,......1'"'''' It ..;, ... nu,l('I ' ~ ' lif~;,,1/, 11..- (,,, " ,lralll,,, ..f "".,m in. II ,.. linl!, I'"".-In. • ,In,l!, ......
... ,w., "...., 10. · .·I " lo,....1 fn ..n ,......"I hi""I "I · l r;M1..",- n .... " ".11,,, n· d Tt '0;' '~"" . (I ) "'"
.J",r 1 1 fnn,, : 11 " 1' ..II-!\I"',..I. U C:.. C. " I ", . R.II 1 Wil~im..n . ( : ft.: 1·..rf".it ·I" nilo..J .,.{Tn 1. "I
l>l.t, ,, ,Inolo: I,;,...."l!,.~, 1"1""1;'- ••..1_1....' . uf.· SU.• 111:1 2.\--1.-'1. 1Q7fi: Di...p''' I-- H.c ... -t.....I. M . ' '' 'lId. . u ..
~....."U1~ <: . ..,..I !\1I1l11.. Ii .: !'n"r in 1..,tt1'I("'od h.1""'",. d.·;oant..·: U...(Tin,i "..h'"' I..~, " 1. , ,{ I" ,,,,, ir.·
t·. ·ar..' · "'11, ,I.......,"'tn. • •In'll: .,{ l>ilo1t inlrin....· dr..n.o.. ~. ill , .... iKtl.cl•...t. l"·rf"......J ..... I" I..........,.,.liun. J,
11....., oL,..1 B.. ,>I","".. '21~ · 1 -li". I 'M _ TolI..rt... nioJ..-s.... ...r:-.W.l- H.c ... L.ntI. M : I,",,<'i" ".",lin"
....,II..,"" · aI...." ~h..tin ", tI, 1",'h" llltnidr. a tint( "j 11... inl rin in II... "'tl.cl..... prrf" ......J nI
It.... r ,...,....'"' " 11"'",......&.in . 8 io 'ph........ I I :tz\--W . 19'i3. Pn'l .w_ J" '" lU I . Chi'llt- M ,~ .. S.....n .
....... ..l Ii..\ od \ 1",,,, ,. n J : \ twn."'·p""n" ......,...... it. noll .. P""'"I",ul" f,...... ;,1 1"1"'11(' ..h'"i'llll i
h,lo1t~ 1...., 1 n""I" k .\ .11..1\ "j
.5 .'§!J1l-,'>Y.1 , I\t>r.'!> I
pn,.........
>1 ,M'uu.......'" tJ;.. II...... .t.....t. p.-n"....J ..... 11-..,., Il.,....t< >&::!'·•
CHAPIH 11 ElM NATI()N '65
TIll' llhsl"",ltinns with di :v,l' jl;\IU an - ill ll lll i nllti n~. 111l' extraction r atln (am i d ea nlllt,.·)
dl<\1l ~l'S [r om a \ .11111' d OM' 10 I.U (ill till' absence of bimling,frt "" 1.0) 10 one d ose 10 zcm
0 11 d ( "'n'; Nn~ till' fnl(1ioll unbound. C ll·;n ly, pllltt'i n hilld ill ~ ca n limit extraction if hintlill~
is high l' llImgh. Howev er, tllis snnatton is lJolip hysiol~e ill th ai tilt' fraction unbound is
vilrit'(l llt·tWt't·1l I .U and 0.05 . a 2()..fold ehangt'. III practice , a t1m'(·fold d mllgl' in [u wnuld
lit· l,msitlNt'tl pa rt it111arly b~l' for a drug bound to album in. UIIlIt>r IIll'M' mort" n-stncn-d
n mditions. till' l'~I It '(-'ft't l n-lanous hip between d l'anlll('c am i/ II holds. 11111s. for diuZl·jla lll.
iu tilt" rt1-.';o n when- extract ion mtio is low (I1}\\'fi,). clea rance is din-ctly pmlxlrtionaI to fit.
At till' otlll'r r-xtn-nu-, in till' rt'¢OIl wllt' rt· tln- l'xtmdinn m tio is high. d (';lnul ('(' \<t rit... litt!l'
wi th a lllotlt' mh ' (: ha n~{' in I".
E n7.~-Il1t' ;\("( h;t~·" :\ ~ stalt'(l ahow·. .....lu-n cleunmce i~ Ix' rfus illll rwe-huun-d. then- is
Sl ' nUll'h Iwpatot, ·Uub r :ll,thi ty th at Illocll'st d m ll ~l's ill tMs a<.1h i t)' cralI St' hu ll' o r no d lan~l'
in d t'anUlt'('. Almos t all tilt' d m ~ is l·stm<.1I'tI 'lIl}w:J.y. Conversely. if t'nZ)l n(" ;u..1 i\i ty is th t,
nlh·. lim iting slt' p. tln-n d t'anllln' is 10..... and directly proportional to ;ll1hi ly. e.g., Will'lI
(' hall~t·d hy induction or inhil utinn hy anot her d m v;.
~l m t of our p n-wllt knowlt"llgt' of t'nZ)111e kiuetics is dl'r1\'f t l Imm studies in d tm in
whklt ' lIhs tr;I!t·. 1·1IZ\11U'. alld (1lfat1n r lUII('(·utmtiol\.S an ' con rmlk-d. Corn-lanou uf Sill'l l
StutHI·.' \\i tll thost, pl: rfnrllll'ti in ri w has 11e't'1l diffil111t . ~l allY fa(1n rs an:' in\'ukt'tl i ll !:i n )
that cauuot IIC.' isolated. S I·\l,rt l\{'ll'ss. tlu- ha.s ic principles of l'lI7.)lll<' kinetics have applt-
('ation in phan llill"kinl't it"s .
1111" llppl 'r l'III"\'(' ill Fig. 11 -.'> is d laml'kristi<.' of metabolism II)-' a ¢n'lI t'UZ)'IllI' both ill
d tm am i ill I'lw. The hl'h adur tlisplay('(I, typic....1 of ~ 1it'hat·l i s ·M {' n h· 1l kint'ties if tIlt' all"
p mad l toward till' maximum rate. \ 'm, follnws th t' rela tion ship.

. Vm ' Cu
Role of melobo ll$m ., K C II
m + "

ill whtch 1\.11/ is a constant, till' ~lidlat'l i s· ~ l enlen constant . In 1;" 111:)111(' kim-tics tlu- m llli'
u f \ '1Il is d in'(·tly p rupu rtillllal to ti ll' total concentr ation o f en zyme, an ti Km is an inverse
fUlld ion of the affin ity IM'tWt'l' n dmg and 1'1lZ)1I1<'. :'\ot t"in F.fl' I I that a value o f ell t"fPI<U
to K". Kin's a ra te- th at is one-half tht' maximum ; this is a l'lIIH'nit'nt ,......1)' of dl'fininv; tlu-
l't" " lan t. An ('stimah ' of tilt' t rue Alii n -qnin-s nn-asun-meut of tilt" 11II11e 1llnd dmg roncen-
truuon al tilt" lI11'tahnli 7jn ~ t'IlZ)'IHI' silt', Lal"kinRthis cap;lhilil)' j'l <"iU I, till" unbound ph~ ll1a
(111l('C 'lItratintl is t'III\'l'ntiollally UM't!. AI unbound plasma t't)fl('('nt mt ioll s well lx-low Am ,
whic-h apply to mmt d nJ~s use-d tht'mp,·u liea lly. rate an d couce ntranon lOU)' in direct p m -
portion . At {'(ltll'C'ntmtiolls ;IIMI\'{' Am , the run- app roaches tilt' m lut· of \'m . Sinl'(' IlnlxJIlml
lIlt'taIMllit' d t'a r;Il11't' is tl·fim'tl iLS thl" r.llt· of 1Il1'talMllism rdati\l.' to thl' unhound pla.s ma
l'tJllt'C '111ratilnI,

Vm
12
Km + Cu

Its " 11m' dt't.' n ·;L'it'S at t1 nl ~ l1l11t'C' utmtiollS app madli ll~ alld l'Xl,( 't'tlin ~ till' " lhlt" of 1\.1/1 .
Th is is shO\\1\ in the' lo\nor part o f Fi ~ , 11--5. S ote Ihat the hiJ.,1fll'st d l'anllll't" is tile' mtio
\ '". / KIII . a \<lluI' "flt'lI {'alll't i the i' ltri ll.si(' "u1abo{ic c/t·arml( "f". TI ll' ' '31ut' may hc' so h i ~!I
tiM! l'l illlinat iotl ill !'it.., is ('IN fusioll mtt' ·!illlitt>tl. Tk,(~<l Il Sl' o f tltt' l'Cllllp l('xities inin-dll l't't!.
till' at1l1l inistn ltioll o f dmgs s lll)\\; n~ satumhlt· IIlt'tal MJlislll at t1lt·...d pt·u tk' l' ltIl't"Jltrat ioll s is
di ffit·ull. l1 ln lllgllC lHt tIlt' w st of tilt' IMMlk t' Xl't"pt C llltp. 22 Oil Dose." :uu l T imt· Dt·llt·ml-
eTldes , d m~ lIlt'ta lMllhm is lLsstllllt't l uo t 10 slluw satu mhilit\' .
:\ Ml"IIl~)ry' Aid , TIll' ~ell('r.ll p r1n<.i p l("S ju st dise.'1ISst'tl 'l~..n ht· t1illkult to n 'Ill' ·IllIIt·r .
~ I I M I. 'I ~ I,f lll'pOItk 1,Iimillation !JOIw"IIe"('1I dl,, 't"lnpt 't lto 11( liln ti~\' d mnges ill d t'ar. lTll,(· wht'lI
'66 CHAPTH I I

Vm

Rate of
Vm-Cu
Hepatic Vm Rate =
Km. Cu
Metabolism 2

. i,;.II-5. \\l,,'n I", >;ol k mo1:4I....i~m r,,j~ "" ..

\ h :h...·lis· M,""h·!l "'in<"fi<.~. tho· rah' tlf m..t"I. ..
1l\l1l ill("ft·;a.. .-s (" 'I' 1o:r.'1,h ) ,,,wlInl a Ul<W mlllll Km
,,,t,,.,, \ '''1, ...'
tIlt- pla' m;,. ,11"11: (''' ll, 'ul r..liu ll i.
Incn-ased. n ..· (uK't'nlr.. tiu ll " I ",hid, .I..· rAil ' i. Unbound Plasma Drug Concentration
< ~h;</f ,he· 1lwa.U"'"1ll i. II..· K", ,ll!,....
TIlt' UIl -
" mo.! " :d" J1ic d .'llr"'''''· (1• •Uu", W"I,I» fall, Vm!Km
will. j n('T1~ <iIlt: .Iml: n >lK't'n troltio..u . n ..,......, ..,-
Irollk ,,, at ·Md , tl..• clo·ar,uK't· i ' tlllt··luI ( tI...
m.n i ll lllm i. a1... tl.., IV" \01.1 ,.... The ''fl' '''litl'n
fur II..· " ·JoIlie" "I,i," art' ,I" ....~, _

Hepatic
Unbound Unbound Vm
Metabolic Clearance = Km + Cu
Clearance

Km
Un bound Plasma Drug Concentration

p.orfUSiHII, p la.~lIl a p rotein h ill(lilJ~. ami .·1IZ)"1I1(> act ivity ;!n' aln-n-d. Om- of IIIt'M' llllMlds.
the 1t,'('ll·,dirn.,,1 "u)l/d , in wl.i(-h instant aneous andcompb-n- lIli.x i n~ occurs withi n lilt' li\'t 'r,
is part it'u larly attractive because it m il « 'atl ily II(' t1l('S(' pn ncipk-s. Even
11.\ ('1;1 to SIl Ill Ill'U 17.('
t holl~h it lila)' 110111(' qua ntitat ive, til(' model allo w s to p n '1.lid: th uS(' siluations ill whlch
OIll'
eitl l('r clearance or t·xtr.l(1iOIl ratio is " fft"{1('1.1 allli ti lt' ('.xp('(1('1.1 drrccnou o f t:ha ll~("
TII(' well-stirredmodel states th ai

QH • /vb . Cl;nt
13
Q H -+ fUb ' Cl;nt

when- Q'I is ti lt' Ilt'patie hll. MI fill \\'; C/,,,,. is tln- tntrtnslc d ear.ul('(· that n-lates rute of
metabolism to unboun d concentration ut the ('111.)'1111" silt·, illltifi l/t is the- fml'lio ll unbound
in hlood. '01(" hepatic extract ion ratio, CI' b." IQII' i.~ then

14

TIlt'S(" 1\\11 equations haw tilt' desln-d p m pt,rtit's at tilt' limit s. Thus. wln-u 1':" ap-
p rnadws 1.0 (tilt' pe-rfusjon mh··li mitt'(l l"omlitil)n ),fi'/t ' C/ " ". is mu ch ~n·ith· r tha n Qu,
CHAPTER 11 ElMNATI()N ,.,
and l'!t'ar.ll1('l;' upproacln-s Q" (Eq. 13). Changes in Cl~,." a ndjil hen ' art' lJOI I'xlx't1{'(1 to
illllllt'!lt"-' CI./1 and Elf much. Conversely. when EJI is small. Qu mu st I ~' muc..h great er
than jill> • Cl~"" . :-':uw E" a nd CI."J! a n- approxinuued hy jill. . Cl~,..IQI/ a nd fill, . C1......
n.'Spt't1i\l'ly: lilt' \<llm' oftlw l'xlr.K1ioll m ho depends 011 all three factors . wlu- n-as clearance
tlt'lx' nds un ly OTljill. and CI.,,,,.
Equalion I.J olTt'r; an explunation for why Ihe e xtract ion ratios of must drugs appt'ltr ttl
I ~' eulu-r [I'W (E" < 0.3 ) or hi~h (E I/ > 0 .;). Suppo se, e .g.• that tln- he patocellular activity
(jnlrinsil· dt'arallw ) varK'(l t'vt'nly from 0 .01 10 100 U m in allloll~ a Illfl{e ~mp of ccm -
pounds. i.e-.. OW'f a IO.CX)()-fold mn~t' , am i tha i none is bound in plasma Ifut. m: !.O).l1lt'1l
slIhsl ilnt ioll of Illt'se vulues inlo E'I . 14 shows tha t only those drugs wtt h an lutrt uslc ch-ar-
,lUt" in lilt' narrow r.1II~" of OA3 . QII 10 2.3 . QII ha\"(' an mte mn-diate extraction r atio.
l.e. v" ItIl'S l~otwt" 11 11.3 alld 0 .;.
Stril1 ly. iLS whole hlt ~~1 t1t'liw'~ d nl~ 10 Ihe llvcr. Ihe Iracti on uubouud ill Eqs. 13 ,Iml
14 should n..fer to Ihat ill blolMl nnt pt l.s ll1a. For tlitlal1ic- pU'lx)s("S, hll\\"("\'Cf, here and
t hmll~"o llt n-maimh-r of tilt' lXIl)k ..... lu-n- Eqs. 13 and 14 are applied . the two terms are
t'(luis-alt'nt. A major d iS(·n o'lillll·" IX"(.llrs when till' blood -to-plasm a concentration ratiu is
mudl grt'all'f than I.

To n 'ill: h lilt' ~I'li(' r.a1 circulation, a t1 m~ ~'''-' n orally mu st ! liI.\ S thmllF;h Ihe liver ' ia tilt"
po rtal "plt'm. The fr.K1ioll ('s('wdpi ll~ ehuunation b~' tlu- hwr. F". is till" IIppt'r Iimil of tilt'
oml hitlilvailahlli !y. It may I ~· calculated from tht, IlI'patk extraction mho, Ell' Shl("

Maximum Olol bioo voilobility - I - Hepatic extraction ecnc 15

Hepatic edmt1 ion rallo run lx' (...tlma !I'(1if tlu· lu·'lillil- (bllllxl) clearance and Iwpatie blood
1I0w an' known o r can bt' approdmated.
For iIIl1slmtin' Pll'lX>St°S, (,m"ldt'f tilt' folltl\\i ll ~ dat a ohtaillt'(l afu-r an tutraveuous (i.v.)
clos e (seX) III~ ) of a d m g: C lIlIlulatin ' 1lI1101ln! excreted unchanged (.4.1',.) "" 15:2 m~, ACe
:: 3."1.5 mg-min/ l.. and tln- blood-to-plasma concen tration ratjo (e ,I C) = 1.:2. Extrarenal
t'!imi nation Is il.SSll lllt'(l to occur onlv in the livef. l1lt' d t'a mlll'l' ( D f)S{"IA VC) is then 1.3
L'min. and the hlood clearance (C U (C1/ C )] Is I.Q.S IJ mill. l1lt"fr.t{1iolll'l{'rt,tt-d lIndliUl~('(1
(AI'''; !>n".. ) is 0 .,104. Af1, m lingly. th t, (('11;11 "l f ll ~1 d l";lr.lllf'l' (fl· , C I .t ) is 0 ..12 l i m in. a m i
hy d ilTt,rt'II("-'. tilt' 1lt'(l'ltiCblfll)(! clearance [( I - fe )C I .,,] is 0.;6 [J min. Di \itlin~ h~· hepanc
hlood ",1\\. 10 ohlai n tilt" Ilt'(l'llk extraction ratio. the maximum oral bioa\<lilahilil)· is

16

which. in th i" example, is 0.56 for a hepatic blood f1nw of 1.3.'5 lzuun. Bt'in g p hpiol'l¢lwdlly
dt'h'nnim,1. 1111 amount of phunueceuncalmanipulation cau Imp ro\1.' 011 this value fnr an
oml dosa gt' forlllulation . AllY dm~ \\i I1l a hl~h ht"lliltic t"Xtr.l(1ion mtio (s("e Tabl e 11- 2) hilS
a Inw oral hi t );l\';u lahi lit~, . 111('fl" may lit.' Otlll' f fal10rs Ihat limit dmg: n 'ac hillg: till' portal
\l'i n and so fu rtlw r tlt'l'fl'll.'i(' h itKl\<lilahility. iL~ tlt"Sl-'rihed In Chap. 9, A1JS(lr ption.

111t, .. lTt"(.is of dlall~ n);( h lotlll 1I0w , intrinsic dt'aran l'i.'. or protein bintling: on nrs l·pa.'is
t's:tmdinll ('ml hI' prt'(!idt'(! using: lilt" u:ell.stirretl m()(If'1 hy sll hstit ll ti n~ Elf . 14 inl o tht'
fl·lalioIlShip"'lI = I - f;,I. 11la t is,
, . EI>'v\INAT'ON C HAPTEi 11

17

II shou ld Ill' re-e-mphasi...t"(l lh<lt tln- pn-dictmn ln-n-, for l:h a llJ.:l·s ill CI." . Elf, ;111(1 "'/1
" it" d langt"S ill QII' CI."" . o r fu". an' Il<l'it'll Oil mode-st aln-rutions. A Inw ex traction rat io
d mg ('".111lx-conu-a high extraction r.l tiu t1m~ if el. II, t (I f fu j, is iucn-awd or if QII b dt"(.' f{';l"t'(!
hy 1I slIffide lllly l a~l' factor (F ig. I I- JJ. 111t' principh-s lu-re n-fi-r to tlu ' n ']atin ' ft 'll dell(:ic's
ti M! 1II11(It'si dla"~t"S in tln-S(' Iacto rs an' likd y to produce.
111l' d Tt'l1 011 first-pass extrac t ion c..til also Ill' ,;suali7.l'tl hy rt'~ardillg perfuslon and
protein himlill~ to he ill t"I llllpt"tit io l\ \\; 111 ('Il Z)lnalic al'l i\ity: pt:rfmiu ll alltl prote-in hi1ltlill ~
help 10 1Il0,,,' dmg lhn lllgh til(' onsm. maktng drug avuilabh- In til(' gt'Ill'ml circulation.
WIWrt';lS t'1IZ)l llt' ;u;·ti, i ty n'moves tl m~ fmm till' l)I'rfu si n~ hlood.
Conside r first tile case uf a dm~ wnh an Elf near ..w m. tllal is, Q" Illudl ~rt'Olh' r than
fill, ' Cl' i'''' 1111'1l 1'"" is indl 'pl'mll'lll of l'l liIlI ~t'S ill Q" , C L ,n, or fill,' This is nul S U T'p ri.\i n~
a\ till' extraction is so small that t'n' !)1 h i ll~ presented ~t'ts P;l\t till' llct-r ,U\~".ty , Consider
Ill'XI till' t"u nd ilioll in whil'lIjill, ' CT."" is nmdl ~rt'illt' r than QII' so thOlt E" approaclu-s l .n.
In thi s case. 1'" ... Q,/ (jiII, . CT,,,,, ), thai is, hio;l\.tilahility is low am i d(,pt' lId('nl on all IIm't'
factors. An illt'n';l\(' ill blood fluw inn l',l\('S hiu;t\"ai labil ity b~' dl'(: rt';l\ i ll~ Iht, lim e t1m ~
spt'm ls ill Ihl' lin 'T', when- t'!illlillalion Ot't·UI'S. An inert-a.\(' ill t'il llt'r ('1I0·tllOlIi<: activi ty or
in f ill, (whid l nuses lilt' unbound couceut ration fo r a ~'l'll i lll,(Jlll in~ total (u lIl't' lilmtiou )
dl'<.'rt';l\('S h io.a \"ailahi lity hy int'f'(';L, i ll~ 1!It' r.th · o f eliminanou for a Wn 'll mit ' of pn-seutauon
In lilt' live r.

Biliary buelion and Enltrohepalk <yding

Small lllul('<.1.1lar ,n' i ~h t d m~s art' fuu lld in hill'; wlwrt';l' pmh'in dml-:s !c'nd to Ill' excluded.
Dnl~ in bilt' i-nte-rs the int estine afh 'r sl o m~t' in tilt' ~all blatld(· r . In lilt' ill!t'stirw umay bc'
f'('ab\unll'tltn comph-n- an t'n tl'mlwpatk l·yd l' . Dm ~ lIIily alstl llt· 1l1l't ilIMJli..e-d ill tilt' [iver,
e,~, . to a ~1 1I(1 lR lI1idc· , The ~1 1I('lI n llli de is 111t'1I sl'<.'rt·h't l into Ihe inlt'stim'. wln-n- lilt'
tl- ~h Il1 1mn id;l\t' t'1\0'llWS of till' n -skh-nt 1I0ra lII<ly lIyd m l)'l..{· it !"u'k to till' d nJ~, which i'
11.1'11 n-absor bcd. E nlemhepatie t)di n~ of dmp dirt'<.1ly <lilt! im lin"('lly 1 11rt1ll~1l a nn-tah-
olite is rep resented sdlt'lI1<l!imlly in Fi~. 11-6, ltecull fnnn C hap , 2 tlMI l'll!t'I'tlIIt'Pillil'
l,-di llJ' is <l (111llIXl!I(' 1I1 of d istribuliull lint (,Iim inaliu ll.
Any dnt~ in hilt· Ilot reabsorbed, l'it lll'r (lirt"('lly or ill(lil'("('l ly ';:1a nu-tabolue-, ist'sl' rl'l t'l l
frrnn till' IMMly via tilt' fl't..-s, The dlk ic'lll) ' of hili"r)" excre-tion (';111 Ill' t'xpn'sSl't1 hy hili,,!)·
e!(·ara lll..•.

(Bile Rowl . (Concentration in bile)

Biliary clearance c 18
(CancenlJotion in plasma)

Hile flow is a rt'lllli\"e ly sh ·;u;ly 0 .5 to OB mlJmill. Thus, for a dnl~ with a n m(1·IlIr.ltioll ill
th(' hilt' 1"tIIl,t1 10 or It'Ss th an th at ill p l;l\ma. tilt' bili;!!)' dl'amm..., is small. A t1ml-: that
('Oll('t'ntra h's in tilt' hil(·. !Iowt·wr. Illa~' haw a rt·lali\"('ly h i ~h hiliar)"d(·ar.lTIt1' . Inll('t'tl. the
bilt·.t().ph~lIla l"tJlK,'nt mlion mt in (. 11I appm;ldl IOIXI. 11It'n ·fon ' . bilia!)' d t'ar;Ult'('s u fSoo
m l /min or hi~t.t·r l'all he al'iJit...·I'll. En 'lllllally, of (1)\1N', h iliary dear,lIll1' is lim itt't l by
Ilt'pa li{' (It.·rfu sioll .
Bil(· is not a pmd lll'l of filtmti oll. hilt mtlU'r of St·c:rt·tioll o f Ili!1' at'i(l, ami otllt'r stlluh·s.
nIt· p ll of bilc' ll\"l.·m~l·s alltltll 7.4 . 111l' bilia!) ' Inlll slXIt1 of dnJ~s, !Juwl...l ·r. is similar 10
lu;1i\"(' Sl'Cretioll in tilt· kidllt")"S (p . 172 ) ill tilat it Illay 11l·(' llIlpt ·til i\"('I~.. illh ihih't l.
A f(,,\\-, ~(· I l(' r.t1 i ....a lions t~.Ul ht, lI1;ul(, n-gaf'(l in~ th t· (,ham{1l' ri\ lil'S nf a dnt~ m '(,II'(l to
1· 1l.~urt· ll i ~h bilhl!)' dl'amll l1', F ir,;t. IIII' <Inl~ mu st Ill' at1 i\"l'!y sC'<.'ll:'t('t1; .st.'I);lTlltt· St:'<.'f'('t!lf) ·
c t-t.\.PTH 11 ELMINATlON '69

Int'l:hanisms t'~i st for ad ds, ba ses, nnd un-lon br-d compounds. SI'l-'(JIJ(I, it IllIISt he polar,
and, last. its molecular wt' i~h t must exceed 250 Winnie, 111l' latt e r two requirements may
1)(' <I ( 'o ll!O(·f lll(·!lt"(' o f tln- apparent P 0 «JII S as well as lipophilic nature of hilt· cannaliculae.
Both nonpolar um] small mok-cuh-s mOl)' lit' reabsorbed. 111t'S(' arguments do not aid ill
prl'llil1in", tilt' nature and spl'dfid t)' o f the St-'{'r(·tmy mechanism s. but till')' do aid in pn.' -
t1il1inR tilt' likdihood of a h i~ll biliary clearance . For example, J!;llIl"uronidl' conjngutes of
dnl~s an- po tu, ioni/"('lI, I'M about 3. and have 1Il01t"(111ar wl'ights t'x("('('{ling 300 WIlIO](' ,
111t')' are ofh 'n I li~h l)' dt'art'li into bill'.

RENAL ClIARANCI
\ \1 11'T1 tilt' ran- of urinary excretion is dt rectly proportion al to the plasma dmg couceutra-
lion .

Rote 01 excretion • Cl II • C 19

n-nal clearance is constant. Thi s constancy forms th e b;l~i s for th e use o f urine data to
determine tl.l· lim e course of a dmg ill the bod)' (C hap . 3 ). Iuterp n -tation o f uri ne Lllt<l
with respect to plasma concentrauou is clearly complicated for drugs whose ren al clearuuce
varies . Factors th at inllueuce ren al clearance include plasma dmg concentration ( SI,"(' C hap.
22. 1>0<;,(' and T inu- Dependencies ), plasma protein binding, uri ne fl ow. am i urine I' ll . How
thes e Factors illllut'I1{"(' n -nal clearance is explained by the 'U1atomy am i pll)'Si(}I~· o f th e
kidnevs.

The Nephron: Anatomy and fundion

1111' basic ana to mic un it of n-eal funct ion is tilt' nephron (Fig. II-i). Basic l 'OIllPOlll'lII S
a rt" tlu- ~1(J llIt'ml us, p roximal tubule , h lp of Henle, d istal tubule, ami (.'OIt{"(1: i ll~ tubule .
111l' ~loll1e m l m receives hlood 6rst and filters abo ut 120 m L of plasm a water each mtnute.
1111' filtran - P<L\ SI,' S down th e rubuh-. ~ I o.\t of the water is reabsorbed. onl), I to 2 m llmin

Flit. II ~. \\ "h<-n a (In'l( Ill) j, aI"",>rilfod (",'n

inlr-<ti,...·, (",-n1...1 in hilo." ......1 " ·..I...>rl......J (",m
inl,.,.r i'll·, u has lltKIc·rxun.- ..nl..n.l"'-p;&lk l.,T1inlt
(,,*......1 lUTl l. .. .. ..,,1"....·"1 u { ,h_lril"'lk""
Liver SimiLr.ri).', .. t n a droR is mnwrt....t to .. " 1;01.>-
Iii.. ( M) thai I. W'crf'I", 1In h iI.-, <"0 " ,...11... 1b ·I. tn
,, drul( in tho.- Inl ...li...., ", 1 dn' l: i, n·..h.o rf.....1
,, (da., lll..l . m"'.. 1. II..•dOOR I "'..) UlKk·f'Io:'''.... ,·n·
, trrut"'P"lk t)t1inK, in It.b ("' irKI;",,1~ ' tlm",!tf,
Portal
Vei n @ @
, I
Bile
a mt1a1".Iil('.

,,
,
@-----@ Intestine

Elim ination of
Drug and Metabolite
110 CHAol'lU 11

1('01\\-' tIll' kidneys as urtuc. O il ]ea\; ng lilt' glomerulu s. rlu- SOIllU' 111000:1 p t · rfU stOS both p mx-
inml and d istal po rt ions o f tilt' tubule lh n mgh a w rit'S of inh'rt''Onm'<.1ing d l,U1I1C'k
Aplll-'ar.Ul<" · of dmg in tilt" urine is th..• Ill'! n-sult of filtrattou. S(-'o:: rt' IiUII , illld n-absorptton,
11,(' firs t h m p n )(.'(' Sst-'S add d m g to tht· p roximal part o f 11ll' IUIllt' 1I of tl l(' I\eph n m; tIll'
last pro(,.ss Involves till' movement of d m g (mill th..• lumen luck into tlu- bloodstn-am .
111t' exen-tkiu mil' is, t1wrt'(on-',

Rote 01 _ I _ F [ Rote 01
Excretion I RI
Role of
Filtration + Secretion
I 20

when- FA is tlu- fr action reabsorbed fm m the 11I1IIl'1I. A schematic n-p resentatiou uf Iht'S('
pn M:'t'SS(:'s andtheir approximate location in till' ne phron art' gi\"t'll in Fig. II ...';. 1...·1 us loo k
li t eac h p n ll't'Ss in 11In! .

Glomerular Filtrcrtion
App mximately 20 to 25% o r ca rdiac outp ut. or 1.1 L or h lucxl P" minute ~cx's to till'
kidneys. or this volume. about 10% is filtered at tilt, ~lo lllt' n1 l ns. Small molecules (moh-o-
ular weigbt les s than 21)()O Wlllole) pa-...s t1m m~h tln- sk'\"t· with ease. and ('\ "(' U for smal l
p mlt'ins SIl('il a.'; insulin unr] my{)~lolm lin , tln- nlt rafiltrate (.. mcent r auou is doS(' 10 Ihat in

Glomerulus
Proximal Tubule

Venous
Return ."'"...~
<,

l oop
01 »>
Henle

.'Jl:.11_1. n ..· fund"' .....! ,,,,w,,,,,,. ;u, llfi;l!mni<:>o! , ........ \M,. Iif',·,J fmm Smith. 11 .\\".: n ..· KMIt.., " StT1K1un·
;uKI Fun....MN' in 1I......Jth 11I..11);........· , S .....· y"rk ( ~ftJnl Unn,. "it) · p , " -\ . 11l'> 1 )
C HAPlH 11 ElMINATlON 171

plasma ( st"(, Talllt' 11--6). Only \\'11t'1I tilt" molecular \\l"1)?;ht of tilt" protemexceeds 211.lkk)
tint's filtmt iun £111 ofT sharply. hnk-ed. \; 11111111>" no al bumin [molecular \\"{"i ~lIt 69,IMk)
WIIlO!P) is 1I0nnally fOlllK I ill till' nltn lfiltnlh'. Ae(."{)n lillgly. as tlu- binding: o f mllst drugs in
plasma is to ulluuuiu or otln-r protcms of similar or lJiglll' r mok-cnlar W{'i~tlt , us it ge,wntl
mk-. unly unl xmnd d m g in pl.l~lI\a water (coneent rutkm e ll ) is filten-d (Sl"(' Tabk- 10..-1).
TIlt' ran- at whid l ph~lIlit wa ter is filtered, 120 m lJmin in a in-kg 20->l'lu -oltlmitn , is
t"{)nH' ntilillally calk-d thl' ~lo lIll' OI la r filtration rat e, G f H.. It fnllnws tha t

Role of filtralion - GFR ' Cu 21

Ht'l.11111hal jil is tlu- rano of lilt' unbound to total plasma drug ronceutration: therefore.

Role of fi llJolion - fu' G FR ' C 22

If a t l m~ ts only filtl'R'l1 aml all filten-d tlmg is e XI're ll"'{ l Into 1111' urine. tln-n til(' rollI' o f
exen-rion is tilt' rail ' (If Iiltratiou. Si lll"t" n-ual d .-MiIllU', c t./{. hy de finition is

CL _ Role of excretion
R pto~ concenlJolion
23

it follows Ihit! for snd l it tlmg its n-ual ek-arance (hy flI tr.ttioll) is [u ' G f R. TIl l' l'xtr.ldion
ratio of such a d m ~ is IO'\\'. For example, t'\,('11 if th e d rug is tOlally unbound in blood ( e ll
= C,,l, IIII' l°:l..tm(>(illll ratio is still only U.II . This follows be cause

FI g . II--'l , n..,~ I. ... 10.10. .. 1 10 11M' h""..., ..f 11M'

noophlUfl ~' filt....u.." ..".I .., Tt"li..... fo"iltl>ll itMI ' 1('-
Glome rulus n ul' pri m.. ';!,' "~
I" 1I... I(Ic,,,..," ,I,,,, .........it.., i.
lo II.., pnw m.al t"I.. ,J... R<-.aI""'l'tit'" 'I('-
s1rit.i .... l
"'" ..11 ,.)...'It tl.., ",-pi...",. A.i i "~.d'.nlpt ic •.,.
, ,"- Filtration ",-brn rT1"'lC,.,t, .,,,i.dl~· ' Il'n,n in tl pr'lO..i"w1IU-
h...Io,.
Proximal -1-- Secretion
tubule - j -- Active
reabsorption

Passive
Loop of
Henle reabsorption

Distal
tubule

Co\\ec.ting - tUbUle
172 EUMINATI()N CHAPTEl! 11

Rote 01extraction GFR· Cu .. 120 ml/min . 0 11

Extroction rene - =
Rote of pre s.entotion Renal blood flow · Cb 1100 ml/min .

Inulin , a n l'xogt' 1l0 1lS polys acc haride. is nett hcr hound to plasm a p r oteins no r secreted.
and all the filteredload of ( ' ll(..h substance is exen-ted into the u n lit'. Al'('()rdill~ly . lh(· renal
clearance is a II W a.S Iln.' of GFR. Under normal conditions. C Fn is rdilt i\"t·I~· ,..tilhlt, am i
inscnsitlvc 10 cI lall ~l's in """ 11<11 hluotl How.

Adive Seallion
Filt r ation alwavs occurs. hut as shown above. extraction of a tl nJ~ Iw this un-chamsm alolle
is 10\\.', lospt'<.1aily if d n 'g: is highly ho und within blood. St'l'rt't io n r,;d litah 's extraction.
Mt"Chanisms exis t for secn-ttng acids (all ium ) and bases (cations], ind mling: (I"a t(·mar~..
ammonium compounds . Imm tilt, plasm a info tilt· tuhnlar lumen. T he !i('('rd Ol) pmt'('sse s
an- located p rcdcmtnantly in tltl' proximal tubule . AIt1ulIIj!;1J at:tin>, these tra nspo rt sys tems
appt'ar to lack a hi ~h dt,,,,trt-c of spt'(ifidt)'. as t!t'Uloust ratt'tll ,y the \~idt, va rit·t)' of sullsliUlI,('S
transported by tlWIII. As expect ed. however, suhs taul,('s tran sported hy tilt' sann- syste lll
1'UlIlpt't t· ....i th t'adl otlw r.
St'('rPtio ll is inft'Tn 'tl wllt'll ra n- o f excretion (CI. n · C ) t'XI'('l,(!s tilt' r an- of hltrat ton
(/u . C f R . G). Stated differently, secrenou is ilppan 'nt wheu CI.n > Jrl . GFR. Some rcab-
sorpt ion may still oc vu r, hut it m ust Ill· lt·ss th an secretion.

Protein Binding and Perfusktn

Tl u- influt'lll'(Oof protein bindi ng O il secret ion d epends O il tIl(' ('ffid t'Ill')' of tilt' secretion
pnx"C-'Ss ami on the contact tune at tlll' S('('n·tHI)· sites . TIIl'S<-' conclu sions are sim ilar to
tlUlS(.' dra.... 'u for 11t'p 'ltic eliminat io n.
Blo(xi r(·sidt·s at till' proximal Sf'('rt·t0l) ' sues for app mximatt' ly 30 $1'(' , \ \ 1lt'1l a d m g is
S('Cr('h'(L hut poorly, tllis con tact time is Insuffich-nt to transport much d m g iuto the IIlIlWIl,
and al'('onlillgly, tilt' drop in d m g roncent rutiou across the n 'wo ll is sma ll. T!tt·ll. the un-
bound concentration at tilt' sec retion silt' is alm ost ideutical to tlu- unbound concentranon
in p lasma . CII, Silll't' tilt' rate o f se-cret ion depends on the unbound d m~ cnucentratiou , or
Jrl . C. it follows that c1t'a rdlll'(od ill' tu sec rencu, obnum-d hy d i\id in~ rate of secretion by
C, is d ift'l1ly p ro portional to Jrl, As va riat io n in renal blo od Aow t1IX' S uot l'iIlN ' im)' cha n/o!:t·
in the plasma drug concentratlou. no (:han/o!:t· ill n-nul d t·ar.llll'(· .... -ith pt·rfusioll is t'~)( '(1('t1
under tltt·S(· circumstances . Furtln-rtuore, tilt' su m of dt·ilr.lIlI'('S il-s_~()l'i alt't l wi th filtration
(/11 • G FR) and seen-tiou. must also he di rt'(11~' propo rtional to / II , Obviously, tilt' extraction
ratio o f such a t1 m ~ is J(""" , Flgun- 11- 9 supports till'S(' pn-dicnons fo r fum st' m idt· in an
isolah 't! nat kidm')' pn-parution . Furosemide is !t('Cn 'h'( l and is boum] to albumin. In thi s
p repa ration till' fract ion unbound could be varied o\'er a w-ide r.1n~t· .
SOli\(' d m j!;s are sud . excellent sub stra tes for tllt' S('('n' tol) ' sptt'm that tlwy an ' \it1ually
completely removed from blood \\itllin th e tilllt' th ey art' in luntad \\ith tl\(' ilt1i\'(· tr.IIlSport
sitl-·. t...·t·u w!lt'n tltt'}' an' hound to plll~ma p m teins o r l(x"db '(l in h l(KKI l1·lIs. III sudl ( ·il<;f.·S .
t....i deutly disSlxiation of tllt· d m ~-p rolt-i ll (1)ll1p lt·X aml mH\l' lI1t'llt of d m~ out of til(' hl(KXI
<.'('II.~ is suffid t·ntly mp id so a.~ to not limit th t' Sf,(·ft·IOl)' pnx'('ss, Pam-alllinoltipp nril' add
(PA H ) is handl ed in th is lTIiUHlef and is not rPabS(Ir!)(>(1. Al'(:(J n l in~l y. til(' t'xtfllt1ion mtio
o f PAil is cit)$(' to 1.0. aml lw ul"C-' its ft'n al bl(Kxl d t·ar.Ul('(· is a lIWilsn n ' of n 'n al hl(KJl.1
lIow . O h\iously. ulI(lt'r tht'S(' drcm m ta JlI'('s, dea m l1l,(' is perfusion mtt·· lim ih'll. Examplt's
of d m gs ....i tlt a \"arit'I)' o f n 'n al extral'tion mlios an ' Iish>(1 in Tah lt' 11- 2.

Reabsorptioll
Heah St.)'lltioll is th e thiftl fa<-1o r <-1)n t ftJll i ll~ tilt' rt'n al handling of d m~s , Ht·ahSt.lrpti oll
mus t OI'(1lf if tilt' n 'n al d('amfl('(' is I('ss than tilt' l'iI!t, .lalt'tl d t,.mllll,(· h\' filtmtio n
CHAPTE R 11

<C/ '/f < fil . C;fRl. SOIll!' v-cretiou may still Ot:<.1Ir. hUI il 1I111s1 be less than reabsorption.
Heebscrpuon " ,U1t'S from bt'in ~ almost ahsent to ht'in~ virtu ally complete. Al1:i\"(' n'al ~
so rption t)(.'{'Uf'i for IImll)"t·ndogt·n ous compounds. ind udin g vt ta nuus. t'll'{1:ml)'tl~ , gIUl,(ISt'.
and amino acids. 1I0wl''I"('r. for th l' \11.\t majority of t'llt~t'1I 01lS compounds . n-ebsorption
occu rs h)" a j);l\sin ' pn )(.'(' ss, TIlt' dl~rt'{' of rcabsorpticu depends on til(' properti es o f lilt'
d m g, ('.g.. its polari ty, state of ionization, and molecular wt.'i~l l t , As wnh mall)' mem branes
thnmghout the hod y. till" Iipoid ill mvmbrum-s of tilt' cells that fonn the Illhul(· ad as a
bnrm-r to wOlll·r-soluhl(· ami ionized suhstances. Thus . lipophilic 1Il0!('{11It·s It'nd to lx'
t'xh'll sin,ly n-absorbed. polar molt'{11ll's dn not . Reahsorptiou ulso dcp-uds O il ph)"siolo¢ <.·
variabh-s such as urilit.' now and urine pll .
Heabsor ptiou occurs all along till' nephron. a.sscx;ah'd with tlu- rcabscrpuon o f water
filn-n-d at till' glollll' m ius. Till' Illajo ri~', SO to 90 %. of tilt, fillt'n '(l water is n-absorlx-d ill
till' p n l.\ imal tu bult" ~t ost of rlu- remainder is n-absorbed ill the distal tubuh- am ] (u U('(:ting
tubules. wlll'rt' urnn-How is con trolled . If 110 water is n-absorlx-d ill tilt' distal tubule. urine
nllw b about 15 to 211mlJmill, Xormullv, however, \ \ "dI N is n 'ahsnrll('(l to tilt· extent that
urim - flow is I 10 2 ml Jmin or lower. '
enllSt'ljllf'ntly, \\; th water reabso rption. drugs cou ceutrate in tlJ(' filtrate. In fa(1:. if a
tim!!: we-rt- nt'itl lt'r rt'ah so rll('(l (gl'm' rally po lar) nor seen-ted. wtth approximatt'ly9H% water
reab sorption, the concent ration ill the urine would be about 100 times as great as that
unboun d in p lasm a, Th us, rea bsorp tion of wate r Ievors the reabsorption of a d rug that
diITu.st's across tlllJlllar un-ruhrunes.
Uri nt' F low lIml Prolein Bindin K. Urine flow can o nly han ' a sub stantial t,ITt'{1 0 11
n-nal dt'<lfitlll,(' if a drug is 1lI0s( I~' n 'ahsorll('(l. ( A,'rt ainly, the (,IT''l.'t is most dramanc wln-n
n 'allScI'lllioll appmadws equilibrium.
Ih ,,"ly unbound dmg dilTu\t.'s thr ough membranes. equtltbnum is n '"dwtl whr-n the
couceut ratiou in urint' and that unbound in p lasma. ell, are equal. Consequently. s i ll(~:

Urine flow • Urine coocenlfation

24
P1o,mo co ocenlfolion

ilIl d shu v e u = [u . e, it folluws that

5
C
E
:::J 4
E •
~
u
c 3
FiX, 11-9, Con l ri h"hco" of ~", ..'n,lar Iih r..l ic..,

"
~
~
G 2
iel ,uKI lul",lar ...-e-n'h"" 1.' 10 II.., 1,,1;11 n'n;a]
{-It'.nuK'" (al or run..... Ill iclt- III diff..... " 1 ,·",1,,,.. "r
~ frar.1ion " nhou nd. (Hall. S.: Dod oral diue rtalion.

"
E UnMmty or Manchl:':<t..r.)
~
~
0
"
~
.... ,...... ....-_.--- _ --_ .
~
....... .... .......
0
o 0.2 0.4 0.6 0.8 1.0
Fraction Unbound
"4 CHlV'l'E1! 11

Renol clea rance " fu · Urine flow 2S

Thls last f"(·latinmllip is it simple test of how du,'>C.' n-ahsorptiou is 10 equilihnum, A dmg
muyhave a re nal d t ' a nllll 't ' hduw this \ 1UlIt ' if iI is ;\<.1 iw ly n -absorbed. ~ l un"( J\ t·r. if dr ug
is highly bound to plasma p roteins, n'lla l dt'ar.u\('(' (ami extracnou mlio ) would l)t· ex-
Irt'IIJt'ly small since II rine How is nor mally only I to 2 III IJ min. :"on- also that n-ual ck-araucc-
is tlin'<.1ly p n llxlrt iuu,t! to fil. ",11('11 u n lit" lIow is constan t.
Ethyl alcohol is an (·xalllpit. o f u compoundthat is 1101 siWlifk-anlly bound to plasma
pmh-ius a ud is n ,,,h so rh('(!lo the extent thai its coucentruttou in uri ne is vi rt uallv till ' s.<t lllt '
as thai in 11K' plasma n..~;IrtIlt'Ss of uri ne How. CO IIM'<jl lt'lI l ly . it folluws From E' ls. 2-4 ami
2.5 thut n -uul ck-anmce of ak u hol is app mximatdy t'tlual to millt' /Iuw a nd. tln-rcfo n -, uri ne-
flO.,lr dt'!'lt·lldt·nl .
Urine pH , For weak adds and weak luea -s. urine p I! is all add itional factor a ITt'(.'ti ll~
rea bsorption. T ilt, extrem e s of Urilll' p H art-· ·1.5 allli 7 ..') unde-r foro-d "t:id ifkalio n and
alkahntzat lou. rt'spt."t:ti\"l'!y. T he se extreuws contrast .,\it l! the nam ",' r.lIl~t· (If plasma p ll .
7.3 tu 7.5. O n till' avr-rage. urine p ll is d oS(' to fi3. TIllis. a larw · p H gr,ltliellt lIla~' exist
betwee u ptLsma amI u rine.
Un ue pH is ahr-rcd hy diet, d n 'w>, ami till' d ink-Oil state of a patu-nt. It aiM) vuri es t1 u ri n ~
the day. Respirato!)' and nu-tabollc acklosls p r oduce s add ifi<."ltinl\, und n -spitu tory an ti
metabolic alkalosis produces alkalilli7"ltio ll. \\1Wll metabolic addusis is of n-uu l ()ri~ n . fo r
example. renal tu bular addos is,lht, urine is alkahnc. D m~s s\l(:h ,LS the l'Olrho lli<' an h~l. lm..t'
inh ibitor, aeetnzolamide, p n khll't' an ,uka lilll' urin e.
Equilibriu m (,'on"id~ral jml1l, Rt'llal clearances o f s('\"('ml wt'ak add.s and bases, listl't l
in T ahle 11......1. ...."t"n' calculuted usmg E(I' 24 . The urine-to- plasma ronceutranon ratlo was
calculated using ti n' Henderson-H asselbalch cquatlou (Chap. S), gin'n that tILl'S(' com-
pounds do not hind 10 plas ma proteins. thai equtllbrtum is "dlit"\'t't.l between nu -tomzed
(I m~ in urine and plasma, and thai ti lt' i0l1 i 1~ 't 1 fon n is not tlifTlIsih ll'. It appe"l'S thaf rlu-
renal d ear.IIl<" · of SO liit' acids , p Ka less than 6.0, can 1)1' mu('h It-' s than llrill(' lIow ( I III Ij
miu], whereas Ihat of all>' base cannot. because uri ne p i I is never much h i ~l lI"r than plas ma
p ll .
....n i ll tt' rt"Sti ll~ ull'it'rvutio ll may 1)(' nmdl' " IJl Ull w('ak b,L'it,~ . .\t low uri ne pll , n -uul
d (' am IK" , hy calculanou, approaclu-s n-ual blood Row, which usually su ~('sh "ti in' sa-en -
non. It is unlikely. !JtlW("\"{'r, that such a hi ~h d f'll.r.mt'(· \~tl ll(' can 1)(' o!ltniut'(l bY !>iLssi\"('
d ifTusion- for thn'(' n 'aMlIIS. First. til(' fr,i('!ioll of l'('nal l)lood flow that n ';ld 1("s tilt' t' ml of
till' d istal tuhu ll' and l,(lllt-'(1i ll~ tuhult" .....llt'r l' till' lIlajo r d l a ll ~t ' ill p I! ( )( 't.1 1I'S, is SllliJ I.
St.'l.'OIIt I, the l-.lk·u!atiolJ o f n 'na! d t·anml,. ill Table 11 --3 is l>iL'it't.1 011 Il.t' mHo n f Urillt'
l'lII<.'t'ntmtiOlI to plasma t,m('('ntm tion Il'a.,ing, mtllt"r th an (' lI te ri n~. tilt' kid lll')"S. ,1w n "-

,.It..
W_. 11-3. C.1c.1
Ac14l•••41 W_
_1 CI •• (_L / •••• " hlecte41 N_.....r
V.rt••• V.I_. . . urt_ pH
U.41.r .~lIIltr1u. C..41It1 ...

COX; ~"-"
""2 '
..
0001
"'" '"..
01
"3
A
B
C
"'" 6'
10.4
0 1
10
02
10
3
10
0 24 10 1.0 10
,
E 64
10 4
QO
1000
2
10
09
03
G 12 4 1000 10 03
 '"
1I0 11Sconceutrut to n hen- is I. ·ss thau Ihal ('ll h'rill ~ tilt' kitlllt·ys. particularly wh e n the ex
tr action rat io o f till' dmg is hi~h -a I'w rfllsiull rdte· limilt"tl u llld ilion . Tln nl . the high \'llhw s
of cak-ula n -d dc'amlln ' ap ply 10 Ih( ~· ha.\I.'s . whit-II al hl ul K! Jill values n-nd tn Iw almost
co mpletely iOll i7A:"(1; thus the rail' of IIll J\ "t'II1 l'1I 1 th",lI ~h rlu- JI1('mhr-.U1c,,;, "~Ii<:h dep"'lIlls
Oil the coucentranou of un-lonbad drug. is n -due -d. :\ simila r af).,'ll lllt"1l1 appli~ to \\"('ak
ad&•. At"(:n rtlin v;')', a n-nal dt'i mlllel ' n thll" j:!;rt'alt' r tha n jr, . G FH for ('itlw ( 0 11 ad d IIr a
ha.\!:· al non nal u nne I'll pmhahly SlIMt'Sb alii\'{' ~'(.' r('li ll" .
A Ra' r P NJ('('1I11 ill Rl!ality. Til t, f( ln ~oi ll V: d iS{'ll ssio ll W,LS IliL'it"t! primaril)" 011 ('(Iuilib-
rium concepts. hut Il<Lssin ' n -ahsorption ilia)' not app rual'11 t'tluililui um. TI l(' primary eon-
sldemtiou i~ hnw rap idly e-quilihrunn is appmadll'tl. III «'ality . thr-n. n-abso rp uon shllu ld
he C'l ms i dl- n~ 1 From 11 khw tk rather than From all t'llu ili!Jrilllll plliut n f ,it-\\,. as "',;I.." true-
for ab sorpuon of d rug s [rrnn tln- F:<l\ lm inlt-sti llal tract (C hap. 9 ).
111(' ral(' at which n -ahso rp lio ll occurs dep(·m ls 0 11 tln- ahility o f tilt" uu-touta - dd mg In
di fTu.\(' ac ro ss memb ranes. its pnJ;lrit)', alld Ihl' fr.tt'tinll Iln-iolli:tA.'t1 ill Iht• IlIlIIt-lI. The pt' r-
('('lIla!{t's IIIl·ioui1.t'l1 for tjn- sauu- d m J!;s listt~ 1 in T allll' 11- .'3 an' ~ \l.' 11 ill T able 11--1. T he
calcnlanou i.'i l ),lt'i(~1 U II t jn - Il t'u dl'N lIl-II ,l-\ St'l1 lald l ('t!llaliclIl (C hap, 1'1 ).
n °t' ak Ha llt' ll . Tilt' ('fT("('" t o f u rine p I! 011 tln- (·ulll lllati \"(· amount of IIl1l'hallJ!;t'tl lllt'th -
umplie-tamine (11M Ill ) that i.'i t'xl· rt 'h~l ill tlll' urine - is SIIO" l l iu Fig. I I - Ill. Aft('r 161m;
aho lll 16% o f tilt' tloS(· is t-.\Crt"l("(l lI lId mll J!;t~ 1 wln-n tilt' urine p ll is 1101 co nt rolled . O n
alkali lli 7j n~ tilt' u rine, (-.~ .• by illV;I'Sl i n~ sodium h k~.i rhn llatl' , ( 111). I to 2'1 o f lilt' doSt:· is in

, ..... 11-4• .-.n... U• •I. .I_"" hlecte4 W_k AcleI_ ••11 W_1r: . ._ _
.. V.rI__ V.I_ _ .. UrI_ pM-

ceo ~ ... ,..

2.4
.. ........
0 .01
" o.ocos
A
B "'~ 64 W
1.0
50 3
C 10 4 100 100 W 7
0 Bo~ 24 W 100 100
E 6.4 10 50 97
F 10 4 0 ,0001 0 .0 1 0.3
G 12 4 10 - 0 00001 0 .003

~u t"l1l;. I I -t O. Thon lll lu1.otr.l' ll riRl" J_"rr h"" "r

""1,,.11" 1'1"1;1.1"1'''' (11 mil ur.lJ,·) In " U.n ",.riM
x " , 11, tl... uri,1<' I'll . (Ao Lopt....1 frn," I\<'(·krt l . .\11 .
w 6 Acidic Urine
;,U .. I It."",-L.,ttl. \1 ,: ViiOWl)' ("U"trh<", l.i'M·lic:" flf
~
c (pH 4.9-5.3)
E nIt1 h~i.a"' p...1 ","i ll"· in frulIl , 1';<1"..... ZtM'i :I2fit lo--
i!
~ - 4
12fi 1. 1 \lfi.~J

~ O
EE
2-
"
::;;
15
2
No pH Control
C lkallne Urine
~
0
E 0
'l! 7 608 2~
-c
0 4 8 12 16
Hours
 176 OW'TE f 11

1111" un ne. wh il,' addifil';.llinll II\' i ll:l:l'Sti ll~ anunoniu m (·hln rid,· n -sults in 70 10 Mt% rt"'l' t",'ry
in till' urim- Clt·arly. for th is ;Im~. unue pit is importan t ill dl·lt·n ll in i ll lo: th,· l'(llIl rihlltin~
of 1111 ' WII"I " Hilt' In tot al t'liminafju!I. Unde-r ('o m litium (,f nn pi I contr ol. II n nt · p l l varies
t1lrnll~t.ulI l lilt' ,Lly. atu] tI... ewn-non o f md halll phdamilH.· lIu(1 \1d l l "!lo '1('t'l JR li ll ~I)·. nit,
t·'pl.uMfioll fur t1w<,(' oh'ot'r.-aliolls is coutaim-d ill Tabk-s 11- 2 and 11-3. .\t In", UriUI ' pll .
both {'Ill ilihrilllll .1IIt! killd iC' ('tlllsidt ' m !in lls (anl T hi ~t. n-ual dl'"rdI K'I ' of ;J. h<t.~K· d m~ of
11M Ill . I II pi.ut k ul ar . til(" p, ·n.' ·111 III1.io ni7'(,,(1, ami 1." IK't· tilt" llu -inn il.t'Ct ( 'O I K 't"ll t r d l ioli in
,I.,. n -n..1 1111.111." is ~ l small tt.at tl lt'n" is li"w opportu llity fo r n 'a"~1I1lt illll " ; l lIill li lt' lillK'
Ih.lI IIII' dnl~ n-skk-s ill Ih(' nephron. Al h i¢1 1II;11t· p H ~; t h a Wt·"h·r pt'n't'lIt uf tln l!! un -
iu ni:fA't1 ill tilt' tubule, !Jutl , ('tluilihriulII am i ra te ('Umillt'rdtiom (a'l lr n -a bsorpeion. I)nl~
tl ldl ,I.U\' tl lt'...• '\ul)l,lautiai d,ang('!' ill renal dt'<lrdIX't" an ' sald In ht· p ll ....·II'\ilhl·.
Tlu- dfl't1 Clf Unlit' p l l111I IIIl' n 'ah"iflrptioll ufh..L'\ic lInl ~. ill !!t·lll'roll. can II..• su mmanzcd
;,'\ fnlluw,:
I. .\ h.,'\it· (ImJt th..1 il' pu!' lr ill ih III1-iu lli7A't1 fonn jl' nol n -ah..urh..'tl. n pnlk '!'l' of Its
..It")!:n..· of iun i:f..aliull in lilt' urtm-. 11111..,,\, at.1 i ' I · ~· Iroln'\purtl't l. The ;lInil~~'{,,,,KIt. ~·Il la .
midn i.. lin 1",.lm p lt·; its n -nal (·k·a r;uK't" is ilHk·pt·nd(·nl n f Unll(' p l f.
2. A \t'ry Wt·OIl1)· IJa.,\k· nonpolar dnl~. whn~.· I'M b an MUlti 6 .11 or Ill·lIM'. '\11t·1I ...'\ p m -
Ill)\:)l)" t·lll'. i.. t'111'II'\iH'I)' n ·a1N:ln lt-d al al l va hn -s of uri ne- p i I 1 1t '(~.tU ....•1I.... I..nent of (I nl~
in tI.... tlifTu'\ih l..• ull-jo lli:fA't1 form i.. l'u fTirit'nt 10 han' no Iimitin!! 1·1T1'(1 11I1 its ran- u f n-al..
,orpt iu n, n1!an ll,~" uf urim- p ll Furthe-rmore, t'l illilih rill lll fa\'(n~ n';lh~ lrption , Tl w n ·n;d
d t';mIlK't' of l'1l(:h a dnl~ lIlay vary with UO nt· pH hut its ' 1dm ' il' Illw. t'!'lll,(; ;'Uy if 11...• drug
i.. h i ~hl)' bound tn pla"lIla pRll t·ins .
3 . Fu r a , Inm!! b..L....• ~illa a I)M vahn- appRiadlillK 12 ur Kn· ah· r. such a... !!u ;lIK·dlilliIW.
litt l,· n r 110 n·aIKl,rp tiu n i.. (·'I)('(1I..:lth m llgho1l1 til(' mll~I ' (If unlit' p H hl":'allliC' ionizanou
i.. \II ,·,h'nsiH· Ihat it lilllil'\ tilt' ran- u f Il"alxorpt iu n . A('('t)nlill~Y. n 'II01I d('arollK.'t· is im k··
IIt'nd,,"t nf urtue p ll 01 11(1 gt·ll('r.l lly hi ~lt .
-' Fllr ;1 ha...k lIollpoLlr tlnl!! ";1" ;ll,Ka Ullm· IN·flu ·.". 6.0 ",141 12. ti lt' t'lh'lIf of n ·ah..
\I,rp tillli ..-aric·s fmlll IIt,!!li¢ hlt· 10 allllmi ('t)lIIpll'f!' <t" l' lililmlliu lI) ~il " dl;m" I"\ in I1OIK'
pll . 'nit' n 'lIa l d ('a m ll('t' of slId l a d nl~ (to.g.. IIlt'lhilllllJ!lt'la m irlt') 'Olrit'!l ma rl.l'l lly \\i th
UOIlt· p ll .
n 'f'" k ;\ (' ilIJi. T Il(' p rind pll's d(·\l'!op('(1 for w('a l. I..L\I·s <I1"CI ;Ip ply til wt 'ak ad d.... 1I11\\'-
,·\ 'I·r. fo r adds. all ill('n 'aw ill I' ll (';UI\I.'" Ulli n. ' i()lI i7~ltil)lI , nlll l..•..... Cu ll....·lIm·utl , ·, ad lL.. an '
r(·'lh ..u rll('tl lt·s" and I.aH·lalw ·r n 'lIal dl ·ar.lII(,(~ <ll lli!!lll' r ..rim ' p ll .
A!!aill. tl\l' t·lTt't"t uf I'M on n ·ah..lIIvt io n is '\1":'11 hy iu"pl..:1in!! T abl..·s 11- .1 an d 11...t
All ad d \, i tll a 'IN' \111m' o f 2.0 IIr II·ss. ('.~ .. dmll lll ~lyd(' add , i.. \II ("l)lI1 p lt·tt .!y iOlli;/'A ..:1al
atl llrim ' p l l ...a lll' ·s that it i... ..im pl, - 1I0t n ·ah "C lrll(·t!: ils rl' lIal d ,·a r'III('t· is ~"'I U' m lly I.i ~"
alltl iU\I'm i!in ' In I' ll. At 11ll' ol l....r t' \ t n 'III(', a H' f)' wl'ak ad d \\ilh a I,Ka \'a hll' ahll\'(' N.O.
\I ll'll a' pll t·II)11Iill. h 1111 11)' lIu-in ni:f.t..:1 I h n JU ~IIolll till' ra ll!!I' of 110 m ' pi I; ils n"1<11 d t'ar-
am, ' h alwa) 'S 1(1\\' alld ill ·II...ili'o'· tl) p lL Dill)' for a lIullpul<lr a(..i d wll"\t' fl 1Vl lk.~ IJf1 u '('j",
3,0 aw l • .5 i, n 'nal d l·..r.lIl('t· t·xl)('(1I..:1 to hi ' p l l \t 'IIl'iti\l·. Noh ' in 'Llh l. · II ....'] ti m! fu r ..II
IIOIlIM,Iar ;Ki d , ('l illilihrilllll fa\1I1"'\ n·"hso IVtio ll.
1>..la supportin!! till' t·'I)(..:1('(lurill(· p ll !o(·II..ithil)· ill n 'ual dt·amlln.· u f nonpol;lr wt'a k
add.. ~i l " '1 p Ka IIt·t\\..'t·1I 3 and 7.5 :IlId nonpolar ~,·al. h .L.....l' \\i tl l a 11M 1 1l '1~ 1 't ' f1 6 :tlld
12 ;tn ' pnl\idt 't l l~' Solli(.,. li(· add . ,JM 3 ( FiJ:. I I-II ). and tl l(' auIIK·llllinlit' ..lil·t1I) k';ln );l.
1II'l:fillt'. IlM 10 (T<thl(· 11-51. n '!lI)('(1in ,ly.
\\'I·aL. ,1(; tL.. <llId lJa...."\ 1" ;11 , 111 1\\' p ll .st·mili\1· n 'al N:)l'plillu ;ll...., !!I·lll·rolll,. , IMM' IInw . roltt'
(lc'pl'm lt'lIn " A!o!:.UII. III,....,...'(·r. 111,· tll").,"-"'· to ,,11k'" n'llal dt·amlt('t· is d lall!!t'tI IJ)' unlit· fI( I\\'
(It' )('m l, (lJl till' l'xll'1I1 IIf n· alN:'rpt iu lI. If 5l )ll of Ihat 6Ih·n..:1 and ....'(·n ·II'(1 U n ';llN:lrlM'(1
011 Illl(llMlurilK' tlo\\'. ,'j( tl} is t·\ (n-It..:!. !lJ('n·a'\{...l lIrim · fl.,....·.. Ic '(n·a.' t,!, n 'a lN:,rptioll tlM-an l
' l·n t. hul n 'lIal d ('ar,uK't" (. lIIllol II(' iIKT(·a........I II)· IIlIm ' Ihall a f;K1nr uf 2, Fij.,'tIR· 11-1 2
 CHAPTH II El.WoI'lATI()N 171

250 1,'1.. . I I _ II . Tt,.. unb.....,,1 rl· .. ,,1

d ";If"'ll" ,/ w1ie::o-lk: ••d d i' llTU .....
• .1r""'"t k ...lI ,, " 'ill. ..." i1.l'n ·u,' , ,,
200 uri".· I'll " I.M· 6.S (A,LtI'h'<1 fn.tI,
Smitl, I'.K.. (;1.. ",u1l. II I. .. Sta ll .
e.G.. ",..I (~"" .;Il.·k. S., Sh..lio.....tI
• tl,,· Iw'.tm ...... h (l , of ....lk, -lott"S J
11""0 ".'04 t:~p. Ttlt·r.. .'J 7:21; - 2.').';.
1946.1
I •

••
•
••
•
o
5.5 6 6.5 7. 7.5 8 8.5
Urine pH

'.~I. 1 1 - 5 . h ".ltI.lty" DI.ttt,t.,.rIHI. . ... . a. _I a,,_IN•

.. Ch..., . I.. Uri... pH·

Not coonolled r-6 3f 86

Ac..:!,c, <55 38 0
Alkolme, > 7.5 10
~""" t"",,", G h i A '" ~ v ~ ~" Onnt, M l E , <rod Woifd, S A
"""'''' ,noou '" cloo.oi'o,,,,,,,t:o ""' I!o- J Clol FlvI'"<>Cd I] 1101--8 12 , 198 1
"I\i><a'pMoI".....

12 t·I!t. 11_12. R.·•...! ,....;1.. . . . . ., • • / Iw,,·•• w>art 'ilal , ,.,..

io... " i tl. Urill<' iteM' in I'WlI. It i. oJ.., ;0 f" "d ielf' uf
~ Uril1l' lIl t " , Ih""t albiitlil..diull (hi....." <in-k-s l, "ill,
lIIbli lli,.;oli.. 1l 1I' * IIl,,1 dn-lt...l. (1t<"lr""l ' r,,,,,, Lin-
.2
0 tOil. ,'-'., 1.1,"", It.G., lUtt.I B ri~, ~l ,() . : ~1 .11 ..~ 1, tlr
c
~ 8 (;IIl....I .I;" "",, ",,,I it. ,ll'p lie" hlln in 1104rhitllllll.. poi-
~ -
Q.c • .. .ninll:. Lant."rt. 2:37i ~WI. 1007,)
15 E ••
~::>
g E • • •
~ -
~ 4 •

..'"
'-'
c
~ •
•
••
•

"' 0 •
0 4 8 12 16
Uri ne Flow (mUminl
"I CHAPTEI1 11

shows how tln- renal clearance of plll' lloharhilal (" Kit • .2 ) va ru-s wit h u rim- Ilow . As ex-
{X't.1('(1. tilt' re nal clearance of this d m~ is p l l M'lIsit in ' ;L~ well as urine How-rate <1('1)('11<1.'111.
Fo~"(1 Diuresis a nd Urine pH ('..u llin)!. I II(: r( ';L~"( 1 u rim- tlow by fnrt"l:'tl intal .· of
1I I1i{L~ and . in sorm - cases. rln- coad m lntstrutiouof mannitol or another diuretic. m il Incn-aw
the excretion of some dru gs. More rapid cltnunanou is, of ( llll N', d.'simhl.' for tilt' P U '1)(IM'
of dd(}xif~i ll g a pal ient who is overdosed. Several criteria must ' ''-' TIle! for fOR.'t't1 d iur esis
to be of value:
1. Ht'lml excretion under condmons o f (nn:'t'(1 <Iinn'sis mu st 1)( '("1111 1(" tilt' majo r route of
dmg eluntuanou, I lwn'ao; i n ~ lhe renal dt'amll(:t' of a d m~ Ill-fold. fllf ('xamplt', does htth-
10 hasten d r ug e1imhmlion [rom 111l' hod)' if renal e1t',anul('t' normally is on l~' 1% of fotal
dl' anUI (,(' ,
2. 111t' compound must normally bt· t·xknsin ·ly n-ubsorlx-d ill till' n-nal tulurk-.
3. If till' n 'ahso rpt ioll ts p I! sl' nsili\"t'. both fom-d diu n-sts and p ll control ilia)' he of
vulue. 111is applies if forced dilln'sis or pl t control alonl' o nly pa rtia lly pn-wnts n-ahsorp-
lion ,
TIlt' last point bears further discussion. SUPIX)S(' thut, o n alkalini7j llg tilt, uri ne, till'
n-absorpuou (If II weak add is decn-ased from un to )( )<;f of Illal Iilte-n- dand seen-ted. 111l'
lltklilioll of fon ,('ll dum-sis \\ill he of lild ,' addi tional \"01111I' ; Ill(' ewn-tiou r an- can unlv lit,
tucre ascd by a furthe r 10%. 111e converse app lies In tln- \IS( ' u f p I! ('(JIIlml wlu-n fUR't'11
diun-sls almost l'tllllplt'h, ly PTt"\'t-'1I1s n-ubsorption.

Renal HandGng af Pratein Dng.

As SIl()\\11 in Tahlt, 11-6. l!l'lTI~', espt"(-jall~' l c ,,"\' lIlol,"('ular \\'('ighl. p rott'ills an ' subslantially
filtered in the gim llt·m llls. yet !itt lt, of till'S(' an' Ilsllall~' found in urine. 11lis low ren al
c k-ara uce o f proteins ari ses Irorn t heir metabolism in rln- proxuual tubule. I" ,,",' I!lO!l,,(11Iur
wt'ight prctetus an ' Il1t·laholiJ'..l'11 by t'1I1.}1111'S 10(';.111'1) ill tht' lmrsh bo rder (If tln- lumen,
WIll'n'ILS high mol ecular weight pm lein.s of tln- Si"A' of alhum in an ' transporte-d tnt o tilt'
pmximal tubular ed ls I ~' t' lIdo,-')tusis and uu-tabohzcd then- b}'lyso wmal t' IlI.}'llll'S. Gt'lJ'
emily, ('alaho lism of p mlt-ills continues until tilt' const uueut am ino ad d s are formed. The
amino ad ds an ' then (.'t I!lS( ' T\1'1 1 h)' rea bso rp tion into till' \ 1L..culatun-. Althou gt. ljllaTllilati\'1'
data art' spa rst', it aplx'ars that for sonu- proteins. and prtlhah l~' also p rotein dmj.,~ , tilt'
kid ney is a, if 1I0t tke, majo r O~lI ll of elmunanou ( St.'!..' Disease, C hap. Ill; T urnover COIl-
("('pts, C hap, 23 ).

DEPENDENCE DF ElIMINATlDN KINETICS DN ClEARANCE AHD DISTRIBUTlDN

111(' physiol~' o f tilt' Ixltly d il'lal('s Illat several plmrma<.'lIkilld it: panllnd t'rs .ITt' n-latr-d
to am i dt'llt'ml,'n l Oil 0111' another. Pt'n mps the most Iuudann-ntal dt1lt'lIdt'lIl')' ill cltnk-al

lATWUVn CON:::f Nl V TJ:)N

fVo9M. CONC INTUTlQN

InloUlin 0.000 0 8Q
Myoglobulin 16,QOO 0 75
Grov.m hormone 20.000 0 72
Superox~ di~lJlo~ 32.000 0 33b
Beocepo" 44 ,000 008
A1bvmin eo.ooo OOOl e
CHAPTn I I E1r.MlNATION "9

phamlat'tlkillt'li<:s is that of half-lift, 0 11 (t nta]) d t'amll(.'t' ami '1111l 1l1t' n f dlstnbunon . 111is
d('P"'Ill]('IK'Y is d('ri n"tl ;L~ fo llows .

Haff-lift in pJasmo
Hecall from Ch ap . 3 th.u IIU' ehmination mit' constant (i.e.. fr;H;tional rate of drug (·Iimi-
na tion ), k , is n-lnn-d to total ch-arauce. Cl., ami vulunu- of dis tribution, \ ', hy the exp res ston

k Rale of elimination Cl
.. Amount in body .. V 26

Bt'(.·;tIIst' clearance is Iht' volunu- of pl.LslIlil ck-un-d of dm~ pt'r unit n f lilllt' ami \' is tlu-
vnl u uu- that drug apP"'ars to {1("i;llpy at a t'tlllt't·nlralioll ("{pia l to Ih;11 in plasma, it is ap pare nt
Fnun El l. 26 thai fmt1icmul mit' o f t1m~ r-lnninunou can Ill.' thll ll~hl of ;LS tilt' fm(;lion of
tilt' volume of d islrihillilln From whit'h d n l~ is Tt' lIlll\"t"t1 pl 'T unil tiuu -.
Furthermore, n-cnll that lIalf-lift·, t l !\!. is n-lated 10 tc . or til \ ' and el. Ihmtl ~h th t' ( 'X -
pl"\'Ssio lls

- 0.693 0.693 V
--; - - CL
27

Tn appreciate tlu- d t'!)('ndt'Ilt'(, of half-lift' on d t'ar.ult't' and \' IIII IIl(' of distrthution. t't lllsid('r
a dmlot thai u lJ(le r'J.t{ II.~ complete t'nlt 'mllt'patk t~l.·l i Tl~ ~l' l di strilllllt'S to hil t' and subse-
fllWlllly to tilt' intes tines in s i ~1\ illt"llll t ;J11\Ul1l1IS a..s a n-sult of slllw intest inal reubsorptjou.
111t, t"lJlist'flllt'lIt"l' (If hililU) ohst m t1iol\ wn ultl Ill.' It dt "l.'n 'lLS('(1 voluun- of distrtlurtio n, hul
no t:h all ~t' in lotal elea raru-e, and therefore a sho rter lndf-bfc. On th e othe r hand . if there
is no t'll!t'ro llt'p:t1ic (} \'Iinlot, tilt' hil(' am i tilt' intl'slim's an' not P:lrt of the \'o tUIIU' of di s-
tri h U!ioll, BiliitTy nhslOlt1ioll . hy dt 'i 'n 'll-sillg d l'amnt't ' \\i lhoutltlTt'di ng distributio n. \\1I 111t1
the n cause the half-life 10 iIWTeaS('.
Fil-.1J.Jn.' 11- 13 illu strates hal f-Ii\"t"s (If dOl~s wi th cu rious ('(l1nhi na tions o f d t'ar.llIi.'t' and
vnlu lilt' flf d ist ribution . \ \ 'ln-n d l'am llt'(' is 11Iw ami \"(111I1I1t' o f d ist nbunon is Iltr'J.t{" tlu- !lalf-
life can Ill.' wee-ks o r montha.Tlu-n- is a paudty o f dOl ~ c-conples \\ilh these characte-ristics .
11 lis is not s ll rpri s i n ~, as d nL~ acc umnlut ion wnukl Ill.· t·xh'1\sh'(, and occu r s1nwly 0 1\ t1;\ily
dusi n ~ , Furtln-nno n -. rk-toxifi canon o f a patient who exlublts toxidty while nil such a t101 ~
wu nlt! Ill' slow without intervention.

HaN-life In Blood and Plasma Wert"

111(' interrelationship s t'\ p Tt's 'it'i1in Eqs. 26 and 2. an' just llS n 'ad ily derived from d t'a mll("('
and " ,lu fTlt' par.1II1t't t'TS II<Ls('i1 O il meusun-uu-uts of dOl~ ill h llll.MI (Cl . " ,,) oT in p laxma
water (CI.u , "rd . Thu s. by tldi uil ioll, ".

Rore of eliminction .. Cl ' C

.. Cl b • Cb ,. Clu · Cu 28

am i

Amount in body ... V " C

.. Vb " Cb .. Vu · Cu 29

~ ()tt , th at each dl'ar.mt't ' o r volunu- te-rm can 1M' n-lated to tilt' othe r using: the dehni tinllS
... flMNATION CHAf'TE ~ 11

I II "" Gil l e illldji'j, = e ll IC!>' For cxnmpl••, C l. "" [u . C I.A1. n i \i tlill ~ each tcrru ill Eel_21'1
hy tilt' n ·sllI.·t:fin ' term ill E,,_2H ~i\"('s
k _ CLu
30
"" Vu

uud Oil s ll hs l i l ll l i ll~ Eel _30 iu tu E 'I _ 2 7. it follows t h aI

'0 '9
20 • 100

•
2' 22
••
23
• 30 ' 000
•

10,000
(hours)

1000 '0,000
Volume of Distribution (L)

nit. 11_ 13. ( :I.... r..'Il~· (" n lm,d.·) "",I ...IIIIII<· .. r . I"l nhu ticm (..1....;,....1n r ..•.. "'-1...1t1rup ,.. ~- ...iolo ·I~·. n" · \b"~ " ll4r
, ..1.. 0. .. 1 1"..-.; . 1.."" 11M' n m ,l,h...lic" " o f .-!t·ar;<'J<'O' ;o'HI \~~ " nw will, tI,,· "... Io"lf.llf,- (IM,u n). ~ "I<" 110..1 .I m~
..i tl, "'" d .·;tr.Ull"l'" ..".1 1,,'1'" " .."', (ril:l,1 Ie"",", '1"...lnllll " f I{r"r>l, ) ;u ".Iiffi<; ,lt I" lin.l: tl..-tr hal f·hw~ Ito.'
" tl<'l1It., 10"'1: fur .10,.....· ,lml«l<> I,,· " 1 r r"'1i<-..tI~· ill .Inll(1I"'r"l':" (A,!..j>l,..1fru ", Tun "., T :'\ .: C'''K''l-pl.I....'k
t" 1,1,.. r",.•,,,,l..l n<'lI<". 11,..rtIl.Ol' .I. n lt·•.. 12. 1l1!j...1 31. I~ I U.. ..I "..ill, p,-m'l... i<." ..
f .."II.... ;1.".1 l"'hli.I,... .) n ..-
.In' l:' "no ..' f"II.......:
I 1',·" l.; 1I1" v
z '\' p lo "
l:l. T..t r...:w li' ''·
13. ( ;' ·III.m ,id " ,".
I)ij.("" in
(;"'IIa1J,,,,,,,
a I ',·" id ll", r: 1-1 :\ ",lLot; " 25. l) iov' l );lI"
~ ( » ."; II,,, 15. n " ' '1,I,}1Ii 'w :26. (:..rt"''''''''A,.'''-
.) t"llm.. ·",lt"· If> ."..ivt,h ",i d. - 27. S" lfa"..-rv i,..-
h . \1 ....)'111"'- 17 s lllfi.. nvJol.· 2\ . \ ·..IP" Jit.- ." dtl
-; \ 1' l ,,-o ,li"••
.. l'r" I'....u"ol.,1
\I I'ro ll·,un_., ni," -
... T" II..'I.."' l...·
III 1>O'....," 1 h~·Il"' l rnm' l".·
:lll 1>o. " ' 1'l"
'"
W" rfari ll
.111. ." ", ic.. Lt" n..-
.11 .""'rI..",·,;";,, II
III C)" ln idll'" 2 1 cJ ,l<.rp"''''al ln'- .12. 1'1..-,..oI...rtril..l
I I ( :Io I" ra" 'I'I"·lIit.d 22 :'\ "rtri l~ li". · :).1. I) ll:illl. in
CHAPTER 11 ElIMINATlON 111

0 .693 V 0 .693 Vb _ 0.693 Vu

' 1/2 = CL 31
CLb CLu

T hus. lilt' value of Ihe eliminatinll rail' constant. k, or III(" half-lift", t lr<!' is indl"pt"ndt"nlof
tilt" silt, of lIl t";L~ lI n" Il U" lIt in blo od.
T ilt" d t"ar:\Ilt't" par".II1lt'lpr kl'it "tl O il m eas ure-me-nt of d m g in blood is IISt"flll ill consid-
cratious of d mg extraction ill tilt" (']illlinatill ~ nrgans. \'ol unw end clearance parameters
h ,L"t'( 1 on 'hI" Illlho und d m ~ coucent ruti on an " part i(11larly t1!wful i n therapeutics . bec ause
it is Iln- uulxumd d n l~ that is thought 10 n-late mos t closely 10 till" t"lTrt1s of a dru g. Both
set s o f pa nullelt" rs an" o f \.l llIe ill alllidpaliu1-": and 1~'ll lIalinR lilt" phannacolduetie ami
tllt"rap('ulic l,\Il\Sl'(llIl"Il(,\"S of eln-ranous in prote in btndtng, billod n O\\' , an d other physio-
lt~l" va n abh-s . In pract ice, p[;l~lIIa d mg conce nt ranons aft" usnally IIIl"<lSIIR"tI, bill Ihl' all-
plil';a!ioll of ti ll" \ '\I h ll1 l(" and clea ruuce pa ralllt1ef"S so ohtahwd is lunited .

STUDY PRDBlIMS
(Answ ers to Study Problems a re in Appendix II.)
I. Th e renal ck-arances and till" Iracnons unbou nd in plasma of th n-e dm~s in u 'O-kg
sllhjl'(1 un- ;LS follo ws :

Renql Cec-cece
Iml!m,n) f' OCli()n Unboul\Cl
Theophyll,ne 10 0.50
F'henyloin 0 15 010
Cetoerod 20 0.02

State the likd y lnvolvemcnt of filtra tion, secretion . an d n-aleorptton ill Ihe renu l hall-
tIlill~ of (",It·1i o f the-se- d m /-.'S, wheu GFR is 120 m[) mill uud urine flow is 1.5 IJI I/min.
2. Fo r r-ach of till" follt MiTl~ mult iple d lOil't" qu estion s imlicate Iht." let ters o f all (om- or
mo n ") of tilt" co rrect answe-rs. Hrid ly comment 0 11 why th e others an" nol ('\)fTI"(.1 .
a. 111l" condutons that ind it'llie till" probability of rena l d t"amlll"l" o f a w,"ald~' acid ic
t1m~ ht"ill~ S("nsilin " 10 uri ne p H art:'
I. " is Sl'(.Tt"l t ,\ 1 am i not reabsorbed.
2. It has a pKa vahu- o f s.u
3 . II has .1 small voluuu- of d islribution.
4. All of the d m ~ is n'nally excreted unchangcd. jc = 1,0 ,
h . FOf(,\"(1diu resis is likd y 10 en ha nce signifil"llnlly Ihe el iminalion kiuencs of a tim.!:
I , \\11it-h is bolh po lar and slowly removed fmm tilt" body.
2. For whic h mos t of Ihe filtered and S("(.'n "It"t1 dm~ is n-absorlx-d aud is ~n".t1l"r ie
than 0 .5 .
3. \\1lidl is ne-utral , pola r, am i hilS a \1.lllIl" of/ ,. !!:n "aIN thuu 1),9.
4. \\11it-h is not secren-d an ti for whit-h till" rano of its unbo und n-ual clearanceto
('n "alillim" cll"afimn" is l.O.
e. A n -uul h lnnd d t "afiUll,(' of 56i mUmin for oxaci llin Indicates tha t :
I, It is scen-ted inlo till' lum inal content s of tilt" neph ron .
2. Its n-uulevtract ion ratki is 0.1.
3. TI lt" majori ly o f ti m!!: t"nlt"rill!!: Ihe budy is excn-h-d ill till" urine ulldl.<lllgt"ti.
4. It is nnl bOllml to plastua proteins .
d . T Ilt" n-ual d t"amu('\"of a d n l!!: is co nsta nt with lillw if
I. li s vahn- t"xl'\'t"t l~ 30n m lz min .
2. TIll" com..-ntrution ill urnu- is im I11 'N." lIdl"n t of urine fI (l'\' .
112 CHAPTH 11

.1. Fract ion of fi ltt,r't't! and ~ '(:n' lt '( l <i nt~ is n 'ah..o rbt'(l.
A l'( lIIS I 11ll t
3. l 'a~l l l" l'I
al. (Pap lt'. J. P.. Foster. D.\'.• Ifill. D.W.• and Wood. D .G.I..: Ohst°r'\";t1 iollS
Oil in terpretation of blood akoholk-vels dt'rlw'(! From :Illal)"si.. of uri ne. Hr. ~t l,(1. J..
3:H19. 1007 ) WNl ' interested . for legal n. 'a.'MJII S, in dt 'le rm iniuK if tilt' l,,(lIl l'l' u t ra tiulI of
alt-ollol ill uri lle could he rela n-d to its blood concentration. Tahlr- 11 - . sunnuanzes
tln-ir findings .
a. K Il(,"in ~
tim! ;lkollol is not bound to l'(lInpo llt'nt s in hlood. whai esplanalillll(s ) ( ';11I
} U II olTer for tilt" \'l'ry dost" correlation
" t ' l\\ l '( ' 1I cono-mrattous of ail-ollol ill hlood
and ill uri ue?
h. Would you (''''1')('<.1: the excretion rate of "!m hol to corn-late \\; 111 ti lt' blood alcohol
('tllll1:°n l m t io n? D iM.'US-\ lmelly.

T..... , '.7. 'NCI.-cy D..trllMrtI_ .. the ....... AIe.h.r C.IIC.lltywt1.II••

UrI_'''ee4
Percent d ~1I()n$ 9 51 J2 8
\Jnne ConcenJl'ollOn
Blood Concenlfohon 1 2-1 4 1.4-16 >16

4. T lln"t· d mWi art' hsn-d ill T abtt· 11-8 t<~et her wit ll sonu- uf thei r ph)~ i ed l pmpl·rties
and disposition characte-rist lcs in 11 'j'n-k~ limn.

,..... " ...

~ny~Q1.AU,(;Tttf>T1C

Polo"'Y d unionized fOfm

_...
Polo, -,
''''''''''' 00"""'"

""'''''''',
pKa 30 90 Not on ccd
(wea k codl [om,ne] 0< (] bene
U$lIOl ~ [mgl 250 4D0-600 350
VoIvme 01 d, ~" bullOll III 25 210 245
F,oc;toon "",bovnd [M 0 .1 09 006
Holf.lile Ih'l I 14 8
Froctoon exceed 027 Ol d <001
unchanged llei

a. lndican- till' d m~( s ) for wlJk h ('adl of t1w follnwill!!: stil!t' lIIl'nts is pmhahly must
appltcable:
I . 11ll' n 'II;11d t·urdlln.· of tltis d m !!: is th e most wusith"(' to d l,Ul!!:('S in urine- p i !.
2. 11lis drug hiLS till' hi~ll('st n-nal d t'arallt't:' of tln- thn-e hstcd.
3. This tim" most likd y shows the " n ·;tll·st d ilTusio n lunnauon in (: mss i ll~ the pia-
centa 10 the fet us.
4. Foro-d dam-sis is most Iikl'1y to 1)(' o f value for this ( I m~ ill a l'L...· o f dn l~
overdose.
5. Fo r 100 Ill ~ ill the- I)(llly. tla- p l.L\ rna coneeutrution is hi~hesl for th is drug aftN
d istrihutioll e-quilibrium is al:lliewtl.
6 . Thi s dm~ ha.s til(' lo\\\'st total d(·ardlll"t·,
h , C irdl' tlu- must appm p riillt> word. t N IU , or \ 11111(' (of those sho w n in italit~ ) for rln-
follo.... ill~ statements:
I. 111t' n "II;11 d l':lrdlln.· o f nafcillin will j rlCn'(IS('" d~'Cn'(I."f·•.shOlt ' l i tt ll' elm'l /!." if tlu-
d m~ is si~lIifit'IU I I,· d isplau:t1 Irom ptL~ Ill;l pmh 'in bi ll tli ll~ silt'S.
CHAPTER 11 113

2. For tilt" d m~ with a n-nal cleanuax- that is lIlusl st>nsitin> 10 changt'S in uri ne p i I.
tJlJ." l il.i:.tltiOlI , fI('iflijimtim. of tilt" urine .should dl''C.' n·il<;t' th e ren al ck-arauce .
3. ~ af('jlli ll ~~, h .wt rhst rtbun-d t...·(·nly throughout and '1<.'(.' )IInt(-<1 fur wi thin th(·
cxtmcellular flurds.
-I. Cyduspo rim' is p rilllilrily t'lilllin "h'i.! by "..1f1iJ"li.ml , n "lm/ loxO'I'ti' l/I .
5 . Cydospo rillt· ran. rannot 1)(· highly bound ifu les s limn 0. 1) 10 plasma p rotems
Sillt.'(· it has such a largt· apP;'l n 'lll velunw o f distribution.
6 . .51,97, 99, 99,9 '.f of tOl"aillidt-' in the hody b )(J("lIIf'C! oUh ide the plasma.
c. Ind i('alt' 1111>d m~( s ) for whlch eac h of the folltJ\\i n~ stat ements is 1II0st applicable.
l. After all i.v. bolus dost" 30<], remains in the I)(Kly OIl 24 lirs.
2. (;i\'t'll t...·t-'I')· S hr . tht s d rug \~i ll Shl J\~' the grea test t!t'g rt'(· of accumulation.
3. Tl lis t1n11-t \\i ll ac hil'n' ti ll' 11J\~'{~t plasma eoncentrutton at plateeu foll' J\\i n~ a
('tlllstanl-r.llt· Lv. infusion of 10 mW'I T .
... \\'he-n Ill(' usllal dcN' is ad ministt-' rt-<I Intrawuously. tllis dmg \\illlm\"t' tl ll> l a rgl~t
ACe .
5 . Fol1 f)\~;n g :t l'flllsiant rate infu sion of 20 mW'lT. this dmg is (·xpt"C·It"C1 to ac hil"'"('
tilt' hig:hl'St pl:lslIl<l enucent rut jon at !'l hr.
.'i BC'i."llll Imm analysis of the- data o f problem 5. Chapter 6. th at tilt-' ~}"t t> ll1ic hillil\' lila·
hilil)' flf tlw dmg d mpt'ri dol From a rectal d m g ddi\"t'f)' <1(...'ice \\~L~ a.50. Gi\ "('n th ai
thl' hIc MM.l-tn-ploLsllI;.I conccntrutiou r.ltin of thts eln lK is l.0. and Jll~Ii¢h le' unchan ged
t1 m g is fou nd in urillt' follu\\i ng i.v. ud ministranuu, to what exte nt ('emld ht'lJil tk' Hrst-
P ,l" \ dim in;.llion ,t('C'(111ll 1 for the loss of billil\a illihilil)' ?
6. In Tal lie' I I -~) en- hstcd some pertinent pharm acoki nenc data. fol)()\\ing administration
(J rall~' (t;'lhld) alltl illlran'll(lIIsly of a HKI. mg tkN' o f a dm ~ to a 6S-k~ sllbjt"l1. TIlt'
bloo d-to-pl.e um concentr ation ratio of th e d mg: is O.Ti ,

,.It•• 11-9.
Intravenous I,Q3 105
0" 0 22 1 22

a. C;.II(: lIla((' tht>ora l hi' lil\Olilabili ty u f the d m~.

h . By appropriate calculatlou. ('Slima tt· 10 what extent tltl' Ilbst·"' 'e 'i.1 hi' lit\"ailahi lit)·
llli~h t 11(" a!lrihu!t'i.! to finl -p'l"S h"IJillk dimiualion .
 I NTEGRATIO N WI TH KIN ETICS

OBIICTlVIS
The leodef will be able 10:
1. li!ol example 01 physiologiC vc.cbes tho! may o!lel me p'In"lOry phormocohneHc pcrcee-
len: o~pnon role constonl, biocMJilability, bepcnc clearance. reno! clearance. and v0l-
ume 01 disrribull()l1.
2. Given pk»mo 101' bkxxll concentration verW$ lime dalo in normal and cseed sscies. de-
termine the changes rho! hove cccoted in the primary and seccodcrv pholtflocol"neliC
poromel9l'S and list the pouible physiologiC mechanism/51 i~
3 Predct and gfophicolfy demonwole the effecl$ of on checnco in poseo prolein Of nssoe
binding. perlu$ion. Of metabolic activity on the lime course of drug in blood when !he
oppl'optiore plirnary pharmocokinetlc pafOITlE!fefS ole k/'lO'Wll.
~ Predid the phormocologiC ccoseqoeeces 01 each 01 the alterations 9'\'$1 in ob!ecJive 3,

HI'fPrt 'Iwt · h frt 'II'lt'1l11~ lIh1d.· loll... \ allll' o f 1I<IIf-lif..· or d t'arall'" of a dn ll~. TIlt' phar-
1Il'!l'tJkirll'ti" par,um 'tt-r. of ;I t1nl~ t-au. hm\t·\t 'r. dJalJ~t '-wilh di"'i!"l" \\ i l l. " J1ItUlIl ila li l
t1nl ~ tlu·rapy. .uulr-o-n \\; 11.111 tilt' \anll' illdi\;tllIal ";11. lilll" , :\ 11 "llilil ~ 10 " "j ~1I lil, 'I~
ph ysiol "!-.'ie ;lll{IIMtb ol,,~ie lII' ·,:I.a uis rm 10 tlU'S(' oh.... ·n ,,, I eh an~, ·s in tln- lilll 'lie ' o f a elm !!
i' importalil . " , i' IIn- prr-diction of IIII' kim-tu-'~ lI l""l jl "' lll"( 'S o f <Ill "Ih'ra!ioll ill ,I pl. .\ , jol, ~i l'
' aria h J!' . Boll. appm;whn ian' takeuin Ill is dMpll 'r ill ord" r 10 illh '~rOIh ' a lld PrOldi(~ ' IIII'
pll ~ siolol!k alll i p hamla,"olirU'!i, · ('olU ~ 'JlI ' h-ann-d 10 Ihi ' point. \:0 allt-llIpl is madc' 10
,'\;llIIill" ,i tllal iu ll' iu \uhin!! allj)()"iblc ' d);lll ~l " of ph~ "';lIlc ~(" \ a ria h l!', a' IIII' IllI'o r('(;ea l
j)(),,;!lilil;p, art' 1011 uuun-nnrv . 111 ' UI"" " !' 1l'1I1 dlaptt ·" . 1"1)( 't 'iall~ ( :hap' . 17 ( 1 1I h' rOIt"l i n ~
I) m ~s ) allll::!:2 (1)",1' am ] Tiuu- 1)1'I)('lId" II(·;pS). adl litio lla l l'\a m pl.·, tll"l d"1I 10ml ral " alltl
n-qutn- ;nl q.,:ralioll o f physiol,~e <llld l illd ie l~ >II(~ ' ph a n- l-,'i\( ' Il.
F rl'ljlll' lllly. ('o lll iitinn' 1",,1 prtltlll("t:' a d la ll~( ' ill Oil" phy,io[, ~i l ' ll;lrOllllt'h' r (';\11 ...·
(·!I;llIg,·, ill ll llwrs a" we·11. Fo r " "Impll·. n 'II;11 <lh,';\'" "pp,·ar.. lIul oll l~ III d''''wa _l ' IIIl" n-nul
dl'aralln ' o f di go \ ill. hili 10 d"('n';lSI ' ih 1;"", , hirulill!! .uul " \lrar"n;tJ ("\" "rall("(' a' \\1'11 (..." .
Chap. 16). T Ill" illh'radioll of lilli llid il ll' a mi di ~o\ill h uuorln-r 1·\;l1Il pl,·, Sim ilar III n-ual
(Ii... ·a...·. ' 1Ilillidill. · d. "(:rt·;l...·' li ' ''1I1' h illt lill ~ and hotl. n-n.d .1111 1 " \lrar"lIal dl'a ra ll( ~ " o f
Ili!!'I\ill . '11111'. IU 'illll ' r Ill' 111(''>(' ..it uat ion-, i' a g,lt ltl ' ·\;l1 n pl,. Ill' tlu- lilu'l ie (, nl\" ' llU 'l' I ~ " clf
any OI W o f Ill(' alll'r'll i'H1' l llill 1)('('lIr, Yd . t l« ·SI · l; m!' o f oh' I'n 'al;IIIl' IN,'('lIr [n ·fl" I'lIl ly. '1'111'
firvt , I.· p ill ,Ul al~-/j ll !! tln-ru i, 10 c'\ a mi ll" lilt' " \Jlt' d a lioll' for all a llt 'ratioll ill ",wit ph ysi -
1,1."",'i(' \ a riah l,' ill\'I,h I" !. T ill' 11\ " rall pktun- i' 1111 '11 l!ai l lt ', I II~' inlt·c,r'lli lll.( 1111 ''' ' \·\ \It" ·I"t i.m....

INTlRRIlAIIONSHIPS AMONG PHARMACOKINITIC PARAMITIRS

AND PHYSIOLOGIC VARIABLIS
. \ " lII ll1la ~ 111' 1111' illlt'rn·blillmh il" ,11 110111.( p llar Hl;l11,l iltdi(' \liIr01l11l'1'·rs and plt~ ...i" rtll.(i t'
\aria h l," i, appmpriah' [n-n-.

' 84
CI1AP1'H 12 lNT£GAATlON WITH KNTlC5 ,,,
Primary Pereeeten and Physialogic Variables
T he p rnt't'Sst'S flf ahsflrp tion am i di sposition depend Oil mml )' physioln¢c va riables. C as-
troinn-stinal ahso1lllion Illay lx- aITN1ed. by blood Row at the absorption silf.' , ~a.sl ric f" IllP-
!)ill ~. an d ~'ls t nlill tes li ll'll motil ity. D islrihution is infillt'nt't'(! by hindin~ 10 bolh plasma
proteins and ti SSIl t' {'o lllpeJlleuIS am i by IxwJ~' composition. He nal excn-tion lIlay depend on
secretion {active tr ansport ), umu- p ll . and unne flow. Eadl of these physiol~c vunables
is aITt'(1t'(! hy num erous factors. Thus. mhh ill,l1; Increases subcutaneous and muscle blood
[low, futxl slows ~a.sl ril' t' lIlpl}i llg, ami diseases and d rugs produce lllany t,ITtds.
TIlt' pharmacokinetics uf a d m~ tlfh'lI can Ix-' dt's<.'rilx'tl by n· lali"t'ly Iew par.ullett'r'S .
Ht"t'all that ahSflllltion ca n lx- charact erized by bioan lilahi lity am ! by an absorption ran-
cons tant . wln-n ubsorption is first o rder. di stribution can be characterized hy tilt' volume
of divtributiou; and eltmtuntlou can I>t., cbaracte naed bj hepanc and renal clearances. As
d is<" usS('(1 ill Chaps. S I hrotl~h I I, each of these !lilr.lIIlt'tt'f'S lila)' be <!in"t1Iy aITt'('kd II)"
dmnges in physiul(~ c "a riahlt,s. Bt.'(-,Ulst' of this direct relat ion ship. tllest:' pamlllt'tef'S an '
n-fern-d to ill thls b ook <l" l ,ri ma n; "/lll n IlllOlki m.1 Ic IJllmmt1en. I'hysioloWt, variables tha t
aITt'l.1 priuuuv ph anI11Ll"()kint't it' par.lIIwtt·rs are llsted in Table 12-1.

Se<ondary Pharmacokinetk Parameters and Derived Values

Ii alf-lifl'. elimination ran- cnu staut , and fracnon exert-ted IInd mngt"t! in urine an' examples
o f WCII/u/(Jry ,J/w nllllcok itU1ic l Hlnl llll'lt'n, in tllat their values depend li n those of tl\('
prim<u} pharmacoktnenc par<lTIlt'll'rs. Furthermore, there an- several dl'ri"t"tl values. Slid .
ax ..H':C. thai ck-pcnd lIot (lilly nn the primary pharmlllUkillt'tic p;.lI'lulll'lt.·f'S hut also Oil
t' itll('r dnS(' or mit' of administmtjon . TIlt'S(' dt'I>t.·ndt'Il<:il's an' summarized brit'Ay in
T ahle 12- 2.
TIll' equations in Tahlt' 12-2 plus a Iew previous equations p"l\idt· tilt>ha."jc· n-lanou-
ships for illl l'rprt'tin~ am i prt'(lic1i n~ alterations in kineti c be-havior. Part k11larly useful an'
till' lIll'lllory ulds of Eqs. 13 and 17 in Ch ap . II. namely

ami

Tall'. 12-1. De~IHI...c. " PrI.a.., Pha....c.kllMllc Pa,.. . . ."

... Ph.,.I.I.,lc Vanaill••

A~ptton fOIe con~lOflt BIocxl flow ot CJl:»otpliOn~. 9'U"1C empfylng tcd}. ~nol
motility [Otal)
BI(XNClllabil,ty ~IC emptying. 1oeO"etion 01 oeid ifl !oIOfTIOCh ced hydro/yhc
enzymes in bile. inIso$hnol motill'Y
Hepo IK clearance. He,xl!ic blood Row, bindlll9 III blood. Ifllnruoc hepoIoceIIub
b!och'ailabiloty" (lCtivity
~ena l eec-eece Reno! blood Row. bonding in blood. OdrYe!lllCl'etion 00''''
~ption, 1,11'" pH. uOf'lIIllow. gIomeruIor liltlation,ote
Bind'll9 ifll*xxj, binding in 1i!oSUM, JX)'fltiorung IfllO lot. ~
compo6lbOn, body ~ze
 '16 INTEGAATON WITH ItNETlCS

r.we12-2.
Vet- _ Pri..-y
D.' c ry ..... • 1
Pwr........
1 ~ D.rl ...

Secondo", P!>::J.'"'CJCOl, ~

"(JrQ~'
EI,....tl(l!1()n hoJ.l~ o 6Q3 • Vo!o.me cJ cb-ib.Aon
Cleao>a
EI'''''nQ!1(lI\ ' ate COf\$IOtlI a....,.",/IV""",, <J ....""""'"
Frocl>Oll e..creed UI'lChorIgo::!
De<,,oed vetoes
Ponol dooo<Ol/lT"""-"
"'eo unde< c"","" Ii v.1 "'-Ia....,.",
~ coeceeeo-oe [, v I lInMion ralel/C\eoIorc:e
Area unde< CuM!' [()foIl
",-.1C>al ~

A"""oge
[()foil
pla teau COIlCeI'IIIO hOtl """""'"
Dow . lOaI biooYo.lobl'trl
C1eoIOflCe • t~ JnteJvoII

" (II" lIlt' clf ( I i ~t ri lll l l i( m t1t'lx'll(ls nn billtlill~ to hotlJ p l'l\ lllOl pn 'h'i lJ\ und t isSllt' {''Ulls lit m 'llh .
For u t l m~ wi lh a large' " ,luIII{' (> 50 1.),

v, · Iv
v _ Iu, 3

w!lil., for d )11'0' " 1lI0) c'(111.'f \t"('i~hf « .')00 JiIOOJ(·) dn l~ wit b OJ s mall m lu llw o f tlistrihutKJIl
« 11.2 I A ~). \ . h 'nlL.. to hI.' ind t-pt'mll'lll of (:h aJl~('S ill / 11 (Chap. 10 ).
TI lt' \ 11}.<,,('(III(·1I1 t"ulIlplt'!i an' an;1l~7..t"(1 m illJt tlWM' n·laltom.l,ips. TIIt" - (·)'I·mpJil).· alt e r-
aho m. i ll intri n..it., 1M'p'llol"l·lIl1l,ar ac:ii\i ty (im lut'fin n allli inllihi t in n ). h(-pati<.' hlo .. t1 RIM'.
,Ki i\(' tubular secrvncn. am i p l'l\ IIl'. p mtein h ill(liu /;:.

Indu<tloo of Metobol...
SUlIIC' d m ~~ {~"II i nduce tt.., 1I J('I OlI M lli ~ 1Il of otllt' rs b" illc,·n·'l,ill~ t jn- m it" of sYll t h t~is o f tilt'
( ' l1l)ll1t-{S ) ill\111\('1I. n il' kim·tit.· alltl therapeunc c,"( mSt'lIIlt'm't"!i depend on wlwtll{'r tilt'
a ITt'tit'll tiOlV; initially t.'l\ a low or a h i~ 1 ('xtr-.t<.i iull rati o in lht' d i m i n'lt i ll ~ organ in wh ic,·h
illtllll"tiull UC,"(:UI"!i .11lI1 on the rout e of adminislmtiull.
Low E "'lnlc,1in n Ruti n . F iV;ll n ' 12- 1 dt'lUlliI ~t mh ' ~ IIII' kim·tic,· d fc,"{1 of induction of
wurfann uu-tabohsrn hy tilt· .mntul x-n-ular a~t'll l rtfarupin. \ \ 'arfarin is pn-dominuutlv me-
1,IIMIIi"n! ill tilt' !in 'r ; liUlt· h ('xc,'n'h 'll ill un nr- 1I11c,·hall ~.·t1 . \\'arfarill i ~ ulso {"( llIlp lt'l (·ly ami
mpitll, · ah'itlrIM'l1 when ~\'t' ll orall, ·.
Tln- datu ill Fi ~. 12-1 ~ II PPUrt warfari n ha\; n ~ .1 Inw hC1lillil.'c'\!r-<tl1iun rutin. nih ("1111 ·
dn~inll i~ I..{'it'll (III a rtllIV:" (~aI(·lIb tin l) IIf t"!t·ilral)c,..-, n ul'. dll ri n ~ 11)(' {"(llll rn i pha....::' ch-ar-
'III{"(·. uh la illt't l I,,· di\;tlillV: doS(' (1 .5 1II w1 ~) h, · .U :C 113fi() m ~. hr/L. calculated fnllll
C (U)/I; I. is (J.OOI I 1 J1 l rll~. 11){' h lcMltVplimna {'UIIl"t·lIl rJ.tillll ratin b. (J.6. ~o that 111(' {"(1m '·
~ IM llldi n~ " Iolltl d (·.lmn{"(· is 1I .tlHl ~ l J1 l rll~. nli, \·alllt· is ItM' compan-d 10 tbe Iu-p.dic
hllMltl Hllw elf .') 1 IJ1lr(;'"U kv: or 1.2 IJ1lrll:lt. I u tilt' p rt~'Ul"t· of rifam piu. ti lt' Al'e n f warfan n
i.. tlt,·n ·a.'>(,1 C,"(1I11 jMrt,1 tn Illdt of Ihl ' contro l va lue. n ·f11"{1illJ: a Iai~t.(· r d l·ar4IK't·. TIli'\
ul""" r"'alioll is c,'on,i ~h'llt " ; 11. im luc,"ticm o f hC1latte.· .·Il~'lllc"S ; 11.., c,·I(~ar.tII("(' of a . I m~ of It'"'
11('fl;il k t'\ t r.K.1icJII rollin is 1·'fIl't.1('11 III 1M' "'::'n~iti\l' to d lallJ.:("!i ill ht· jla hM.'t·lInlilr ('n~1llatic,'
;...1i\;~ . TIll' (L da Sll~( ... t un l'fT(, 1 of rtfampln 0 11 warfa rin di ~trihu l ion . TIlt' ("'!ootim;th'tl
\uIU lllt"!i of di ..trihu t:un . uhlaillt'll Imm CU I.. are U.lI' !J and n.l~ l A~ tln rinv; til(' c,"(lIltm l
.tlU) rifa mpi ll pha-'>(''\. n ·'IM'l1i \ dy. n ll' s(' \-alllt'S an' p n ,hahl, · IIul si,l.,1JlihC,';J, utly d ifft·f(·nl.
OW'E ~ 11 111

111l' IIlt'mp"'IIIil' l'(JIl~"( l ut'Il{'t' of induction can ht, app n'l1:t1ed [rom Ibe d iO'..-n-nce- in
th... n -sponse-t inu- l'II1'''''S, sllO\\1I in tilt' botto m ~mph of Fig. 12- 1. R lW}J{IIU t ' here is defined
us lilt' ... I,,·\·alion in pmth nJlIlh in lilllt' ahow' a h'"<;f·lilw vnhre of 1-1 sec. TIll" II\l 'rall n ·spoll<;.t',
!-orin 'lI by lilt' un-a muh-r 1111' respouse-tinu- l'III"\'(' aft N Ih... singl.., oral dose, is suhs lalliially
n .... hu-...... 1 ill II...• pn ·<;.t·Il('(· of rifarnp in. Co nst"(Iu(·l1 tl)'. 0Ilt" wo uld ..·xpt'l1 under sh ·ady-slalt·
coudtnous that Iltl' dosage of warfarin mu st he Increase..1 in the p rt"St..'lll'''-" of rifampin to
main tain the sa nlt' prothrombm lim e. TIll" n -ason fur the app.ut"llily puo r l1.lrrelation be-
tween r"'spon~' alltl plastua warfarin concentration dn rin~ til(' first 4S h r after war[ari u
uduuniv tration , wln-u rt·SPOll<;.t· is i!ll'rt'a\i llg a nd conceutratlnn is falling, is d i Sl'm~'( 1 in
Chap. 2.1, T urnover Concepts.
Hifa mpill is a known im llllt'r of IlI'pa lil' dOl~ metabolism. •md the ..Llta pnl\i d.....1in Fig.
12- 1 un- g"'lJN a lly l1msis!t' 1I1\\i th ind ul1ioll o f wa rfa rin lIlt't alxllisll1 by rtfarupin. II fl\H,\'l 'r.
thcr..· an' p roblems wi th resp"'l1 10 Ille Int e rpre tat io n of IheS(' da ta, in addit io ll 10 ti Ll' aIXI\'t"
ml'lltio ll('tl pro blem of rt-"laling warfari n concentration 10 rt's po nS(', \ \ 'arfa rin ts lIIit rlwlt.... 1
'l' a m('(' malt'. It s euantioun-rs 1m\"(' d iO'e n' nl all tk1);I~u lan t !x ll..-uci..-s a nd (liO''''n' nl kim 'til'
pmp, ·rti,'s. Fu rthe-rmore. tln- dla ngl' iu prorh mmhlu h llw Is a l1J1lst"fIUl'Il(,' of d lan g:l's in
sevr-ml d o tt ing (;1<10,"" Han :'maltos a re common ly used today, instea d of a p ur... r-nuntjouu-r .
O m' Isonu-r Illay potentiate- or inhihit tile kine-t ics o r d)lla mk'S of lilt' ot l...-r. As lo ng: as
ra(1'ma h 's a n ' udmiuiste-n-d, killt'li<- am i d)l l<un ic data on lilt' pun ' euanuom..-rs, whjh-
helpful 10 d t'fill(' mechanisms in\uln.... I, a n ' of ques tionable 'mil
c \\i l ho ut l1Irn.'slx lIld illg:
da ta ff)llo\\i n~ t h... ra('('mate 'l' \\'('11. Clearly, cbirahty is a major issue in therupeutics .
lIi g:h Edmclio n Ra tio. Induction of metabolism of a dnt g: with a lugh Iwp;tti<- extrac-
l ion ratio h,l' kim-t ic l111lst"(IUl'lll'('S w ry d iO'('rt'ul {rom those of a d nt g: \\ith a low h"' pa ti('
ext racti on rano. as iIIustra tt....1 ill Fig:, 12- 2. Prt't n-a tlllt' llt with tilt' Indue.... r po.' ntnha rh ila l
ap!)('a rs 10 h'M · Jiu l.., effect on tln- phurmaco ktnencs of alpn-nolol aflN its in travenous (i.v.I
ad mini,tral ion . Fullu\\ing oral ao.lminblmlio n, 11tJ'\"(" "('r , IX>l:1. tilt' pe-ak ('(}JR,' ul ralio n (C ......)
am i At 'C' an' t1 mmal it'al ly n .... ). L(' 't 1. althou gh then- is liltl(' appan'll t d l;l.Ilg:l· in 111(' half.l if(·.
Tl u ~ ' Oh~·I"\~ll io lis . al first g:lalllt', app,,'a r 10 h e tncouslste-nt . Kml\\ing: Ihal this d m g is
lIw lalxlliu ... 1IInly in tilt' lin 'r a nd olll'llll11t lling: (fn ull dose and AUC follo\\inj.t i.v. ad m in-

20 fill:. I t- I , 11.., I,alf·lif., ..f ",,,,f a·

n il , a dnll': "'ilh a ..........lr...1i..n Mi",
;• •h"rt'·"' ·11 am i d ..a ranl" · i . ill -
l...·;!,! 1 "'....." 'I l. IQ'I'''' (" 1" '11 n r-
cI..,,) , a , inlo:w ,1<.... (Vi rnw\lit) I....
o flIrt' (l>I..J,; hIK' ) ;&I..J " hik' (..ul<Jl\..1
<in ·..... an..llin..-) II ;lItl"l~r, rifa", .
pi'" 1. 1. ""1: ...1"'i" i n ..I ... .. filWt..
"'lit I""" daily f".. J d;!,~., pri.. r In war·
farin admini.ttr..lw.,. n,.. I"~ol lUKI
,I"nolw. , of II.., t-It."'"lw., in tiM' pn..
thnllnl>in l inw ( ft" IX"'''' ' a ft' Ik"
l... ~........l wi..." ri(;!,mpin i. ('< . . I"'ill·
hh 'n ..1 (J,"">"f j:(f"I'I., (I mwJ . - ::S.J
40 j.l M), UI,,,....I,,......!. ",ill, I"·n lli..,i"",
30 fn" l1 CH t' '' I!>', R A.: 1111. ,.....111>11 ,,(
20 ....h,Ul, ", dati" alK I n f"rnpi" , ,.... 'Ul.
Inl" OI, ~l '-. ~ 1 :J.17_141 1. 1117-1 ,)
14
12
2 4
Days
 O W TE Il 11
"'
"-1,it. 12-2 . 1,,<I''' 11O ''' O( ..ll'n·r.. ,~ .r
""1"'..>1,... , I~ 1.. · "t"i~r"'il ..1 I,.· ·
" wnl I'no, l "t~ .. ",..rl<, ~1 t!;(f,.... , . 0.1
' " 1/.. • I'l.., n~, " ....~·" l r-.. h.." "' ·11
II,,· .lntl: j\ Io!lu- n " r..lt:-"(::!I n "' ~.l . I" '1
11. >1 wi"·,, Io:iw.. h . (5 "'It)..\ ll'n·" .
,,~.I "'.... ""\", i,, i'Ioo...-.:II ..·(..,.- (1)1;0<1
I"....., e , i ,\ '.: O. "rah and III .L~." 0.01
1Il1" (" 010,,, ..1 li",...:..,._
j ,\ '.: 6.. ",;oil

a po·ntnh, rlo" ..1 "'\on""·,, " f " Ml '"l/:

.01 I".,h ,,,... (1 1tl1t/1. - 4 ,IlIJ M )
IF m ", _~ h;", . ( ;., l'l..r.h. ~ .. ),it,, 1.
\1 IKI " '" It,hr , c, Eir.'t1or ,,,.,,- 0.001
, rI,,'..1 'M' tI ..· ' h" iti.." or "I·
lm -,,,,I, ,I. <:Ii" . l'Io Mn ,-<:,I, T I..., .. o 2 4 6 8 10
21,31fi...'l:.'! L ]<177.) Hours

h f r<ttiu IIl 11 dt·;lr.UJ('( ' IIf 1.2 I J lIliu in tllis ind i\itluitl. all l'Xp lml a lill lJ ean 1"-· o lT('H'(1. Pen-
loharh;!;!1 im llll1.·s alpn-nolol nn-taboltsm. whit·1I llI;lnif(·sts itsdf 'L~;t dl"(·rt'ast' in alpn-nolol
oral hit ); l\~'il ahili ty . Tin' ar~lII llt 'll t for this eouclusion follows,
TIlt' !l" Il:.ltie ,'\tn K·tio n n ltiu of «lpn-nolol is h i ~h ; its dt·ilfann .· llppn),;,I(.'lws Iw pa til' blood
flow , a pp m \ imatdy 1.3.5 [ / m in , ami its o ral hioa vaila hility ( F) , ("d.!<-u la!t'(! hy ("I )Il1 IM ri ll~ tlu-
dOSI' -U lrrt '<.11'(1 A UC ilft N uml ali<I i.v. adruinistrations. is 0 .22. G h 'l'll thai tl a - low h io-
'i\"llilah ilily is dIU' sol, · I~' 10 Ilt'pa li<- l'xtml1iulI, tilt' ht·ll:.ll i<' ('.\tml1i ull mho ( I - Fil l is 0 ,78 .
Bil),;,I\'ailal,ilily ft·f11'<.1s till' ha lall n t- IIl.,twt 't'll pt 'rfllsi,m, whil'h fon..-s t1 m~ thm ug,11th t' organ,
and 1'll1)lllati l' aelhi ty, wh idl n- moce-s dm ~. AftN ind ul1inn . whil'il i lll'rt',N~ t'lI ~lll(' ac-
tivitv. nrul "ina' ~l ila hi l i t\' (Il'L"I'(1 on c..,m ll:.lrisu ll of :\ UC , -alIl1's ) dt'(·rt·a-....-s 10 n .IHl, almos t a
fOIl;li ,ld ('h'III~'·, ami ht:lIl"' lh t.llt'pal il' ext raction ra tio tncn-aws 10 IUJ-I . Bt'<.-dU~' d t'a mnl'"
h I't'rfllsioll ralt'·limih 'tl llm l lll.'('aust' then- is 110 t'\id pl\('" in hu mans that pentobarbttal
altl'rs IlI'pa lil' hll '0Il Ho\\" the-re- is u llly a s mall ill('f!'a",' in clearance. 111" lncn-aw ill 1'('lla !i('
extructtou rat io . and IWIl(l' clearance. is oll l~' 21)'l- (from O.7foi to OJ).j ). T Il(' lack of dl;\n~, '
ill tr-rnnual half-life arh'r inducttou also il\(li<'alt's that l'Il.'nloharhi tal l,as 110 dTI"(1 Oil lilt'
\-t, llllll" uf t1h trihllliUll of alprenolol. Thus, im lll<1it'll of 111(' ml'l al"Jlism o r this d m~, or ;IIlY
otln-r d m J.: wi th a h i~h hqMtie t'\ l r..l·tinll rat io. lias tlll' T;.IIll.'u lil' im plil'lIlioll s wlu-n a<lmin-
i' h'fl: '(1 llr.llly, bill not wll('l1 ~\'t 'n intr.lH·llllus ly, A laTJ:('r urul dust', or mort· fft>( IIlt'1l1
ilclministralioll. is 1l("I'(II"I1 in tilt' p rt'st 'nl'" " r lilt' induce-r III Ilrl Mllll, ' lilt' sa nu - " ITt'(1 , as-
' IlI n i n~ all ;1(1i\'i1y n 'sh l" s "illl lilt' t l m ~.
;\ lp w llolol. likt, wnrfarin . is <lIst, mlminislt'fl:'(1 iLS" ml1'lIIah'. ,,·it ll liUlt, t1ilTt'n 'n n ' in tl u-
killt'!il'" " r l hl' i"" mt'rs , the - ('IIlId ll,ions he-n- rur III(' m i\l ufl:' a pp ly il'i wel l to ('a(·11 or the
Isouu-rs. 11lI!" t'(l. if the ft' are \i rt u<lUy no pharmal'ol og il', I n\il'u l( ~l' , o r plliln nul'IIkint'l il'
i1ilT" WII(, ·S 1" 'lw('('1I lilt' tsouu-rs. a lx-m-flt in us ing, lilt' ml"l'malt' is Iha l It dtM'S nol Incur
III,' ofte-u l'llll s;t!t'm hl" l'us t o r "" Il;ml l i ll ~ til(' tsonu-rs.

E\.<1111p ll's o f t l m ~s that inllih it tilt' 1I1t'Ial" ,lis m ur IIlll('r t1m ~s an ' ~\ l ' n in C hill" 17, 111-
I l' r.ld i n ~ I ) m ~s . Ht'(lu(..'(1 IIlt'l illMJlislll can alSfJ I,,· a l"l lllst't IIlt'IIl'" o r IWPilti<' d ist',LS(' (C l.a p .
Ifi ), di d .u"'" d l' fid l' lll'il'\ . an d nt llt' r ("I II1t!it inllS, " 'h ah "'l 'r II\(' ruuw of 1I,'('no.<-", '(1 mt 'tilIMI!i{·
'l<1i\ dy. 11;1' kinr-tic ("IJIlSI'tIIlt'IIl..'s i1I'Ill.·1lt1 011 tlx- Il('patil' ext ract ion r.llin o r tjn- t1nl~.
Lo w E 'l.In l l"li n n Rlltiu, TI lt' t' ITI"(1 o r t1''('f(';ls i l\~ Ilt'pal lll'l,lIubr a<1i\it)' fo r a d m ~ or
low !I" Il;llit, ,'\lrad iull ratiu is illll'l ra h'( l by dala ror l·h lorJ'.m:azOlII· aml l'blonlia>'.l'I'Mnitil' .
 C HAPTE ~ 12 ..9

T Ilt' concentration-tune p m filt' of tilt' muscle relaxant chlorzo xazom- in a subjl'd after
a 'j!)()-lIlg oral doS(' is W I) ' diffe rent from that seen 10 h r after a single 5OO- m~ oral dose
(If d b ulfi ram ( F'i!-t. 12-.'3). TIll' uu-au clearance- and half-life va llies we re 3 .3 mllm ilv1g ami
1.2 hr ill the absence and 0 .5 mllmilv1g and 5.1 hr in th e p resc nt-e of disulfiram . a se lt'{t ivt·
iulnbltor of m:idali\"t' mctnbolis m. Till' cha n~ lI~ co ncentra tion of tilt' Inlulntor (a mi its
lllt'talMllill' s follo\\i ng tht· sillglt· 500- mg dosc ) and the limited lillie of sa mpling ill tilt'
p rl' St'lI l·t' of th e inhib itor preclude ht.'in~ highl)' queutttative. Nonetheless, the effect of
ck-creased lx-patoceflular act ivity is ell',n for a drug with a low t' xlnK1io li ra tio; elt.·am.nl"t·
decreases and half-hfe Increases .
Another example is that of lilt' '1II,.iol~til' d nl g chlc rdiazepocde ( Fi~. 12-1 ). Its half-lift'
is increased and its ck-arauce is dec reased ill pat ients wi th hepa tic ci rrhosis. Ord.! bioavail -
ah ilit\" ;1IIt.! volume of distri bution (110 1 Sh(1\\ 1 1) are unaffected.
TI~at chlordtaa-pcode has a low hepatic extraction rati o (' V{' II in Ilt'althy subjt"<.t s can Ill'
dt'tllll't 'l i From the data in the figun' if one also knows tllat the drug is ellmlnated primarily

_ 100 tlK. I 2-3. n ,,· pt.. ''''l lu M,,·nll1dinl1-

'iE3. u"" , pn.fi\o:-of clJlonrl1Ul""' llf,..r . sin·
~ ~m!tond dOM· I. ) i~ dr..mllh r..,.jh·
inl"1'\"lU.l..1aft.. , di." lfinun ,...lOIn,,·n l lei.
c
••
.~" • ••
l>i...IIi,..m (.500 rng ondJ~il "<I.' ~ ... n 10
hr h,-for.. ,h I' .,hlorzo lUOno·. Th.. In-
c
~
10 ('R''''''' in half·li ft' lind t1,-cn- in ("!c·ar .
u al....- an- .-xp''('If'(1 for 1I 10 , trM1i..n
c
0
U ....Uo .In'K",1..'11 1Tll'1;.hohc adi i~· b tIt·-
~ e re.. .("<1. ( Rt't1ra...-n h o m Kharn d •.
c
0 E.D .. n,n m ll .. >!. K E. Mh)n .. J.• ;I'M.!
~ I .iJl ih~. J.l1.: Sin.t:\t--<l..... ,li.. dfin m
x
0 inhihiti<lIl .,l d ,I"I7;<''<&'''''1O' n..-tllh"li. m:
~
0 A d ink al p robe- for PoISO 2F.1. Ch ll.
:E Pharmacul. Tb- r. 53:64J....fi.'iO. 100.1. R...
u
~ produ ced with pN mln io n of C .\".
E M o d '}".)
~

if.
0.1
0 3 6 9 12
Hours

Normal Cirrhosis
1
"
'"se . s
~
1
Normal Cirrhosis
22 0
.'1,;:_ 12-4. c l.I"" liu"'p'''idt• • half-
lif.. p j, KTl"..... ·d ;oJKl tut al d,·aroUM't· I.
tIt'l'n 'a",-d in I""'twILI5 ....;Ih l..-patil' ctr -
§. rho. i. """ "[';I n..ltc norm"l subjrth.
50 1.0
~ ~
~Il"".ul ( ~ S E ~U and ilMlh-i<I,,,,1 _-allie'S

.
u ar .. . ho" ·n. ( ltt-lIn "' n Irom s ..II,·n.
c
~ 40 e 0.8 t: . ~l.. Gro"'n M;oIl , O J , Gil. ·•. 11<:..
;; ~

E S aran;-,. C.A.. t.:..,.t;m. 11 ,. IU><I ~I ;K"

~
u
"
~
30 ~
0.6 I. ·ott, S , ~l. , Chlon.li...... opoxiclt- ;0,...1 'n-

." 20
~

0 ." 0.4
~

0
vrpoom t1i' p""ilion in dnt~ltks. e li" .
r h. m,a,:ol , n WT.• 26 ,24U-246 . 19'; ll
~ ~

•• " '1' n. IIXnl "~Ih ('t"mli..i<. l of C.\".

f
~ ~

.!ii to I .!ii 0.2 ~ ~I ... I'Y')

'2
U
0
:E
0
~
~
U 0.0
$
 '90 INTEGAAlION \MlH ncs CHAl'TH 11

hy Ill'p,;,li l' lIIl'la holislll , tilt' h luud-plaMIl;\ U II ll',,'u trdl iuli mtio i.. di N.' In 1.11. mill ,,\'{'mg,'
11l'1l;llk blulltlllo\\' i.. 21) 1Il 1 /Illi l1/"~. III subjt'C.1§ wnb nnnnallll'pa til' flll K1io ll . t1K· 11t1};lhc
(",l ml:ti ull r.,!in [CI.,IQII = (0 .5.'5 JIl I )rn i nf1,;~ )/(20 IIl lJm i n/\; ~ ) 1 i.. the-n " 'f'l't11't! In I I(' o nly
ahu lIl um u r I,......
IIi J;:h t:d nlf:t ion Ratio. n it ' 1ci1lt1 ic {,lIlSt' IIIt· IIC't·" flf inh ibitio ll of IIM'r.,It" li"lII o f a
( Im~ \\;111 ... hi ~h IWp' l!il· (·\tr.K1inll ratio 41.1'\' iIIl1..tn... I ('(II ~' tilt" (u,Kl m inistr.ll iun of dnlt'h·
t Jillt· ;til t! I.,ht'lnlnl ( Fi ~. 12-5). TI la! la bcrolol is a dnJ ~ o f h i ~1 h' 1l;I!tC." ,"lr.K1 iulI rdfiu is
, 1,'(11I{1't1 [rum ils dt·;lrdlll'('. 1.06 lA ir {t-sti mah ..1 bv d i\ idi u J: tht· i.v . ( 1o:1"ot" In " tlKo (um "-
"ll lflc liul: .-tee ~\ l'" in ti ll" arnck-L "ppm;.K·hin~ ht.palk' blond fill\\' and fRill; 1I.I').::I)(,wl ·
I.. I~I ' tlMI t.hdulul i.. (·limill"h.. 1<tJ 1I)(~1 t"xdu!oiH.ly hy h'-pati(: 1U11id • .ti..m . 11 M' i.v. (liN ' o f
I;lhd o~ol h IIllldl ~lIlall('r than tiM' oral (LN' , IJl"l'auM' 11)(' ( I m~ i.. hi~hly (·,lr.tt:11oc.1 in tJ)(,
li\(·r. ;. lIcl 1I1'I M't' ~ lthjt "l1 10 1" II' min' fi rse-pa,.... hl'patiC I,...... and IJl"l~.u l'i.(· lIw pha mM(uIt ~c
;K1 i\i l~' primari l~ n .... iIL.... \\i l l. 11.(· drug. rather th an wi th ib 1I )( 1 ahohh~ .
11 11'" ' i.. a tllJ:t' iIK'n ' a ",' in AC C fo r lal w.'lok.1 wlwlI at llllill i ~h'n .. 1 e Jr.II ~·, hilI IKII ",1wlI
~\('Il intmH·IICIII..ly . in tilt' pn""'IK't· (If (;IIX'li d iIK' . This oh"" I'\'aliou i.. '·'I)("l1... 1 fn llc""iul-:
in l. ih itM lII IIf IIII' 1,lilllill;lfw lII of ;l dm~ ",ilh a h i~h lM'p ali(' 1"lrdl1wm r.tlw•. 1111' lark of
dMII~t' in ,m ';' follcMillZ i.v. Oltlminislr.tlicm n'fil"l1s IIII' minor (L."l'n·a.",· t'du",oc.1 bv l'i 1ll11i·
(lim' 'ill 1111' h t11.,h(· 1·\Ir.~1iIlU mfw' ",)(1 ht' IM't' in ck -arance. t:\iCLt.'lItl~', MOI.I ReM' t.~mlilltlt ....
In h mil till' 11l'11.Ih( · l'1illlin.llwm of Li))(101ol ('....e-n wlll'lI in ilih itilill llIl'(110. nl i.. wuu kl nol
I",· "', if 11M' dl1:n..• uf illh ih itilill ",'n' ..IK·h a'i 10 n-d uce LaI .1nl ullo a (Imlot of u M·lll-patic.·
1·\tr.1l1 KIII m iKI. 11 11' la~t ' irK"n 'd \( ' in .-\CC folln",in~ nral al lmini..t ranon i.. a ('Im "'''I" I' IK'I:'
of iIK'n';l"",, 1 h « .,t\ -ait .hilit\,; IlI' n ' ti ll' iIKTt'1II1'u t i.. " IJlJIII 56'1 , w h ill' 0 111\, a m in o Tclc"l'Tt";('io("
(:!U'l) W;L" \("'11 ill ti ll ' h;1l;lt it.· t"l mt1«1Il ran o. n it' tllt' rdj llt'utic ,urnild f) ' of till ' kinl·l il.'
d "U l~("" in ti l(' prt"i.(' IMl· of l'inlt'l id iIM' is Iwi~h h' m,l ac.1i\ity of lollllt' llIlo l w llt'll ~\l'n nr.u ~"
h ilt lIo t ",111'11 Wn ' lI intraw-uou..ly.

AItlfod Blood Flow

As prt' ''''' IIIt,, 1in (:t."p. II , d l ;III~I'" ill O~dll hl n ocl llnw ;llTt"l1 (·II·"r.1I1('I:' I IIII~' when t,,,trote.1 io ll
ur
mtiu is hi ~h . This t"lilld us iu ll is l lol-" "I 011 t1w l"lJlJl'l:'p t 11 pC'rfll.sillll .r.lt(,lim ihl.t io ll . It slMlUld
IN' I. ,n lt' ill nund. !JnWt'\l'T, thai t' lT("l'h !;('"l 1ll(6f)' to all ;altt'n, 1 I»ltJl.1 fitM'. Il.Irt it1.lldrl>·
",11('11 t1' ''l·rt·;('l'l 1. lII " y SUIIlt' f';l'C. k' lw rfn sillll (llll .. id t'mtMllls ;lllIIlt' . FliTt' -. u llp le'. It cll'C.."n'iA.\t'C.l
h l' JlNlll u'" liMy p nJl llll"t' lUlII\ ill. wllit·1i in h Jnl 1Il1ly llfTt"l1 lll'pat ul't ·lIubr ;tt1i\ i ty a l1l l l" ' lll 'l:'
tIlt' ('\tntttin ll mlio . 1111· 1" t m(1 ill ll mtin ma~' ..Iso Ill' alt t' n oc.1 hy a d l'C. ·f('ll",,'C.I Mool.! flow

. '1". 12-.\ . " "" ' ''II.•I..h'~ ;I"·h·,,,'''1. AUC CL F

I,", ..I,...,..,,,... . 1o..w,..1 "" .i"nifi...... 1 Oral I.V.
(:\ .!'\.) d'''"(I'. .. t ..·" f> 1,,·..III,y " ""II' 80
h .. -n ...·n · ~ •." w.·,..&e" ,·,11.." .....
~ .j.. "'( ,10 ...· "r.Jh ' .. ... .. 1I .~."'~1."
.10 ...· •• I. ·f",.· 11/.. 1,.., II..· f.." ,d, 'Lo:- 60
,of li " .. -1"I"..· I ,. ·..I II "l l ' '''Il: '''' 'n
f> I,r •.TI"........1" ,,, 1 1..., II . 0(. g
",fic".." , <t"'''(I' '" .-\! "C -of" ., ,..--..1. 1..,1 c 40
'..01 -oflrr, 1"'i''''''''..I,...,. ('-\,"" 01,...1 £
~
(n '", u.., I"'w·,..1. T ... . ",,.1" ..I ·rt \ .
C J c .: n ..· ,·fl''''1' .. f "'~ 10"· \ 1.",·· 20
"'.." 1r llF.\lO..· i" IIII..I" " , ' .., 1..1.1'" 8:
luipt m ... .li'.. 1.... K. J e l",. 11"".
o
" ... " . I ~ :Yl1-4U I. 1Y'>4 I
~
- 20 NS.
CHAPTER 12 19 1

hl'('aml' t'n'I)' bllllxl n 's<;(,1 in tilt' o~all may 1101 pn l\itll' lilt, sallie t'xpos un' of 1111' dnl ~ 10
Ill'p al il' pa rt 'l 1l'h~ll llll l't'lIs , aud tln- p'ltlt'nJ of chstnbunon o f hlood How .... ttlun till' eltmt-
nal inl-: ory{an may d l<U1I-:t', T his alh-rution ill tlu- dl'~n'(' o f sh U n l i ll~ or b~V'L..si ll~ of tl\('
pa n' lld l~l nal l't'lI s may oc cur ill certai n lrepatk-d iM'a...e s andunder a varie ty o f condmons.
( rlllxl t'\<lIn plt·s of till' kiuet tc l'tIllSl'llllI'lIl't'S o f uln-red bllxKI now an' hard to find . Tlus
is nol 11("t.'l.U1SI· tll('y an ' unconuuou. hut Ix"t.'l.II1St' a 1I111111x'r o f ad d itional comphcanous
alwil~"S st"t'1I1 til IJI.,(·ur concurn-uth-, For (·X<tmp l('. l'tJlld iticJIls such a.s l1 11l~l'st in:' l-.tn lial'
failun-, in which ca rdiac uUlp lit is dr-cn-ased, an' oftl'n a...sociated \\; 111 iUl'rt'a.'it"t1 thinl-
s p;wi n~ (build -up of fluitl in Intestina l Spill't'S and botl, · l'U\; til's). diuuntshed lu-patk- ami
n-uul fll11l'tions; and sloWt"tl dt stnbnuon to the tissues . A dec rease in hepatic bloodHow,
h n ml-:ht ahout hy cirrhosis. l'hnmieal1~· I ,·m ls to po rt al hn w rtt'ns ion ami t':lJrdllt'patit' shunt-
i n~ of portal blood. Th m , till' kim-tjc ('tlllSt."tIIll' nl't·s o f altered blood flow art' suhSt.'(llIt·ntly
l'xalllilll'(l aknu-. with th l' n-ahzanon tha t in therapeutic Sl:.'t'lJarios th l' t'ffe"" s of dmll~l's in
1IIon' than 0111' phys i olo~ic \"ariablt' 1J1"t"t1 to lx' considered .
Fo r this theo n -nca l pn -seutanon. ('tll\sidl'r the- two d m gs ~\"l' n ill Tabl e 12--3. D nJ ~ 1.
is 1·limina!l'(1 in IMJtIL Ill" liver ant! till' kid ll('~'S ; its major pml)('rty is low ext ract ion in both
o rgans. D m g II 111l'i a higll Ill'pali<: extraction rano ami is almost t'xd usi\"d y d iminalt'll hy
tlll· liw r,
L ) \\ ' Ill'plllil' E ~t ruct ioll Ruti o . Figu rt' 12-6 shows th e t' fft"t:t of a doubling of lu-patk-

Illlllxl llow for til(' I'Il KJrly clean-d d rug . drug I ~ 1~'edUSt.' (Img L ll;l'i a 10..... lIt·!l;lfi(: t'xtra(1 inll
rat io, alte n'll bllKKl lIow has Iittll' o r 110 ('fft'<.1 011 the pharmac o kinetics o f Ihis tlmg.
lIi~h Hepau c Extral"t io n Hliti n , 111(' events folll:l\\ill l-: Lv. adnuuistrut ion of a tlmg
with ;1 lIigh Il('pat k extraction r atio. d m g II, w 11t'1i hepatic blood no..... is Iucn-ased. an '
n 'ad ily appart'nt. :'\ot so apll;lrt'lIt an ' ti ll' likd y events th at follow w 111'1l e1 m~ II is ¢\"l'1l
or.llly. Ht'<.'all that F · DoSt.' "" Cl. · :\lIC or AV C "" F Dost'ICl.. Altllough 111(' half-lift'
i.. ..lmrll·lIl'tI. dc·anll1c't· ami ura l bina \lli1<lhilitv an ' iJl l'n'll~"t1 simultaneous]v; oru l hioll\"ail-
ah ility is l'Ic,\'alt"tl hC"t.'l.IIIS(' drug ill blood n -mam s in lilt' hep atic SinUSl:litis for II sho rter
!'I'ri IKI o f !inll' with all lucri-used hlood flow, am i thcrt-fon- tln-re is less chance of d m~
l l('ill~ e]im inah 'll. Al'('t l((l ill~ly, Ihl' n-sult lIIay Ix' litt le or 110 l'ha ll~l' ill ,HI e (last ~mph of
Fig. 12....f)). T Ill' HIIIC1 111W tll'!w lIlls 011 wllt't1 w r or nol tilt' illc'n-a.St' in hio;l\'aiiahi lity is t'xac1ly
lrIaldll'll hy thnt of d t';l(ill\C't' wheu hlcKKl lIll\\' is incn-ased . 111l' IlWllmry aiels of EllS. 2
and 3 prt "tlid 1·lllIlll t'ffn :ts . in lllilt thl' rlltio o f tht'St., t'(lnation... (CI.I/ Fu = CI.'~I ' fi ll,) is
indl'IM'ndl'IlI of hlolKlll uw. Uu fo rtunah ·!y. II1I'n' is II lad , of glXKI ' !Ualllilath'I' infonnal ioll
10 hI' slx"t.'ifil- Ill'rl' .
All l·xamp lt· o f a d la ll~l' in kirll'til..,. \\i tll a d l an ~l' ill h lIKKlll n..... is ~\l'1I \\i tll lidol'aim'
in Fig. 12- 7. Udlll'l.lilll· is a d m~ \\i tll a hi~h hl'patic c'xtm l1inJ1 mtio am i wlu r.w d ellr:1II1't'
is (X·rfllSinll filh' limih 11. lI e ((', iL'i t'XI)('<.1 I"t1. tIll' l1J1l<:u m 'nt a<1ministrdtiun o f t'itlll' r
P-hllx,kN . pmpr.ll1uln] ur Tlll'tnpm lnl pnxluc't·s II dt'('n 'll'il' in till' d t'anu lt't' of Iitloea itw.
p. HIlIl·le ts (('(hll't' l"lrt lial' nutplll aud ht'Il<'tk hllxxlfl nw. 11\(' dl;lll~l' in lidl ll'l.lill(' dea ranl't'
follo\\i1l1-: p m p r:lllolni acllllinisimi ioll is 1 1I~l'r tha n that (.'X!)('<.1 t'll for thl' dmngt· in !I'1l;llil'
hllllxl llow, suggt'sting thai Ollt' ur lllO((' (JIliN Il\t"t.,h;U1isllls lllay alS() lx' 01'K:mtin~.

T. It•• 1 2-3. "-.......c.kl... tlc P. ,........ of Two Hypo....tlc• • D.....

"''''' '"
OlST ~WTON CLE"'~
"''''ON
EJ0E1W
Wl/IoCTON lAl l()

""" III().l.VAA.ol8llIiY"
• .",., ~o !-f'AIOC .~

l 09 7 26 6 OW 0.0 3 0 05
H 005 A30 77 005 0 05 0 06
· ~ O:b "" , ful ... oc c~Iot""'I, ~_ .. ..... "'1..oo
'C_. ,._.,._'cJ~,"blood
 ..... INTEGRATION WITH I(f\/fTlCS CI-W'TEi 12

Intravenous Dose Oral Dose

0.1 Drugl 0.1 Orug l

0.Q1 0.Q1

~
g 0.001 0.001
c
c 0 6 12 18 24 0 6 12 18 24
~
;:
!l
c
c
<.>
~

2
Q 0.1 0.01
<:
.2
~ ..
0.Q1 .. Drug H 0.001
..
Drug H
. ..
···. .
.
0.001 .. 0.0001
.
..
.. ..
0.0001 0.00001
0 6 12 18 24 0 6 12 18 24
Hours

nit- 12-6. I,K-o·;o.....11>1,..1II<..... 10 11..·1i,,-, h.......,.,.. linl.· "fT...1 "" tI.... li"'. · . .... ,.... · ..f Il mlt I ~ ;O f".JrI~ ... I...M1...1
<In'Jt. idtt'l" ,; Ih. 'r lUI n...ol! or l,v. I .~",,,
.\0.... 111'1 " , " p nlo.."'K 1d T 1 "" Dm lt II. ;0. hilthlJ d. -;o.n,1 ,Inllo(.
r"IIo:.....; 1l1: sill""" l.v. (lS-1Il1U ...,,1 or,,] (31IlJ""'ItI ,It -s. Ah.·n..I lili (· .. --l: ronnn.l ....... lili.... (--). 11,..
;l.hsorphnn half·lif.. of holh t1nl~ is 1.4 hr. s.... T,.J,Ic· 12-3 fur uti pharrnamk illti il: P"'1)C'r1 it-s or th.....· Not>
.In~ _ :",11:,- ,IiFT.·.... ....-s in \". iUt'S fur D n ,!: II.

Altered ActiY' ToMIar Sea,tioo

FiWIrt· l ~ s!low!' tilt" efred of i llh ih itill~ tilt' n-uu l tubular secretion of alllm.killin by
prolx-ncc id. An Increased A UG of a moxicillin is o ll.i o \ls; it rt· lIc"(:f:s a dc,'(:rt·a<;t· in clearance.
Tlu - pn llllJl ~lIti(ln of ehminarion Imlf-lift' is also dlle' p rilllarily lu rt"CIUl'{"C1 elearauce: Iln-
volume of dtstnbunon (CU k) is changed rt'lalin' I" littl t', i llt l i {';tlill~ that p m h(·l\("C.i d doc's
nut afft"C.1 the di stribution of amoxjcilliu. Til t' inhibition o r renal excre-tion ur this pt'llidllill
by pmIN.'IJ('{·id he'c-'umes appare nt w!lt'll this pa th way is Isolated. HC'nal dt'ar,lIIl,{', that is,
th e exert-non rate n-lanve to Ihe plasma conceru mnon . is d t'ar ly 1't"CIUl'{"C1 hy pmIN.'Ilt"C.·id .
TIlt" substantial renal excretion of allloxk illin explains why a rt't hl('{'tl n-nal t:lt'ar.lI1('(' hus
such a p nlllou ll{'("C1 c'ffc't.1 Oil total t'lc'a nllJt'{',
11l{' dt"C.'n·'l'i{· in rt"llal d earam'(' occurs bv inhihiliun or rlu- tubular M"C: rd oTY mechanism
for umoxjci lliu, a dru~ that is virt ually ullhCll;m llo pla.sllm prote-ins. TI ll' de~rt"C.: or Inhtbttlon
or this pml'('Ss is ma.sked by Ihe contrtbu riou o r filtrati on at ti lt' ~lo l1l{'m l ll s . lf seen-non is
CHAPTE R 12 193

Control n it> 12-7. n ..· t-lt·ar.u K~· " f Ii, j o-

1.2 t;U "'· f,......... in ~ a -I·min 1.\'. i ll rll~i"ll
(3 ",~ltl i. " " 10...,,..1 t1,," ,,~ "'0"'"
1m..... (50 "'It) "r pm"r..'....... (-Il l
" 'It) ;w1", ini. lr..li"" ( ,, ' 6 hr 1 "-
<> ~ n"; "1t 2-1 hr , ...·f" n' tI 10..1 01 •
't: ",,·n,af"' rl.
,," , I ,n" li 1\I linjt f,.. " "r
5 0.8 Plus n M...· olmlt" ' -n·a" ·,..nloac,...,II''' 1
~
u
Propranolol ,uKI I" 1"'lil· " 10 1H.....-. lI"'I,"",a"
~ 11I.....'..Ui' ''' h, - ",I.id, tI..· d . ·ar ,,·
e~ "fli."",'lI.i,,,· ;;11""'1:""" I..., n"I, " I,
~
zs
~
II mW] . - -1.3 "M ) (.-\' !AJ",.. I f" Hn
C....,nocl. K..-\.. K~,·n. J.M,. FI,,10.,.·.
~
0.4 1' ,11.. a llol Kunoham. I. : I.i<".... il"·
110 .·Iiminah"", Elf of l1I.ot.."n .1
:5 a".1"f I'n 'l' '''' .1 eli". 11"' ", .1
n ,,·r...11:I3.1-I." ". 1\h1 .l

100 Control

~:;g:
'u
-;::<
E
-
10
o ~
Plus
~~ Probenecid
~ "
E ~
~ ~
u
-~
0. 0
~

0.1
0 2 4 6 8
Fl it. 12-'1 . 11" ' 1,1", 111" .... ". ·"Imh"" ("" I,·ftl. a,,,I I"'''l''' ,I,,· ,U'C. fill" .",,,,, iliUm i' ;,,,·n·;o, 1",f"1' .')l. l lll l>:
..n· ", 1"""i,r.·n~ I"r;.I1~ ill ".I"ti"" I" f", I'''1>: ~Il hjo. 1. ill 1" •• l'n.....II..· l ..... 'n,,1 ,,,...... 1,,,,,1..I ·IM. · 41>1 1 <1,1\ ,, )
" f Im.l..·"••i,1 ' I 1:. 12 lor ..", I II..." I lor I",·f" n· II,,· a" l i l>iI ~k ) . 11,.. .·1f,..1 i• •111.' 1"I,n",,·no.:i<I .....·n· ,IIII: ,I,,·
n 'lIa! d .·......" ", "f "111<"idlll1l h I" "It''I ). tI..· ", ,,j" T'.""p'''''·''1 of 1,,1a! d . ·ar....... · ' I n'lt!l . _ 2.7 ,, \ 1) (Dat" fRlIll
Sl.",ili"tI" I> II . j...'I.... ",. U.. CI..,1..,·. II L . al1, l lI"rt,, ". It: A" I<,\killi, oI,·L." ,1.l" ic: .dol n,.· .·O'. "1 " f 1'" .1".,.......1-
J !u,li" ,;': n.l, <:I" ·"I<~ I ,, ·r.. 12:27.1-27.';' 1 ~1.)

(~)lIlpld, · ly h lnl:kt'll. n-nal dl ';U';1I 1 (~' u r Ihis polar an tih iotk is ('xpt 'l'h'l l to " a Vt' a IOWN limit
uri ll . C Hi Ill'l',IlN ' it is lIut n'ahsurlll'li in rln- t ubule.

Ahered Plasma Protein Binding

I\nm\-II'(I1--:I' u r (untlitlolls ill whid , lilt' h i lld i,,~ to pla.s ma pmtt·ills is ahen'll is cri tical to
ptLSIIM t1 m g: rnuce-ntrutiou lIlnTlitorill~ (Chap. IS). \ \1 \(>11 aet ivities. rk-sin-d an d undesired.
n-lan- tI, tln- IllJlll>lll ,d couceut mtiuu . d la"~t·s iu hi lld in~ di n -'l1:ly afT(-'l1: tilt' inlt'rprt'l;llio ll
of total n lHl~ 'n trat illlt lb ta. 111i.s pr oblem ilppli(·s to t1m~s or l" lth low <l1lI1 h i~l, (·.\tradi nll.
\ \1wl ht 'r ti l" !lol tile' a ltt-r.·d bimlilll! afTt'l1:s lilt' unbound ptt-slIla com-entrut ion , a nd tln-re-
ro n ' tilt· (~ Ill(~ ' II I r<ltio" ill 11.1' ;ld in ' silt· is 111t'f';lpt'"lkally important. nl(·Sl.' lLS!)t'(1: s a n' nnw
addn-sv-d ill tum.
' 94 CHAf'lU 12

Low E :-.lrad io n Ratio . C " a ll~(,s in t jn- tlwra peutic ....i ndllw of pllt'lI)'toin i t ' a fUlIl1 ioll
of serum creanuim- concentrat ion , an index of renal function. is show n in Fi ~. 12-9.111('
h i~l1t'r tilt' r-n-atinim- concentratjou, tln- IUWt.· f is till' n-ual Iunct lon. The ' \i ndo'>'" falls
1",'(,.lUs('[u, normally aheml 11.1 , incn-ases tu 011'0111 0.2.5 10 0 .3 ill patu-n rs wt th S(,\,\' n ' re nal
f' lIll1ioli imp'linne·lIl .
For examplt-. gin' lI that lilt' u nhound ccnce-nt rauou n-qutn-d 10 pmtlul't· a ~H 'II re-
"POliS(' ill till' pn's('lIl" of n-nal di st,;('i(' is ti lt' c um- as thut ill tilt" a h""'lwt " it {" lInw' tl.al

fu · C - fu" C •
whe-n-III ' and C ' aft' tilt' Iluhm llld rnu:tioll and Intal d m v; concvut rutkrn in tilt· prt'S('m, -'
(If till' d i<w.';lW . n ·..pt't.1i\"d y. O il n·arr.Ul~(·llwllt

c - 5

COllt't'nlr.lho l\s u f 10 ,ulIl 20 lIlWI. in IIu rmal l'lJlld itio liS tilus hc."'Olllt' t'flui\'llll' llt tn ... ali( I
~ Ill WI , wlu-n III <lndfrl ' art' 0.1 and 0.2.'5 . rt'Spt"(1hl.·ly.
I' IIt'II)1uill is a 10\\' t' \t r.u.1iu ll d m ~ r-hmtnan-d by Ilt'p'ltit- lIIt,t"hnlisllI. O JllSt'flut' lItly,
t·lilllinatilln is rt'! ah't l to Its unbound concenr ra non (C ha p . II ). Tot al e11'amll tl.' (I", cr.,,)
hll'l"t"L"t·S ill n-nul t1ist 'iLSt' . hUI tlll,rt, is 1111 rt 'flu in ' llIt' lIt fur dusi ll ~ rate ad justlll('lIt ht " 'il tlst '
IIllhU1l1\(1 ck-aruuce, tln- p m po rt ionality constan t [wtweeu rod e or input and unbound con-
ce-n trat ion at sll'ady stall', is lint aITt'(1t"t1 h~' til(' hi ndi ll~ dlallgt'.
lIiKt. E \ t m l'lio n Rallo. Fi gun' 12-W sho w s how hluotl clearance, volunn- (If d istri -
bu tion, alld half-lift' o r propranolul \~lf)' " i th Iht· rr,t(:l iu ll unbound in slx ht'ilh hy malt,
volunteers. C lt'ar. U1t't' ilppt,.lrs to II(' Independent of p r otein " illdi n ~. 111e \'0 111 1111' of d is-
tn hulioll ( h IIMMI) and hillf-Iift, IMlt! 1 int'n'iLSt' \\i tl l an iIWf"('iLSt' in frl. This is the hd m\ior
t" I)I'(1t"t1 fo r a dnlg "it t. " larKl' \"1)111111(' "f d istrihlliio u and for wh idl t'l im illa tion Is 1)I'r-
fll\ illn ran--lunin- d. 111t" dmg is prilll'lri l)" d imi ll<lh "tl hy lu-patk- IIwtaII(I!islII. and th l' nu-t -

n it. 12- 9 . TI,.. tl"" "I" ''' 'io- nn",· "r

1,1. · n~1"i" I",-", ~ I ,.., t"l;J 1'1.... " ... u'Un'lI·
t ..~li"n , Io~'n'~"'''' "''il l. tI ..· , Io .". ~· " I' n'nal
fu"d io..., hll l~o.i," "'''t. .., ""',,,,, n~II~' "" .
n " " '.,.·..''''i'..·. 1'" ,,,, t1 n. n..1,"'I "f
W In ::!l l ",~il . n ,i. , -n i. a ''''··
' l' . ',w.~'
"f n ~ I,w.,,1 1..,w.I IlI lt, I'id , i. n··
1..1,~lln tiM' .....' · n l ~· "f l!..· n'n;J ,I'"'IL''' j I
",~ . - 4 n 11 \ 11. ( H, ~ I ...t \\ll f nu n fl."i<Io·II·
,,."'It.
\ 1 \ 1 .•" ..I .\ lf ri ll ..·. \f .' In n' '' 'nn ' " f
,I,..·.. ...·
"II 1>I,..lmll: " f .In, lI:' I" j,Lo.,m;tl'n..
k in•. "" '" ~ \. ,...,·;011 .....; .. Z2fi,I I5- I:2fi.
•2
1!l73.1
o
o 50 100 150 200
SerumCreatinine Concentration (mgll)
CHAl'TtR 12
'"
" IM,lie (h lootl) d l'lll"lllll't' approaches Ilt'pat il' hlo odHe w ( 1.35 [l m in 011 aH' m~t ' ) ' 11!t· in -
l'n'<l.'it' in ' 1)llIlI1t' of d isl rihu fion ....i lh/u is au ttcipated. us is tilt' Increase in half· lift'.
\ \'ith th e lncre ase in III and 110 dlllU ~l' in clearance, t1ll'f(' must ht' a l":Jrl1 "!\ptl ll tl ill .~
dt-cI1·.l<;f· ill lluhOlllld clearance. Silll't· CT./. "'" I ll,,· C1••",. Thls means that tln- uubouml
couccntmnon under co nstant-rate L\". infu sion l'tllllliliom is Increased w In-n bi llt li n ~ is
c!t'l'IT'll'il,(! am! tilt' ('t)JI\"('N'; a n dTl'l't wi lh pol<'nlially im po rta nt the rapeutic consequences.
An alte n mli\"t' vi ew o f Ihis situation is to n.·IlIt'III!Il·r Ihal \\'11t'1l cleurunce appmadw s bloo d
flu\\' in Ihe t' l i llli n<lt ill~ 0~'1Il . ltltal slt'ady-stah' conceut runou is not cxpecn- d 10 dl llll~t·
....i th aln-rrd plasma hi ndin ~. An iJll" rt' ll.\t · in I II Illt' n ·b~· ratws tilt' unbou nd ('t)lll't'u trat ioll
am! tilt' d rug's (·fTeds. Although then- are Illany d nl~s .... -ith a hi~h hepetjc extract ion ratio,
Iht·), are fo rtllnatd~' Sl" 1tI0 1ll ~\'(' n dmlllil~d.lly hy tilt' p an-ute-ml ",lItt' under ('t)Jld itilllls ill
whid l hi lltling is altered.
111t' oral bioa\"ailabi l i ~' of a dnJ ~ ....'ith a high t'xlrad ioll rati o is exp('l'tt'(l to t1t'l·n·.lSl.·
....idl an Increase in I ll. as M 't"11 Irom E' I_ 17 of Chap. II . wlu-n eL lnI is much gn 'ale r tha n
Qlfu. l ie n ' Cl.ulF "" C L ln l . 111l' 1I1('m Ol)" aid 1I100:ld uf C hap. 11 pndlct s [itth- ur nil dl'lIl~l·
in tilt' steady-state unbound concentration or till' thera pe utic rt>spon 'ie a fte r oral udmhus-
trution , ht.'l~d llst· el. ll ot is 1I11c1 1'III~t'(l.
Small Vo lu m e o r Dislribution. TIll' l'Ollst>fIUt'lI('(' o f 1Il1t'ri ng hillt lillg to ph~l1l a p m ·
tcins is illuslml('(llw clofilmm-. TIlt' lialf-Iife of clofibnc add (the al'ti"t· mat eri al fonm-d
bv IWtlrnl,,·.;js of til(: i1d m inist(·rt'(l l"Ill,,1 es te-r, d ofih m le ) short r-ns From tilt' usual Ill.5 h r
I;, S.7 1lr ill patie-nts ....-ith til(' nephmti~ s)lldrnlllt' (T ah lt' 12--t ). It is tt' mpling to mnd lldt'
thai ll11'taho lislll (0111)" ll% uf clofibrtc add is r-xcn- n-d IInd langt'lt) is indul't'(1 and tha t
t1t)sa~t' n'f lu in' IIlt'1l1s need tn I~> incn-ased in the-se pa tients. From a p harmacokinencpoint
of , i t""" . lilt'S(' l'fmd llSio ns an- Incorrect . as 11ll' fnllIJS\i ll~ sllows.

1.2 • • A .' IR. t 2- IO. Tbe d" "r~"t... " f p r"p ... ""I,,1
( ;r~," AI. 1........1 .... ibu"...~ ..'l r..h' ''' i " "'... 1.
~
u
c • ,h .. 'd aw "r In n lfR'lot.. " ill, 11.. · fr..di""

"' -
~ .=
- E
1.1
•
11"1",,,,..1in 1110-...1 of six ....a1lh" m"lt· \1 ~ u n h~''''
..I1..r ;,,1111\1"" " " ;It!tnlni\1r.41i,,n " f 2t1 Ill". (h,
the- ,,11... r " .ond. lilt' velum.. of ,li. lrll>" li""
"' ::>
<l- 1.0 • ( ~ , tI ) ", It! II... half·lif.. ( 1I::r"l ~1 C ) .oK" "h·

5l "·"'t~ 1 I" iI ...Tl·",, · wi'h ,m ilK"""'" ill II,,· fr....'

• li' ''' .."I "" " KI, nu. Id",-tit.· 1,,01..., ..... i. ""hd ·
0.9 pod...J f,.. " dml(.. . ,.......... I'n'1>r...",I"I. Ihal l.
l' i~I)-' M1r...-t..d ill tI... I" ...r. (;Io-·"r .......· I., ·n· h
- -z: 280
• B I"·rf" . it,,, r.&l... li'n il....1. liin,Ii" " I" pi...,,,,.. pl'l"

t
Q c
~ Q l<"in. ,10", ,...It inA......~ dMmu .... • 1" '1 ,10".... f_
E -
~ ~ 240 f",of I"" , ..t " n... "f d1drll,,,t it"l ... ,,1. 1I"·n .(,,....
o:g • 1111" half·IJl;·. TI,,·I! "" ~ 1.... 1.....1 lito ">-1;,,,.....
>1n
i5
200
•
• n "):l'1....itm_ ( I
m"". - 3_~ J,l lol l (1).,1.. fn,, "
fo;, ,,,.. . (: 11 .. ..,It! S1WlIt!. 1> (;.: Ili~IM .. lli< N' " f
flrofl." " " I"I . VI: l nde pe nd e-ut .... ri..I'Cl u in
6 • C
" .....I}'••'~I ••(in'tI Lttlnjt dnlKt."Ot""'T,lr"'",," "' 101
• l...lf·l;f,· ... a """nil of rLun... ,In'lI: I"'K I'''K In
", ..n , elin, 11...n ......0I. Th·r _. U4fJ.h'jUJ. iera
5
:5. -
..
-~

"
-~

4 •
•
K'l,n "Ii...~ ~ 1 "' ilh I"·nni. , it"l u f c .\". M,.. I,;,.)

•
3
0.D7 0.08 0.09 0.10 0.11
Fraction Unbound in Blood
'96 INTEGAATICN 'NITH I(lNETlC5 CHAPlH 12

T. bl. 12-4. Ro.. o l F",..c.I M• • ,..,re " S.nlll'l Alb..,mln, Dally ~1.I..
. lttl HaU.L1f. of tho Actl Fonn .f Cloflbra", CI.flbnc Acid. I.. Poll.... WIllI
c"""••,
..... With.",. tho N e p hrot ic Syndr . ... . •

NephrOlic g roup
(N · 51
, .
'>I ~ ~I
~ .,Al .... · . '

1,3 :!; 0 , 1
..
CKA''''''''

,""'
CLE"'AI'£f

100 :to L4 13
......
."'"
101'"
:!; 05
oo esc "'CO
'"<Al.H ff
~,

87:!: 35
~lfN
!XCI'fTlON
".
13 :t 12
Conlfol gfoup
IN - 81" 1 2 :!: 0 2 98 :!: 20 44 :!: 0 4 165 :!: 47 0
"f..".GokI>oog,AP ~.O J .Haa>.18 ..-de...n.n.l, JD e.:"...,.<J ddob""''''''' '''...... ...-c~'9¥-.........., 0<> ~ n0.-
113 17-125 , 19n
·0 'IlI'<I. • 118 10">\
"" ~., .. """'-cJdo..O'-'<Jddbr"'oco:l .. O I I LfI,g. .. ~ ~ ...pn...., ~ O OJ .,...,. . I.xr>ot> ~ _"':lrqod
.. 000 ro-""'BonOI,tZ <>'dW--"~ 1 ~ . I i'ln.~oIo:>go<:b><J~. a"'ed Ed.-.dn"AG ~ TW i al
I. S Noooo,anc/P lo,b ,,"-Y""_Mo<~ IQQJ I

In lIlt" nep hr otic synd r ome. there is ;III ('xtl'mivl' loss of pl. lSlIl;\ p rote ins into I lll' mi nt"
whic h fl'SUlts in a tw ofold drop in se rum albumin. as shown ill Tahl(· 10- • . T Il(" Iullueuce
of this drop in se rum alb um tn o nfr l cau he l'st ima ll't l From rl'alT;lII~t' IIlt'1I1 of Ell. IS (C hap.
(0). TIll' normal se rum alhumin concentranou reported is 4.3 WtlL am! for do rilnk add
III is 0 .0.1. Giw nl hal /"" , tln- fraction of available hil\(lin~ sill's unoccupied. is r- qnul to I,
III(' vahu- (If #\/1 is 7.5 dIJK. AI a serum albunun couceut rattou of 2.3 WilL. tilt' calculated
fml1io ll unbound in nephrone patient s is then

Iv - I _ 0 .055 6
1 + 7.5 x 2.3

C lofi h ril' acid IIiLS11 low cxtractluu ratio ill thai its ch-arance- k ak'u lah '(! fru m k ' \') is 0 .32
lAir in lrealthy subjects. a \11111l' much smalh-r than llt'p;lIk' hlood lIow, S I lAir. :\ lth()lI~h
oue miv;hl argm' thai hluod clearance is much largt-'T rlum pllLsllla dl'ara lll't· (also c/e" >
I ). thi s is impossihll'. \'irt,w.Jly all drug in 1111' I M )( !~' is IMlll ntl to albumin (" = 0.11 1A g).
Thus. plasma d m~ co ncentration COIll ollly h(, ~rl'at(' r th an blood d rug ('tllll'('niratioll hy a
factor o f 1.7 (1/(1 - ln-matocnt), M'(' Appt>lId h I- F.
With clofibric acid betng a I,,\~' extraction ratio drug. ch-amncr- is ('\1)('(.'11'(1 to illcn·,L'\l.'
in llt'pl lTolie p atie nts. TIll' value o f unbound ek-arance , CUI". is 10.7 IJh r in Iwalth)"
subject s. If otn- a ssumes the same un bound d t'ar.l lll't' ill uepl rrotic (llttil'nls, tlu-n d t'amJIl't',
I II ' Cl." , in this ~roll P is (1.59 l Air.
TI \(' volume o f dislrihutinn of clofib nc add , giw n in Ill(' f()(I!Jltllt' 10 Tahir 12-1, is 7.7
t / i o kg. This \~J1Il(' depends lit tle o n ('ha ngt's in p l'l\-lIla pr otein hilldi ng:. This is ",,'('n fmm
Ihe n·latio lls!tip I-oI'IW ( '('1I \ ' ilm1fi' for a dm~ with a small voluna- of distrihution (Eq . 25 ,
Cha p. 10), namely.

v II: 7.5 + Constant · Iu

Will. an apparent volume uf 7.7 I... III(' coustaut is 6 .7. IfIII is illl:n'a\('(llo O.<'L5.5, t1 WII th e
lIppa n' nl volume bec o mes 7.9 L TIll" \-'Illum e unbound (\'ijid , 11Il\\l'\-l'r. decn-ascs fn nn
2.5710 143 L. 111(' calcularedhalf-bfe (0.69.1 ' VlCI. or U.69.1 · , 'II/Cl ..,, ) in Ihl' m-phroric
peueuts is tln-n about 9 .3 hr. a \".1111(' \ 1 ")" dust' 10 tlml 011....·1"\"("11. S.7 h r.
TIl(' two questions origi nally posed an' now an swere d. TIlt" hal f·l ift· is s!tortt' Ill"l! ill 1!It'
nephrone pauents because- of dec re used hinding 10 album in; me-tabolism was nol illd u('t'(1.
Unbound clearance was 1101 cbanged. and tl u-refon- no dlallgt· ill tilt' uSllal (lIlSing mit' of
1.5 10 2 .0 gltlay is nt'('(l t'(l in m-phrottc patients to p rodlll't· II\(' sanu- aW"'dgt· unbound
l'lllK't' lltmtic)IJ in plasma . as ad lil'\l'(l ill pat h-uts \\itl l nonnal Sj'n llll ;Illllllllin. A sho rter
 INlEGlI AtlON '<V1tH IONEtI( $ 197

dosillg inte-rval (a llll l"(,rrt'spo lltlin,l?;ly sumlh- r mainh"n,uu'(' tim e ) m i ~"l 1)(' couskh-n -db e-
c..IU St ' IIf tlu- slln rk lll'l i half-lift' ,
111l' l"('lIlhinatinm o f l"(md itiom and s o-nanos in dnl~ tllt' mpy M (' multitudinous. This
chapn-r hiL\ pR'st'lIlt 'l1 «pp r oaches and e xamples tnwun] i lll (,~r.l ti ll~ kinetic pri nciples and
physi ol l~ l' l"(lIIl,,("p tS. T o l,,( lInplt'h' th is iu tl',I?;mtiun, Tubh- 12-5 summa rize s tilt' (·fT"l"ts
{'X I)('(:h'l! From incrt'a.'it'l i ('n 7.)"III{' ild i\; ty. inhilut ion of 1l lt'Iahlllislll, decn-ased h1uotillow ,
and ill('n 'ast'll ji, in bioI 11.1 for <l dOl ~ eltnuuan-d ('xdll .s iwl ~· in lilt , ltcr-r. Co nd itio ns irl\'()I\; n ~
d n l,l?;s nf both low and hi,l?;h ext raction ratios an ' l,,('"Sid('n'll. 111(' ('\I 'Il"('tatinll s an ' similar
for a dOl ~ l'liminah'l! only hy till' kid m'ys: 1I0w('\ '('r, inl' r('awt! adin 'luhub r secn-ttou ruthe r
than inl'n'iL'it'l1 t'll 7.)lllt' al·th ; ty applies. Also , oral hillil\.\i tlhilit)' of a t1n1,1?; hi,l?;hly l'xtnll'l('l i
in tilt ' kid lll'Ys is IlllafT('l'!t'l l by dl an ~(' s ill fi ll' ph)'.,;iulll).,ric va riabh-s l"(ms id('n 'll lu' n ' ,

, ..... 1 2-5. AlltlclfMrIetI.tfecb ef AlferMI••• I. Seledetl PII.,.I.... ac V .

•• V.rI_. Pa_ 01. 11.1 Se..Iy ..,. Dr.,•• U_r
fH~OGICV ~ enec
N:IlEAStD
9APM'f lf ~S
oe
tNCJfASl'D
,""W -'>ON OlC IlE~D
0000
fUCTION
weoc-o
~Sl""'llON 06Sl' ~"'TI(;lf'6 ""fMTv" '"
.... l "'ecVi.....
""" NOooo
low H<>p::ll, C E..'roc Otl 1()1,O D,,'9
In"ow","",~ HoIl-·Me I'
AUC (bloodl 1
001 BlQ(MJ,lobol,!y
AUC (bloodl
H,gh Hepohc I ..nooco ~()rlo [),U9
Inltov<''''Ou~ Ho ~~ ,1e I
AL.!C ll*lod) t
001 BoooYOllabillty
AUC (blood) ...
I

''II > ~l boldr.og>

" """""""""'""".• onc_ booonoei ........ _ _ .....~<n~a<1_ otdot _ 0/ "" _ <J>OoiQb,l... ei~b •. d--""'''''9
' 1 "",_ 1 <:Io<:...-l _ I.... O/",,~
"'"'- <:10<:_ .. ~~ '. ~., boo oq.ooIy"""""'-'l boo 0 ~_ ,n ~'eo<ono:.

STUDY PROBlEMS

IAnswer$ 10 Study Problems o re in Appendix 11.)

I . U st 10 t'xam pll"S o f physi() I' ~l' \<Iriah lt·s that alter ph anll;\n lldTwt ic paramet er valu es .
2 . C..o lllp ll'!t' T abl e 12--fi 1ll.' Iow to shuw It'nd t'lll'it,S hy lIIarki ll ~: T for incn.·a.'it', ! fo r
dt"('n',l'i(' , and H for Iittl{, o r 1Il1 d lall ~{' in tlu -{'lIIp ty SP;\l"l.'S. T ill' d m ,l?; is oll ly elinuuah-d
ill ti lt' liver , and its \l llUlIlt' of dis tribution is ~n'akr than 1011 L. Then- is 110 elJall ~e
ill illi rillsk d t'a r:U1I..,(' ,

H~h
HIgh
HIgh
l~
l~
l~
I.' CHoIo.PHi I2

.1 . FigllTt· 12-11 ~ lll l\\'S plasma d m g: conceut mnou-tiuu- pmlih-s r()lIu\\ill~ ural atlmillis -
lratio ll u f I\\U d nl,!:::" (hull. d nl gs an' d illlill alt 't! I'xdllsin '!y by Ilt'patil' llIet"ho lism)
1I1l1 1t ' r the- fo lltJ\\i ng: ltm d iticms :
Ta" Gm,,'" I J IW t'xt nu.1 ioll r auo. 1'1;l-" 1II01 protein h ill(liu,I.t is : normal k uo
w :\ l; lIiIIH '(!
(l'a~ ' B. twofold in e rt·a ...• in fit): am i <10111111'(1 ({';.N ' c . twufold t1t'(n'il'>L' in I").
Ronl1", Gmp" _H igh c' xlnu.1illll ra tio . Tisslw hilli lillg: is: I\lITlIlal (l'a'\(' A): 1'111\1.'(1( { ';.l-Iit'
II, twofold jllt 'n ' ,i.\( ' i n Jil T); and dClllhl('(1(e a se c. twofold d t '1.'Tt'l L'it ' i ll j ll r ).
Altered Binding to Plasma Proteins

Time
Altered Tissue Binding

TIme
. "IlC,. I 2-11.

Draw II\(' {'u rn 'spolld ing: t illl(' profiles of Iht> unbound {"t)llI't,'ul ralioIlS for till' tlm '('
situations ¢H' II for ('ill"1. uf lilt' hm t1m~\. Be sure that (Oad. ~ru ph show,; ti l(" salk-nt
CI-tAFlEl/ 12 INTEGAATICN WIlH I(INETC S '99
featun-s i lldlldin~ n ·J..lh1.· arens under Ihe curve, peak umos. and half.hves. 111t' "01-
nun-s of distribut ion of hoth drugs art:' ~rt:'att' r than )00 L
... . :\ 1t 11fl1l~h rl'<'1~liZt 'tl for lI1any )1.·urs. rln- interaction l..·tW('t·u allnjlunllnl. 1I>;('t1 in tilt'
tn-atnwnt of J.:0llt, am i fi-nu-rca ptopu n ue . an allt i lJ{"()pla.~tic aJ.:t'III, wa... 1I0t wt'11 1111'
d,'rstood nnlil tln- kim-tk-s o f Iht' Interaction WR" elucidated. l1 w ,\lIe vallies of l'i-
nu-n-aptupn nne- 11I,fon ' am i aftt'r pn·tn·alnwlll wit h allop uri nol ( 100 1lIJ.: o mlly Ihn't'
lim es a d,l)" for 2 days ) f(lIlo\\ill~ oral and t.v. ad ministmlions of (1.1; nuuole of f)..
nwn'aph 'punm' an' ¢n·n in Tnbk- 12-7 , Botl. drugs an' nlll~t1y elim illilh 'tl h)' nn-tah-
ll!i SIJ1 in tln- liver .

'."1. 12-7. Ay._•• Area. U.tI_ th. PI••_ 6.Men.P"eP-rl_

Ce_••"..,I...·n•• CUrv•• I.....I......,. ..... A..... AII.".rI"•• ."..tr•• I.......
..... ..
TIlt' half-life of f)' l!len.-aptopu nue was not Si~l ifk~d.lltl)' dlaJlJ.:t'tl h)' allop urinol treat-
nu-ut . For 11.1' pU'l xJSt· of this problem . 11.<;(' 11 blootl/pla srna eonee utration ratio of n.6.
a . calt:lIlatt· lilt' dl'ar.U1l1· anti hioa\ ailahilil}' of fi-mereaptopu riue ht·fore and 'lftN
alkrpu rinol ,
h. I'rmid,' a IOJ~ktll ktnettc explanation for the enhanced t·flk';.I(')' of fs-nn-rcaptopuri m-
in til(' prt'S('IW(' of allopurinol.
5 . Tlu- phunnacokus-tics o f U1.-thn'O-llwlhylpht'lIidal t' (Ritalin) shows ('llanliost'!t't1h i l)',
Tah le 1 2~ sutnm.mze s the ohservatlons aflt' r Lv. (10 Il\~) and oral (-i f) m ~, immediate
rl'le,l\e ) dust's of ( + )- anti (- )- i~O IlW rs .

, ..... 1 2-8. AUC ..... H_H·Uv MathyI...... ltI...._ ••n A..... h.,.rwte
I...,."••••••"d Oral AtI.I.I ..
IN1Uo,tNOUS 110 '"'111
I. ~SC>".·U 1-)6CW{ ~
AUC !JJ.g h,/ l) lAB B9 120 15
HaIH,fe (hri 60 36 57 39
·Adopood ltc:n s.--. N ~ ~JW ~,EO <r<lM4o:l.' )( E,............. ~"'"""'d~..
........,.,. PIo..,..n~.. 101 4·11 1<XI3

Cnlculnn- tilt' fullo\\i nf; for each isomer

,I ,
I , C lt·arJ,llt't·
2. O ral h ioam ilahilit\'
3 . \ '0111 111(' o f di ~!nhutioll
b. !o.lt'lhylpllt'lIidatt' is gi\l.'11 o rally, Bn efly di st'Is..~ tln- dilTt'n:'lIl't"S ill ah~o rptioll anti
dispu~ il ioll o f tlll'<;(' two tsonu-rs.
e. ( ;iwlI th at Ihe kinetics of t'ild l of the- iso me rs is 1I0t alTl'<-1t><.l by the othr-r. cst tmatc
til(' approxi mate isomeri c composin on (ratio of amounts of (- ) and ( +» of abo
so rllt'1:l m.l!enill t' nh'n n~ tilt' S)1\tt' m k- ei rcula tiou . Do yu u t·X!x"<.1 the ra tio o f the
isomers ill plasm a 10 dlan,gt' with time? Co mme nt bnefly.
6 . A tim?: highly lxmnd to plasma p r otein s ifu :::: (J,O l) bas a volume of di slribulion of
2"'0 I jj'O k~. Tln- li\l.'r is the on l), organ of el iminalion. 111t' hepatic ext ract ion ratlo is
lUI.') dl'~ pi lt' the fad th at Ihe Fractio n in blood that is unl xlIIlld,ji,,, is (111)' O,lMl.'; . 111t'
hepanc hl(xltl Rnw ls "l1 lAir.
200 NTEGAATIQN WITH KNfOCS Ct-lA.PJER 11

a. Est imate tlat" vulu('s of til(' f()II(J\\i ll~ paramet e rs fo r t his d n ll{: hllMMJ dt'a nUlt'(' (CJ.h ),
clearance (e Ll . volumes (If dtstrtlrutkm h;(.......1 0 11 d m j.( ccmenn unous in ri a-slim
" 11It,,, (\',1) and in h ltMld (l'b), and half-lift·.
b . In uremic pali.·1l1s til(" volume o f d ist ril m !iull 0111(11111' Iraction uubound in ph\lllil .
I". u\'t' ragt' un L and (UJ3, I't'Slll'(.1ivd y. Is then- any t'\ide un .>lhal tlu- un-mtc sta te
alTt'(1s tln- tissue binding? If so, in what tlin...-t ion ami by wha l Fadm is lissllt' hilltling
ultt'rt'tl?
c. \\111'11 th is dnl g is in fu !it"tl infm\ 'I'!lou sly al tilt" sanu- tl ms la nl m it- In it 1l;llit' n t w ho
is and hits 1)('('1\ Tt"t't'i,;ng another d m g. the " 11m ' o f ji'l, is 1I0W Icund tu Ill' O.fH.
Unde r stt·;jtly.s tall' 1"lll\(liti Ol\S fo r bot h d m gs. pn-dict tilt' ml io (If lilt" Illlholilld <:0 11-
rr -nt rations of t he dm~ ill tile prt'M ' ll<.'(' ami " b M '!I<.'· of t h~' ot her d m ~.
f. Ampicillin ha.. tilt" f(}lIowi ll~ lI.\"(' m~e phamlal'uk int'li(' pa nUllt'tt'r vallll's ill a 70-k~ sub,
j~"(:t :

F(om ll • 0 .6 V = 20 l

Ct '"' 160 ml/min Ie "" 0 .8

Ddl'nnint" tilt:' minimum orulmatnteuancc doSt, of a mpid llin. to h~' ~\'t'li ("I'l'I)' 6 hr,
to keep tilt' u rina ry d m ~ l, mn'llt ra tio ll (in Urt'f('rs) aho\"(' 50 IIIWI.. Tl ns value is tilt'
minimum inhihitorycoucentratiou a~ainst an alltihilttil'-n'sbtallt tlrga nisllI Ik,lil"l"("t1to
Ik' p n kill dll~ tilt' !l<llit'Ilt' S uri nary tract infl'l1 io n. Use all ll\"(' m~t' Ilrim ' nllw o f I III I /
mill. I ustan tam-ous absorption a nd d i.stri lJlltio ll of .unpk-illin a mi sh'a dy-sta h' l'fllltiitil lllS
apply.
Ii. 111t' effects or rO(x! Oil tilt' oral hioa\"ailahi lity, s)'slt' mic ck-a runce, am i ~\ VC o f p m -
pnlllo lo l art:' summarized in Tahle 12- 9. Pmpnu lOlol is t,lilllillalt"ll h~'IIl 'pat ic lllt'tah-
O!iSIIl .

, ...1. 12-9. 1"-1 ....... _ .1....1....lllty, .~. . .Ic a-_...., .... 0-1 AVe ..
Prett-_I..•
P~TlI S

B;oo-.oo,labil.ty (%1 27 ,t; 2b 46 :!c 4<

Cleorooce d lV minl 1 (X) ,t; 006 138 ± OI2<
001 A~ lmg,tlf/U 2 1,8 .... 26 27 8 .... 100'

111t' a uthors SIl~I'st t hil! a ll illl'rease in 11t'jl<ltil' hlllll(llI lIW is, ill Iilrgl' part . rt'Spollsihle
for tilt' ohSt' r\rdtio llS. Do )1111 illQ't"t· ....i th tilt' au thors o r lIot? JlIs ti~..· ~' l ur pos itioll .
INDIVID UALIZATION
 VARIABILITY

OBJECTIVES
The reeder will be able to:
1. liS! six major sources of variability in d".1Q response
2. Evoluatewherhefvoriobililyin drugresponse iscouMK! bye VOfiObil,lyin phorrnocol.inelia,
pholn'lOcodynomia. or bolh. given respcose and phorrnocol:.ineti<: dolO
3. $lole whyvariabilityaround rho mean and ~pe of the frequency di$lfibuhon hiSlogrom of
a po1omelef ole as impor1Olll as the moon llseif.
4. Explain how variability in beccuc enzyme activity monifem j~1 in variability in both phar·
mocokinelic pCllomelefs and pIoreau p1a!>lTlO drug oonceolmliOf\s fOi' drugs of high and low
hepatic ex"oction roses.
5 . Sugge$lon opprooch lor inilial ng 0 dc»oge legimen for on individool potenr, given potent
popuIorioo phormocoltinetic dota and the individual's eecsocbe chorQCfefiylO

Thus far. I)l(' ass umption Im... IIt't'1I made-that all p('()plt' a rt' ahk e. T rue, its a species. human s
art> rt"l~m ahly lJ(ml( ~t>IU'()II S . hUI di ffpn'lWtOS a 1l1 01l~ pt·opl p do exist indudin g tln-ir r e-
spnllsiv("IWSS to dmb'S. At'(:(J nlillgl~·. t1lt'rt· is a Ireqtn-nt llt't'(! to tai lor d reg ad mi uhtmlion
10 the Individual p ath-ut . A fail nn' 10 do so can h-ad 10 im'lTt'(.1 in 'lllt'ra p)' in some )lalit'lIls
am! to ocitv in otlu-rs .
This S{~'Iioll o f the hook is de...o tedto indhidual d nlJ.tt1wmpy. A bmat! 11\" J\it"'~' o f tln-
subje c t is p resented lnthls dlaptt' r, E~idt'JI("\' for alit! causes of vartatkm in d rug rt~POlIst',
am i ap proecbes toward i lld hid llal i7jn~ dn l~ I!lempy an' t'xaTllim"ll. Subsequ ent chapters
deal in much gree te r t!l'tail wuh ~t' lwtil"S (C hap, 1-1 ), alo::l" an d wt'ilo::ht (C hap. 15 ), tliSt,lt'i('
(C hap , 16 ), iut eracttons ht'lwt"t' n dm w; within Ilw hotly (C hap, 17 ), and IIItmilorill,i: of
pia-una ccncentrunou of a dnJ ~ 01.'1 a ~ Iidt' 10 illdhitillali7jn ~ t!m.l: tllt' rdp)' (C hap. I Ii ),
Ht'fon ' prot't.'\'\lin~, a di stinct ion IIlIIsl lX' made hl'lwt'1'11 ; 111 imlhidmtl and th e popula-
lion. Consider. t'.~" tilt' results o f a sludy dl'sip u "Ill o examine the l'(m trihn tioll of an acmv
tlist,01.'it" 10 varia hility in d n l.l: rt's ponst' , Suppose. of 3n pat ients studied during am i aftt' r
n'covery, o nl)' 2 shll\\'("I1 a subs tantial diffen'lIl't' ill rt'SI'ltlllst'; in tilt" remai nder tilt" d iffN-
t'lIl'(' was insibynifil'llllt , \'it'\\'t'(.! ,1-'1 a wl lolt" tilt' d ist',l-'i(' wfluld nut 1)(' couslden-d as a si~­
ntficaut SUUR't' of \'ltriabilil)', hUI to Iht, IWfl afft'(.'It'(.! Il;ltit'nls It would. ~l o R"t I\'\'r, 10 avofd
toxici ty , Iht, t !()sa~t' R,;nlt'll o f the dm" llIay 1lt'1"(1 10 ht , ll"(lul't"t1 in these two patit'u ts
during Iht, disease . 11l(~ lesson is dear: A\'\'r.l.l:e d ata an- useful as a ~ Ji de; hut ultilll att'ly,
luformation rt·rtainin~ to th e imlhidual!l;i1il'nl is all-important ,
011 a sim ilar but broade r pomt. substant ial di fTl'n'lIl1' s ill rt's!'ltmS{' to most dm~s ("xist
;l lll{)n~ !);,Itit'nls , Such /" tt'rind hit!lIal \'llriah ilily is oft eu n -llected hy a \'llrie!)' of marken-d
close strengths of It d m~. Because \'ltriilhili~' in rt'Sj'ltlllst' within a subjt"Ct (I" t rn illtli\; t!ual)
is ~t'nt'ntl l)' much smallt'r than jrlt('tind i\idual vartaluht y, oncv w«'1l-t's tah lb llt'd , tlu- n - b

203
, .. VARlA8IUTY CHAf'T E ~ 1J

mually little Ill '("(! to slIhs('(IIIt'ntly adjust lila i lJ(li,i dllil]"S do sage rl '¢lIIl 'lI . C lear ly. if i, .tm in·
t1hi dual , "anabilit y wert- l a~e and uupn-du-tahle, tl')in~ to lilmh- t1l1Sagt' for all lndlvi dual
wfluld lit, an l'xirelllt' ly diffi cu lt ta...k. partkularly fur dn l ~s wirh narrow thera peutic wi n-
tlows . St ah'tl d ilTNt'lltly, a t1nl~ t t.al ('xhib ih a hig l. i"tmimlhidlla l va ria hi lity ill pha n ua-
(~ )k i lll'l il'!i ( 'ill I lit, pn'S('rilM:'t! only if it h ,l' 11 \\1<1(· tln-rapt·ulk window.

EXPRESSIONS OF INOIVIOUAL DIFFERENCES

1-:, ; 111'11('(' fo r Inn-rindlvidual di !Te n ' Ill" ... ill dnlg n '., )xlIls(' ('1I111('S From S('\'(' ml SOUrt '!'s .
\ "ariahility ill till" dosagt· n-qnin-d I " produce a ¢H'1l n ·'poll....· is iIIuslm h 'l) ill Figurt · 1-.'5
(C hap . I ), ",hid . s!lows t jn- nidt' ran g" in tlu- <Iaily dust, o f warfarin m-r-decl to pmdm'(' a
sim ilar de~n'e of alltk,( "I'~\llallt control. \'a ri,lh ility ill till' inte llsity llf n.'sl'ICmS(' wi t h tim e
tn 'l sl'l dl lS(' is M"(' U \\i t h till' neunnnuscular <l~ellt doxacumun ( Fi ~. 13- 1). As iIIustmlt"(!
ill Fi~s . 13-2 and 13- .1. which slul\\' frt"(llIt'lll 'y di st rillllticlII h istowmns of the plan-an pt LSlIlil
r-nnce-ntrunon (If tilt' a lltidt'pressant dnl~ no rt riptylim' , to a d t·filll"(l {Ia ily doS(' of the dm!?:
alltl tilt' plateau unbound plasma concentration of S-wiufarin required to pr oduce a similar
dl 'J!rt"(, of a llfi{,( lil~lIlan l cont r ol. vartahtltry e :lO isls in both plraruuu'oktm-ncs ami pharma-
{,( K I~l lillll il'S . \ 'a riah ility in phanna{'()killdil-s was al MI Illustr an-d by tl l(' n i dI' sca tter in the
plateau pl"\" 1<1 roncentrunon of pht 'n~1oill wen fll lJo\\ill~ vartous daily doSl'S o f this dnl~
(Sl'l ' FiJ!' l -fi, C hap . I l.

The Need fOf Model.

TIl(' IlIaJ!nitmle an d n-lat ive co nt ribunon o f p hanml(,,(lkillt'lll-s ami plmnllal"lKI)llitlllil',. to
\"a n ilh ilil)' in n.'sl'IC)II'il'!U a ~\ 'l' n t1osaJ!(' wi thin a patu-ut population \ '01 1)' \\i t h th e drug a m i.
10 souu- exte-nt, till' co m litio n hl'ill~ t rea ted . Fo r example, wil lt a uonste r oldal antl-Inllam-
matury d mJ.:. tln- rl'!ati n ' contribution of pharmal,,(KI)llamil' \' ln a hilit)' ma)' 1)(' different
when t ht· e-ndpoint is t he n-lfcf of a lu-adaclu- th a n wheu it is tilt' rl'! it'f From chronlc iwilt·s
ami pain s a.\sol'ia lt"(l \\i l h illfla n u't l joint s. In d inil',,1 praet ice, all t' m pts 10 a.s siRJI the n-lative
(,,(llItrilmtil lll to pha n llal 'flkillt"tll-S and pharlllill'f){l)llamil-s lIlay '"" mad t' ha.s("(1 O il di n-ct
ul l'il·rva tions of p lasma ("( IIl('('lltmtillll an d rt'sl)(lIl'il' , 1111' lL\sih'l lllll' llt coukl 1)(' s l n lll~I)' In-
Hm-nce-d. hOWl'\- t-r , hy till' Ii lIli ll~ of till' ohS('f\-ations a nd I lit" lIlal?;lI it udl ' of the response,

100

75
HI:. 13-1. T ln- . ..~,. "f l1<·u",m,,~ ·
~
." 1 1.",,,1 ...ill, ti nH' aftc" an i.\·, 1.,,111, ~
0
,I, • uf lH l4 "'10<~ ,I<'....."ri'lln I" " ....
IlI'n h ' ·...lil.,...' ...·k ( I mJ.il-. - ll ij' Ii\ IJ
\ \ IcOI Iifi< ..1 rn" n ~-hrn ill.. \"D .. F;"..II.'r.
'""
~
50

Io;. ·l ~' . J.. " I. >lI· D" ni<c, \ 1.. III1 O'" mn.
c.s.. ,tI,.1 (; ,.. .. ·1... T i l.: Pup uLol il. ' "
~
c,

1'1,an " .......~'};u nM.., o f .I<........' nni n , C hll , 25

l'l.,m n,om l, TIlI'r ,•. 'i2 :."j2~').16. Im .l

o
o 80 160 240 320
Minutes
CHAPTE a I J ...
as Illustrated in Fi~ , 13.....1. Here. a t1m g that displays htth- iutr-rpatient \~driah i l i~' in e......
t-. a nd in maximum efTI't.1 . h ut J a~t' vnrialnlity ill hitlf-Iift and concentra no n nt'1'(lt't.llo o

produce 50% 1Tl...xhn u m n ' spuIISt·. is ~H' n OrdUy at 1\\11 tic lSI'S. Onto that adlit'\l 'S d ost· 10
maximal rt:'spo nse in all pat ients and oUt· that dOt·s not. .<\ t ti lt' hight'T close. Ohst·n. ltiuIiS
millie at C_. wo uld SUAAt's l litth- va riahi l i~' ill e ither (''UlIt'(' n l m t io li o r phan n a('otl~lI;lI n it"S .
'Ai lh pcrhups a g n'a tt' r a.SSiIQHllt'llt of variab i li ~' 10 I"t' fo rm er. "'0; va riation in pl a.sma cou-
ceutrut ion p m d ul 't' s n·lalively liltll' dmll ~I ' in rt'SrNlIIst' . AI later time s after thls higllt'T
dOM'. su bsta n tia l va riab ilily is uhst· r'\1.'t.! ill INJlh l't lllt1.·l1tra l iu lI a m i rt'SpUUst·. In cont rast, fOT

•
99 B ••
30
A ./
•
90 •••
•
"
~
Q
20 50
•
•
• ••
••

ilE •
z~ 10 •

o
o 0.1 0.2 0.3 0.01 0.05 0.1 0.5
Plasma Nortriptyline Concentration (mgll) Plasma Nortriptyline Concentration
(mglL, IOQ scale)

.111:' 13-2. A . TI,,· pI"" ,,,,, pi".",,, n"K~·n l r.llic", "f lI.. rtriIN~IIlM· \;trio-s ...i< "·I~· in 263 poh... 'h n,,-...i'ill~ lt n ~"K'II
..f 25 n'R ""rt ril't~"il>t· "....t1I~· th · h"' ,L.il)'. H. Th· n"K~·n l r.<lic >l" ,,"" " '!o:"">mlaily clioln!>" " ..!. " r..,,,,
110.· ' Inal"" l I"............., 11K' 1"..n llli of 11K' '11"",LtltW numl>l·f "f polito" t, ..... l..nU....J ou f'"~,jl "",,un,t
11K' "'!o:;(ritIUll .. r II..• "">t~ .. 'lfll.li"n _( I ",!:,' I • • 3 ,1t IoI M l i H, ~ l r~l' "' OI l •...k~ 'lltl ..d rromSj" 'l'u l . t-.. Bt"}ta . ( )..
;uK!0 011<'. ~I.I . E. : t"UIKLt" K·III.tl, nf d"'i...a1 I'I>;(nnOOl' .It~ . In [) n'j(T"";(lnK·nl. t:.Jit...l b). G .S. ......" . E. lmlMu'l/:h.
Cln",-!lill lJ 'l"lC'l<>lK·. 197" , 1'1'. 1--11.)

• •
• • ••• • ••
•• •• • • ••• • ••• • • • •• ••• •

o 2 4 6 B
Unbound Plasma S-Warfarin
Concentration (J.1g1L)

nil:. 1$...1 . Th· ""J,<MlI,,1 pLtt... u ''OIK~·ll lr.l.l i,," .. f d Ol' pn~l"min...lt·I)' acti\'t" S· arfarill "" "'I(;"h·d ..., 110 a \Jmil".
dt1/1t"-· nf Itllllt.~~,t..I""' , ,..rit", ...;. 10'1) """ >1'1/: ll !U''' II' .. r 3.'i 1",,1" 'nlo n...... ~'in~ mk' """rf..rin, ( I "'Wi. - 3,,1
11M) ( "'d" i>t.~l fnltn <:1""11. t: ., ~kl _·I,L.i, . ." ,J . I','lCI{. \ 1 . Madu,y.'" I) " (;1..... R, R.. ;UKI Rt....L . KI. ~L l)i' p,.. ,Ii""
nf ",,,rf;inn .·n...lltic......·n ..", I n><1...h"I0"... In [""Iit..'h ,I" n" fo( nmltiplt· '''"inl/:. Hr, J-e lin. 11""01." '01 . J7,5fi.~.
I""
 CHAPTH 13
206
''''''''"''
15 1

0.75
10
0.5 large
Dose
5
0;-
c ~ 0.25
0 c
0
~
0
~
0 ~ 0
'"
~
u
c
0
0 6 12
Hours
18 24 '"E
E
0
0 6 12
Hours
18 24
'-' .~
0
2 :;
c
ee
E
~

'"
Q.
0.08

0.06
'"
~
c
0
0
~
~
a:
0.1 5

0.1 Small
Dose
0.04
0.05
0.02

0 0
0 6 12 18 24 0 6 12 18 24
Hou rs Hours
"' ;J/:. 13-4. n ..· into-,.;,,,I,,iol,,...! uri.t"; I ,~·I " " " Il'l' n lnd iu n ;l,ll..1 """p'If'''' w .nt'S " l I t, ,I. "tII.I Ii" .....( ,~",·n,.li< .. "
st..........n· pi.." ,,., " "... ·nlr-..ti<.... I" ·ftj . ".1"""I""'''''' (ri,,1I1l (,,11.....; ,,11: ...~•• ,KI ~"...Il tI ,,( IIdru!!: ,I..., .Ii.pl~,
111110· inftorl'"tit 'lll , ,,riahi hty in C-. . I_ "Ill,1n...\im um n"'l'l "'~. hod Ltr,.:.. Inl"'1"""'n l ,,.ri.. hility· ' " l...Jf.!>ft. ..",I
..."..,·" 1..-", ..,,, 11••• 1...1,,, p"_I,,,,· ."ill'l ",..>,i ",,,,,,"...,. . ..... ll i ~ 1 [...... (l" p l: ;o.l '-.. llw llIouitlium ""'1""'.... Inal l
1);'1;'-11" i. rn"IoK. ..1 wit h li ul. · ,-..n..hilif:.' in ,';Iho·r C _ , .,. 1'Mp' " " '" C ..... ,,·. \'",,.;..,"li l,. ' " n .." ....'I ..-..tit .. IUIlI
" ,.. ""•. i. ....·n ..' td .-, Ii"'.... I ~." .k....· ' t."U" m): 1<1 1_ •. \.. ri..JMlit)c' '" C_ i. " ,[110,\.... IM,I th.., in ""'1". '''' i.
'M ' " .".i<I.·r..I>I.·.

Ill(' IO\\'N dos" . a ll ~.,.. then- is slill liUIt' inh' rpati('nl va riah ilily ill C........ bu t IIUW rhr-n - is
l'tlllsitll'rahll' \'ari;lh ilily in rt'SllllIIS(' , nib (1I'lx'm ll' lIl't, nil dmO(' sud tinu- in tlu- ,,-~si~lIllt' lI l
of vari;lh ilily is lIliuilll i;r.l,'t! hy t" p rt'Ssillj;?; '"<Iriabi lity nut ill u-rms or UhS<" n.11Iinn.s hut rathe-r
ill terms or tlal' pan ll1lt'It'r vulues d('fi ni n~ p hennacokmcncs and pharmacodynamics. tha t
is. ill f . ki,. CI•. " " d , . rn r pl rarmacoktue-tics , am i in maxuuul rl'spc.)lJS('. coucentrunon In
aeh ien' .,)(l'k or li lt" maximum rtOSpOIlSl·. and th l' Factor dl'fininp; 1111' steenness or tln- CO Il-
1"('ntra liu n- n 'spUIls(' re-lation ship Ior p!l;l rn lill't Il!~1mll\ it"!i (C hap . 20. PhanniteuloJ.,rie He-
Si" mse-], O nl'(' \"<Iriah ilily ill Iht·S(· pa mn lt'tN 'S is t1"fillt'(l, IIR' I'XIX"l1t't l va riability in l"()11-
re-nt rattou and n'Slllllls(' wi thin the p atn-ut populalioll assoclated \\;111 ¢\'(' 11 dosap;l'
rt-p;illll' llS ran hi' r-stuna ted. 111(' ill"('ural')' o r ti lt' IIltlllt·ls dt .fillillg pharmacokincncs and
pl\;lrlllill,(ll l~llll lllit"l; is " h, ; ons ly critical to an IImll'rslamlill p; o r \1lria hi lit)" ill pa tu-ut n-.
SpUIIS{.'. \ \llt'n ' appmp ria t(·, the-se- 1Illllids shou ld illl,,(l'llllr.llt' such Iactors a.. protein hind-
ill~. ae livl' lIlt't alllllilt'S, uml toh-rance.

DESCRIBING VARIABILITY
K III l'\\;Il~ how a particular parallll' ll'r varies wit hin th e 1'I<ltit'lIt population is importa nt in
11 11·mpy. Tu Illustrate thi s stan-meut l'l lllsidt ' r tilt' rn 'fIUl'lll)' di st ributions in dl'ard lll't· o r
CHAf"E~ 1J VA/lWllUTY 20'
lilt" thn-e IIHlolllt't il~dl d m~s s!lcMn in Fi ~. 13-5. 11\l' mean, ur central tendenc y. fur all
th ree d rugs is tilt' sa me. hut till" \1I.ri<lh i l il~· about IIIC' meun is \ 't' ry cliffe R'lI1. For D m .l'\ :\
ami H. Ilu- d islri lm lio n is IIllim ocLtI u nd normul . lu-n- III(' 1lI1';llI represents till' 1)'Pil'al \'al.l('
(If c!c'anllll"l.' 1.'''l ll'<.1c'(l ill tilt' populanou. ,h \Nd ria hi lit)" alMllI1 tlu- mean h mnclr grt'HIC'f fo r
D m .l' B tha n fur I) n l~ A, on e has much II.'lis l·o nficlt'IWI.' thut lilt' 1I1l"<l1l of D m ~ H ap pli,'s
In all indivi dual patn-nt . For D m.l' C , di slrihllli ull ill dC';lnlll l.'l.' is bimodal. sihrll i ~\i n~ th ai
the n - a n' twu major ~n l1l ps within lilt' populatmn: IlIoM' \\i lh hi~h and luw d c'am m'l.·s.
O ln ious l\', in this I.':l\l', the 1Il1' ,t11 is run- uf till' lTlost 1I111ill'!\' \'alllc~ 10 lx- found ill Ih h
popnlati,;n . "
( ;" Ill'r.clly , dts trihutlons o f pha rmacoki m-tic parame-ters o r ohsc:·....-ations art' uuimodnl
r ather than polymodal. nnd tht')' an' ofh'll \ lc'\\l'C1 m lllt' r tha n normal. us see n, e. ~. , in ti lt'
fn 'C IUl'IK'y clistrilm ticlII of plateau plasma rmrre-nt ration s flf lJllrtriplylil\l.' (F iF;. 13-2A). A
mon- s)'lIl1llt'lri m l dtstnbu nou is ofte-n ohtaim-d with :1 to~?;a ri t i ll nil' tru usformatiou o f IIII'
paramen-n such clist ributions a n.' sa id to II(' Ing:-llcJn Jlal . A common met ho d u f c,:t4ll11illing:
for 1 1 ~-II(1nllal d b lri h lliio n is 10 pillt rlu- (1111 1111alin' fn.11111'lIl' ·, o r percentile. 1111 ,I pmhi t
S<.'<IIt' agains t tilt' Ic~ari tl llll o f tilt' \<tria bl,·. TIl(' di ~ l rihll ti()1l is tak en to II(' IOl?;-non nal if lilt'
poi nts lip 0 11 It stnU!?;hl lim '. :\.~ l':111 1M.' sc.'C·1I ill F i~ . 13-:2B. th is is the m .\(' for tilt' plan-au
plastna l'C JIll'C 'ntntliu lt of no rtri p l)'lim" III such C'li.\t'S Ihe IlIt'Cliau , o r \".cIII(' lthou ' ilm l ll(-Iow
wh ich th ere an' equal numbers. d ifT(·rs [ rum lilt' mean. Fur nort riply line , examination uf
Fi ~. 13--28 lnclic-all' s tlmt t ju- nn-dlun 1'C )IlC'C'l1tmlioJ) is n.n') mgfl .. Wllid l is 1('Ss than tilt'
:I\'('mgc' \1l11lt' o f (W69 IllWI_
A comment o n tilt' quautitnt ton of \1lriah ilily is 1\('C'C lc'C l lw n'. Varian o ' is a nl(':LSlln ' uf
Ihc' (I,'\i ations of It.c' t1bsc.'rva licllls ubout ti l(' flI('all ; tt is dt'fillt 't:l a.~ It.c' sutu u f t ill' St'lllan.'s
of theS(' d l'\i at il1ll5. \\' Iilc' usr-ful to l"lm\"('): va riahility wi thin a particular set of oh sel'vali ous,
vari ance dOl'S nu l allow ready ('C 1II11l:triSlJll of ,-.uiabi lity "l'",SS M'ts u f ()hM'~l ions uf tlif-
Ien-ut lJla~ni t lltl(' . SIIPIXl\l.' , (' .j?;.. d ('ar.IIIC1' in all inclh icillal is 5C1 m l/mi n and th t' uu-an is
IOn m l/mifl; tI... \l Ilian'll t1t'\;atio n is 2SCln (m IJ lllinf. If insteacl dc·a rdlll'l.' had hc'C' n
' 1IIo!t'C 1in l.Jm in, ti l(' squared dl '\iatioll m m ld 1M' (O.l )'') - 11.1 )2, or 000'25 (IJ lIlinji. O: M'lTi-
ciout of vurtatjou. which " "p n'S\I 's \1triah ilil)"wtth n'~ lll'<.1 to Iht' uu-an value, on'n1llllt'S th is
pro ble m. Spe-ci fically. it is lilt' SCllliln' mo t u f va riance (IIIC' ~ lallc Lll"( 1 dc'\iation ) nonn;tliz('C l lo
till' menu. lu tlu- I'Xilillplc' ahon' , Ih(' d c'\i at iollllonuali;l.c.'C 1to tilt' m t'a n is 0 .5 wul is illliepl.om i.
('111o f ll.(' IInits ofd l'ardlll'l'. Fu rt lw rmcm ', a la rgC' l'C J( oflk 'il'lIl of \"arialioll llUW iU"''ll~'S SiWliHl's
a hi~1 1 clc1?;f\'C." o f \ll riability. Suhsc'C llIt'IIII" , in tllC' lU ll. h igh lIlid lu u: w rl(//J lllty n'fN to di s-
tribu tions IhallJa\'l.' h i~1. :1IIc1 10"': cut'lTidc'lIls o f \1lri:t1 ioll. n'spt'<.1i\"d y.

A H K. 13--3. .\ s lho· fn ~ lt .......,.. .listri""l""'" f..r II..•

d.·..,..,,,.....f Ilon I,~l""llt'1 k;oI.lru~ (A, B. C) .1......,.
Iii••• ;"'I.'r1.ItI I t.·fin••~...I''ilohllity an . ,,,,1 dll"' ""'IU'
,,,..I ll..• '''''1.' " f II", f....I'IrtIl'Y .h..r.nl. lllun .~IT\.....,
il ,. ,.. ,t.·filM" lho· fTW"" it .. ·lf.

c B c

Clearance (arbitrary units)

20. VAitABlUTV OWTH 13

WHY PEOPll DIFfER

111t" n 'a.'i01IS wily pl·opl!· differ in thelr n-spousiwm-ss In d rugs ill medici nal pn xlut'h art'
manifold and include, i ll ~('lll'ml on k-r uf importance, ~1 ·lll'lil.."' , t1i "t';l \( ' , "W', d nl ~s ~\'(' n
l'tml'(llllilalllly. an d a \'aridy of cnvi mmm-ntul fact o rs. :\ h holl ~h i ll ht'ril<lll('l ' ;In :oullls for a
substant ial part of th t, d ilTt'n'Il("('S ill n 'slxJIlSt-' allloll~ ind i\idllak mud. of this variahility
is larRd y unpn- dict ebh-. I Il l' n·;l~ i ll ~ly . howew r. tilis soun:t' uf , ·ariahility. par1il'lllarly that
n -lated til dOl ~ na-t abolixm , is ht'ill ~ IIl1d t'r;lood a nd mad (· ilio n ' pn't lid:;lblt· Ilsiulo: tln- tools
of I!lO!l'(.11Iar h iology (C hap. 1.J , Gt'!wlks ).
Di st·;L....• ('lUI !)(' an addl'll soum- of va riation in drug W'ip oll<;t ' , Usual lluS;I!-:(' n,,"w m
lIlay mx-dtc be modified slIhsla nliaily in paucnts with n-nal functkm lmpatrnu-nt. hepatic
diso nlt,l'li, l'Un~t's l i\"t, l'U rdi al~ Iailure. thY1'u id disorders. ~'l\ l millft>slill a] dtsonh-rs, alii) o!l lt'r
d io;(·'lO;("5. 11lt" modification lIlay ap ply In Iht" t ! m~ ht'i n~ used to In-at ti lt' specifi c t1iSl'llo;('
but may apply t·qu all), wf.'l l to other d m ~s lilt' palit'lll is rt"t"t·i\;llJ.':. Fo r example, to pO·....-ut
l''({'t"!lsi\'(' accumulation am i Sl) reduce tilt' risk of Im;itily . tilt' t l usa~l" o f Ihl' anlih iolit·
~1 'lItam ici u lIS("tl lo In'al a plt·uml in fl'l:tioll uf a pali t'nl must hi' rt'l !LI(''l! iftl lt'llOllit'lll also
has compromised renal funonon. Sim ilarly, hypl·rth yrtlid it· patients rt'tp lirt· hiJ.':Ilt'1' than
usual closes n f di ~o\i ll, 1I d nt~ used to imp mn' cardiac emtit' nl'y. \l on 'tlwr. a mod ifi(';llion
in dnSlI~t' llIay arise nol on ly (n lln the tlin 'l:t Impairment of a di st·'L\t'd o'X.1lI hul also Front
s.t'(.'(mdal)· ('\"t'llls that lI('l.'tIlIlP<Uly til(' diS('a.<;t." Dm ~ met abolism, t'.~ . , ma)' lx- mtMlifit'(! in
patien ts \\; 111 renal d iM'a-., '; plasma and tissue bim l i ll~ of d nt~rs m ay lit· aln-n-d in patu-nts
\\; 111 uremia am ! hl'lllltic disorders.
A~t' . \\'t'i~ht . am i (,ml'nmila ntly ad lllinistt'n'(l d m ~s an' importanl 11t."t';lllSl.' tilt")' an"
sources o f \'a riah ilit)' that can ht, taken into account. Cendcr-ltnked d ifTt·rt'lll,("Sin hormonal
IlOtl'U1l 't'. hody compo sition, an d acti vity of certain l'Uz:,l llt·S mani fesl tht'm sc:·lvt·s ill diffN-
t' nl't'S in bolh phanuacckus-ucs and n 'spo nSi\l'lless, h ut overall. ti lt' I'fft't."1 of ~t·lltlt ·r is
small.
Tahh- 13- 1 lists exam ples uf ad d itional fat1 0rs known 10 luntriblllt· to \"lI riahi1iI~' in dm ~
n'SpOtlM·. l'crbeps III(' mos t importan t fal1u r is nOlll'timp liallt't·, Xu nl'tllnplialll't· Includes
tilt' l aL:i l\~ of dnl~ al tlu- \\'n ltl~ time, til(' omi ssion or sllpplt'llIt'ntal iun of prescnlx-d duS(',
and the stOppi ll ~ of t!lt'mpy. r-itln-r ht'(.'alls.t' ti lt' p atient 1 1I~ 1lS to fl'(·I III'lh'1' or 11I't'1llISC:' of
dcwlopmcnt of side-effects that Iht, !lOllit"nt consldr-rs IIn'll'l.'t'ptah lt'. \\ 'ha te-o-r tilt' n-ason.
tlll's(' problems lit' ill tile area of p ath-nt {,( Il lll sell i n ~ and t't !tI{';ltioll, O('{';Lsiollally. ptlsma
l'tI!l{'l'lltmtioll (Ltta an' 1IS('(1.LS lUI nhjt'(1i\'(' lllt'llSUn ' u f 1l011l'tllnpliall('t.',
Phanllill'('ulil';ll formulatitJll am i lilt' pnlt't·ss IIst'(l to lIlll11ufal1u n ' a p n ltlut1 t';lll Ill'
im portant :tS IMIf!l l';tIl afft"C.1 tilt' m h o of n· lt"lSl'. and 11I'tll'l' t'ut!)'. iutu lilt, 1MIlly (C hap . 9 ).

T."•• 13-1. A4WltI_I.___. K_ _ .. c..mt....... V.ri...lllty

I.............

A maIO' p<obIem ,n d,nocol procll(e: $OIuhon I.e~ in p:ll>enl ed"'0100n.

Pot;enl r~ con \lOry on changing The roulE! 01 odmiOl~llotl()(l Not only
pIlormocoi<,roet>c.s 01 d,ug bu4 a lso meIOboI'lE! concenIlO1l()(l~ can change
'ood ~'"" ond occo~11y edenl 01 o~P',on Ofe oflecled by eat'ng EHec~
depeod on COlT1po$lltOn 01 food 5evet'e pt"oIeon rtl$lfodoon may ,ed",e The
'0 ,"" cJ d,ug melOboIiyn
Drug el!ecb Ofe ohen ~ "' w.oler~ and WQf~er5 oa:upol,onolly exp«.ed to
peshc;de$; a ,esuiI 01 enhanced d.ug melOboI'$fTl.
[),u,nol\lO'1Q\l()f» Ole Ioeefl in phormoco'.,netlCS ond on d,ug re~loe The!.e
effects ho-.oe beeo suHl(1efl1!y ,mporlonl to Ieod to !he deYeIopmenl 01 a new
$i.lbted, chronopi>ormocology
Clol!.e requirements oIloOfll& dlug~ d,f!e;o between p:ll,en l~ liv,ng ,n IO'M'l a..d in
!he cou~"'"
CHAPTH 13

A wdl-tlt'sig:lI('(l forlllulation d iminislws tlu- d('!-'Tt'(, HI' \1uiahilil)' in rlu- n -h-ase charact e r-
istk-s o f .. tim}: it! t"i Ul. Cood Ill all u fadu ri ll ~ pracuce. wi th careful contro l of the p n K't·ss
\"lui ahlt,s. r-nsu n-s tln- mauufact u n- o f a rdiahlt' product . J) nl ~S an- WVt°n l' nh"mlly, topi-
("ally. pa n 'lIlt'rally. sun ] hy inhalation. Houte of u dnuuistration not only can afft"(1 tlu- con-
('t'utmtio ll loeally am i s~~h' lIl il~ally hut also (";11I alh' r tilt' svste-mic concentra tion of IIwlah ·
nlite l'llln p,m'( l wtt h thai of drug (C hap . 2 1)...\11 these- factors (',11I p m folludly lIffl"(1 till'
rt'spo liSt' 10 a ~iVt ' n dost' ur n~ lIlt'lI .
FIICItI. parti('ularly fat. sluws g:,lshi(' 1' llI pt~i llg: lind so decn-ases tilt' mh' o f dm~ absorp-
HOIl. Oral h ina\"ailahilily is not usua lly alTt"('It"t1 h)' fond , h ut then' an' mall)' t'X('('ptiolls to
this start'lIIt'llt. Fond is a complex mixture of chemicals. {'<I("11 poh'nlially (";'pahlt' of Inter-
ad ing wit h dnl ~s . Rr-call fnun C ha p. 9, I'.g:., Ihat lilt" om! hioa\"'li!ah ility of II'l r.le)'diJw is
n-du o -d wlu-u taken with m ilk, pa rtly 11t"{11l1W o f till' fonnalioll of an insoluhh- complex
with calcnnu. Ht,,{~.1 11 also thai a SIIMi llg: of g:aslrie t'lIl pt~i n~ lIlay Increase tilt' oral hitloi. l\·ail-
ahilily of a slloi. l ri n~ly so lubll' d m ~. sud l as wl se(Jfulvin. »it'l lIlay also afft"C1 tlmg metab-
«llsm. EU ~ lIlt' s~1 1 tl lt's is is .. hilllatd y dl'!ll'"dt 'nl 1111 protein intake \\1lt'1l p r otein inl akt'
is st'\'('rd)' n'lllll't'1l for p mI Ol I~t'l l pt' ri( ItL~ , pa rtit11lar ly !It"t.'llllst' of an imbalall(,{'ll di d , d m ~
l1wtalMllislll may 1M' im pi.in'd. O:IIl\l 'rst ,ly, a " i ~h pr on-tn inlake Illay cause t'n7)l l1t' Indue-
liun .
C IIOIllupl.arm<l(dlJK\- is lilt' ~ I u dy of rlu- illllllt'nt'(· of lim e nil d rng n 'sl'ltlll'it'. ~l allY
t'lldllj.!l'nolls s llh~ l a nl't's . e .g., hormones. an' kno w n til IIll(lt' ~(J t')t:lit' d"lIl ~t's ill coucen-
trution in ptl~lI1 a alltl lissllt, \\i lh tinn-, 11l(' am plilude of the dlall~e in coucent runon vuries
, 1II10 1l,C: sub stauo-s. T Ilt' 1'It'riod of till' (.',-clt, is ofh-n di urnal. lIppmtinmtd y 2.J hr. «lthough
tln-n- lIl a~'I It , IMIII. SlltlrtN lilld 111ll)!;N (1't'll'S Ilj'lt lll whit'h lilt" dai l~· o lle is SI!pt.'rilll!'ltlst'tl.
TIlt' menstr ual (')d e and seasonal variattons in tilt' (1)1\('('utrdtillllS of some {'1It 11~t'nollS
suhslam'{ 's an- t'\lunplt,s of(')Tlt's with a lung peri od . Dm ~ rt'S!'ltJllst'S may the refore dmll~t'
with lillw of day, day Ill' tlu- month. o r seaso n of tht' )"t'ar. Particular not e of th is phenom-
('11111I is ta ke n in cumx-r eln-mothcrapy. ~I any ehe lllut he rllpt'lIlit" agl'nts ha n ' n' ry narrow
lI1al"}jllS o f sa fely lIlItl an ' giWll ill co mbination . Appropriate ph a.\ill g: in the liming o f ud -
miuist ratiou u f e-ac h d m g during ti lt' day m il improv e tilt' margill of sa fety.
C i~,u'l'Ift> smoking h'm ls III reduce d ink'lll am i toxic efft"{is of sonu- d rug s. illd lld ing
(· h lo n l iaJ'~·I'1tI\itlt'. d iaJ'x'p am, and thl'llphyJlitw . TI l(' d m b"" alTl"{of("t1 an ' t'xlt'n si\"t'l y 1111'1al>.
ol i J'~'1 1 h~· Ilt'palk' o\i dalillll; iml u(iiun of til(> dm ~. n \t"taI M,Ii J'jllg ('1I~1 11t·S is tilt' likdy (·illlst'.
\ 1au)" 1" 1\i n III llwnlal p"lllltallts l''{ist in hiRllt'r ('{lllt'l'ntrations ill lilt' lily Ihan in IIII' L'tlllntl')';
tllt'Y (',Ill alstl stilllulalt' S~l l l l lt's i s til' IW[Xllk IlwlaIM>li(.' t' n ~1 1ll's .

Identifying the Sources of Voriability

III p ral1i('{·. aH tl1t' aIMl\t'-l1wntiollt'(l fol(i u r.i ('an ('{ltltrih uf(' 10 ohst,,,,,'tl \<lriah ility in n' ·
SPOUst·, and m n ' mllsl 1lt'lakt'!l 10 t'llSlln ' an app rop rilllt' t'tllldllSiotl is n 'lu.·!It'1l whe u If)inR
to ,Lssign eaust' S o f \·a riah ility. ConsidN, ('. ~. , tilt' dat a tlispla~,"{1 in Fi ~. 13--6 wh it-" shll'\'
lilt' 1IlII f-li\"t·s Ilf pllt'nyl bu l lV~ J lIt·, a on t'(' uidd~· u'it'll dmg, in Iwalt h)"suhjt"{ofs and in l"ali,' nls
\\i th l1t'p ati(' diw,l'i«' (p rimarily drr h()\is), Inilially, 110 t1ilTt·n 'l1t'(· WilS n '\l'alt"tl llt,twt"{'n Iht,
t\m gnlllJls. t" ('t'pl for a ~n'atN \"ariahilit)· in Iht' h" lf-Iif(' among tilt' patit-nls uith IWl'atie
distw,t' (Fig. l.'l--fiA ). \\1WlI, IltJ\H,\·N , Iltltl. Rn lllp!' Wt' rt' furt llt'r slllltli\i dt'1l o 11 till' hll~i.s
o f whl'l llt'r I h,'~' rt"{'t'in "tl ollw r dmWO' a d t'arer pit:t lln ' ('nw rgt"t! (F ig. 13---68 ). O f l)lOS{'
n"{'{.'i\ill ~ Till ut llN d m gs, pa tit'n ts \\i lh IWPiitie d ist,a.'>t., hall(!lt'(l plll'nylbutX'JlIlt' mon '
slmdy Ihan did Iwalthy sllhjt"(·ts. E\idelllly, Sllllle of till' olhe r dnl~ n n 'i\l "t! ha.\ t('11 pileI!'
\ IIJlltiVJlIIt" d im inlliioli.
• Varions slrah -git's (~1Il hI' t'mpIO)l"tl to id,'nti f)" Slmn'('s o f \<lriahility in n 'S!xlIlst'. n it,
d a_~ s i(' dl's i~l is IlIle ill whit-I. ll~ man)' o f till' \"driahlt's as JXlSsihl(· an ' fi\t'tl, apa rt fn llll till'
Wit' tIl' illtl' n osl. Fllr t'xamplt' , 10 It'sl if n'lI al tlist'a.<;.(' alTt"Cofs Iht, pha n mu.·o ki,wl it.'Sof a dm ~,
 2 10 OWTUIJ

A B Hepatic
Hepatic Normal Disease
Normal Disease No Drugs Drugs No Drugs Drugs

• 197 . 197
130 • 162 130 • • 162
144
•.
• 144
•.:•
110 ..
•
..:..
• •
110
•
••
•
:..
...... ....
•
90 :• ..•j.

...... '
---"-
~

;.
.
.-.."• • :;~ " .'••.
70 .....:.
•
~
'.
•
--- ~
w
'<
~.
•
~

-.'.
......
..
•• '.
••
•
.:::
.:i:
,'"

50 J ."o ...
.. • -,:.'.
....
.•:
·1· ' ,:t
l'
• •
.:. .e.
30 'n
•• 30
•
•·
10 10
55 95 36 19 34 61
Number 01SUbjects Number 01Subjects
"".e. 13--6 ..\ . :-.;.. t1irr,·n· 'It~' i. .....1\ 1 1\ , h.' ;t\1·r~· I ...J f. lif" "r ph.. ,,~lh.. toon....· (hu rilJ.u ,;d Ij".· ) in Ilnn nal

" ''''''''' 0 (Iot" ''' IIt'' ''Io) ~ I Kllh"l in I"",w-nl ilh t""P'-lic.· di..•.....• (u ........ 1 puinh ). Ii...\flr••.,wrllhn ,K ' 10, ... • " ,
,,,,I<.. ,>lIlt·. ,In,lf' {lIltl,! I.. ~ "h l f.." " ' h....· ,,~ .., .1.. ".., (,Ltrk ,'U",.). I t.. " P" .....,I:'.. I .. h,nirwli<ltl "f pl"·"Jih" ' ",,...
in p;,tit'nt' ...i t l. 11t1"" ;" ,Ii..·,....· I""(,. .,, w", ' -';''-'11' . In h", I, li:n" ,f" ti M' hilf.lir.. 1,-", 1, ' n h, . d"lI1o" ",1"," .., ......
" nolo..... ~"· l ..l .·n <~ " K' , m·n l ly . ( H , ~ l r_1' (ru m 1.." , . ,\ -J.. \ 1..·,1<>(,,,. S.. ;",.1Will".·, . n,: 11....,,11..'1...........· 1tJ.. 1 i",,-
IIiv.i<1 ""·I..IM>li",,ill ""h,·,," "';110 li..-r ,1;...;<... in ...l;1Ii"" In pn"i""" ,Im l: ll ,,·r..,,); . 1,;",,,-"f1. 1: 127.'5- 1279. l ijf;.'oj. l

all o!lwf f act ors Slid, as agl', g,' mlN , otln-r dru gs. and did should 1)1' he-kl constant. TIlt'
idt'al 1.I., 1II1d \1(' a IOIl~ l udilml l·m..s-u...-er t1t'SiP l in wlik-h t'ad l p"til'nl ;I<.1Sas his or he r own
cout ml. Th i.. d t 's i ~ l is often nol pnss iblt" hos\, ·\t'r. TIll' pa ti('nt 1.I.; t1l renal d ist'lL'>t' is Kt' n-
t·m lly not a...-ailab lt· for ..tfl(l~· prior 10 tilt' dist';L'>t', and n -ua l dh,';t'it· is gl' m' rally ir n -ve rsjbl e .
T Ilt' 1"II'11<I.lly rnr d(.... ial i ll ~ [rnru such a d("S i ~l is ~n'at t' r q triah ilily wfth lo..s ur t'ffidt'llt:)',
sud l that Illany ilion' patients are needed to allow a firm co nclusion to he moult' aho llt the
l, mlrih lltiOIl or a I actor 10 \·a riabil i t~· . 111l' 11l'lll'fit or luost'n illg thl' dl'sign , 11Il\\t'\"I'f, is that
lIIany IXlli('ut s wllo might o!llt' rvvise I",· ('xd ml("tl ca n ht· a part u r Ihe ..tudy. In thi s (·llll-g0l)'.
(-.g.. a re- (·lderl y patu-uts Sl l lTt'ri n~ Irom St....x-ral tliSt'a'>t's am i rt'lilliring lIlallYd nl gs, indlld ing
the mn - or intere..t . Can' mu ..t ..liIIl ",· taken, howev e-r, 10 ensure thai a suffidenl 1lI 11l111('r
or pati t' nts an' ind udt'll with t·11l·1I or !llt' at tnhutes or condiuons of interes t .

DIFINING THI DOSI-RlSPONSI RlLATIONSHIP

\'ari a bil it~· h;t\ an impo rta nt I",'aring on the " ,,",il1U1t/tlll o r dose-response n ' lutio nships ill
clinical trials. " rxunmou p-oe-dun- is 10 t1hi dt' p.llit·nls into St,....vral ~mllps. t'at:h gnlllp
n"t'!'i\i llKa <!ifTt' r!' nt dost, u r dm~ such ;L~ S. 10. ur 20 mg. An attt'lllpt to t"Sla blislJ a dOM'-
n 'spIJI I"t' n ·laticmship is tlu-n malIt, 01 1 Ill(' mea n data for each ",rrtmp. usiuV; \'arhlhilil)' within
~nlllps 10 h'St rnr k-vels or slatistil'al SiKtlifi<''lUI('!'' :\ problem anses when much or the
va riilh ility I",·twt'!·u doSt,· and n-spolls(' n-shh -s in pbannacoktne-ncs such th ai then- is ( ' )11-
..id,·mhlt· un'flap in IIU' p l,Lsmil concent rations amo ng t jn- pUllpS. T hus. ind hid ll<lls From
CHAPTER 13
'"
till" I. i ~h - lind Inw -tlost, group s (111I han ' tilt · sanu- ph sma conce ntration (mul n'spoll s(') .
nault'I)". Ihost· in tilt' !o\\l-tlost· gn lllp with a Inw cleumnce and thuS(' in the hi ~h -t lost. J'n mp
with a high dt'anlll t't' of till' d m g. The overallef fect , by i ncn·a.~ i n g vari;lhilil)"within t'adl
J'n m p , is to weaken tlJ(" lIb ility to dt'lt'd : a do st"-rt'spo nS(' n-lat ion ship.
Om- solutiu n is 10 inl·n ·a....• thr- 1I11 1111)('r of suhjt'l1s ill each gn lllp to n-duce til(' uncer-
lainty of estinmting tlJ(" IlW,Ul n 'sl:M l1Iw at t';1t'1l d USt, It·...d . Here. tilt' p roblem is Oftt'll om-
of 1I0t km J\\ing in ad\"ant't· 1Im\' ma ll)' slIbjt"(·ts \\1.lIIld II(' m-cded in till' trial . ,lS \\1,11 ,lS till'
mldt'll t·xpt' IlSt· of an incn-used uuml x-r o f slIhjt'l:ts. Anot he r so lutio n is to {'XptN' t'al·il
p;ltit'lit to S(...r-ral deN ' 11.....· ls of ti lt' drug. 111is I,lst solution has the di stin ct ad"'lIl1tilgt' of
nut un l)' im·f("Lsing Ihl' chances of ('s tahlishing u doso-response n-lat ionslup. h ilt :llso of
pn)\i d ing an estlman- of inh''1'''llit'1I1 va riahility in tln- n -Iat lonship. Unfo rtu lliltdy, ill p rae·
tit'(', Ihis dt'Sigll is not lIl\\-d)-S pussih lt" ('spt'('ially fur c1 m gs for wh ich till' full t'ITt't.1 nn l)"
occurs " fiN several months o r IOIl ~t'f into d m g administrat ion. A thtrd solutiun is rlu-
cono-nrration -controllcd d inim l trial. III this approach. tln- pharmac okine-tics uf lilt' tlm g
is fi rst I...-aluuted in tilt' pa lit'nt cohort am l tln-n, b'L\.t'tI 011 th is iufonnation. dUSt'S an-
aeljllstt't l !itl Ihal tilt' pl;lS Ill ~1 conceutmuon in ('adl patient lit'S in OIl<.' o f st''o"('TiII l i~ll t ly
dt'611("t! ba nds . This mort ' t·laho mtc , and !it)IJlt'lilllt's mon- expe-nsive. "I's i ~ 1 t'nablt,s Illlwh
d l'art'r stah' lIwllb to 1M' IWldl' ahu lII Ill(' t111ll't' lIlmtion- rt's l:M1Il!it' n '!alio nshi p and about
Interpattent \1lriah ilily in phannal'tlkilll'lit's , lI uwt...vr, it lIlay Imn ' limil t'tl utilily fur tllN '
n-comme-ndanons, if a poo r corrr-latiou is fOllllcl IM'lwt"t'n plas ma d nl g rmn-en trution illlt!
Tt"SPUIISt". ~ I a ny orlu-r t11 ·s i ~Il" . ... al)i n~ in t'tllllp!l'xil)-, t'adl with llc!\1I11tagl'!i and duadvan,
t;lgl'S, can 1M' t'll\isa~t'Cl. III all t.'<l\'('S. ...ariab i li l~· is a ccnt ml issue.

KINETIC MANIFlSTATIONS
Conside mh le \1lriahil ily ill t'llz)"llIalit' adhity am i, to a lesser exte-nt, ill p lasma ;1II11 tiSSllt'
bindi ng exists t"''t'll ;1II 101l~ Il('altl.y iml hitluolls. II nw SIKh \llriahility man ift'sls itsl ·lf. ill
pha n mlt'tlki nt'l il' paTilIlU'le rs ancl ill such IIIt'<l' lIn 'II1('n ls <l\ p latt-lill pla.sma ('tlllt1.'llt rlllioli .
depends 011 tln- Iw p;ltit' I · ~tmdioll rat io uud m lllt' of ad mmt stranon of the- t l m ~. F ur e x-
ample. tilt' I" Tgt, Inn-rin divklual variahility in ha ir-lift' of IIlt"ophyllillt' (Fig. 13-7) <''0111 1M'
l'~pl ai llt'Cl p rimarily b)" variation s ill hepa tic t'1I0111(' at1h i ly, prul J;lhly :L\!itK:ialt't l with \';Ir-
ialio lls in Iht, alllo unts uf tilt' t'U0'11t'S rt'sponsih lt' for lIIt'l aIK)lism o f tltis <.'tlllll:MlulI, l. T llis
t'tmd usic m is lJ;l\.(1.1 011 Iht1.)phyllilw IK'in ~ p n 'tlo lllin;llItl)" !IIt't aIKlli7J.', 1in tilt' lin'r , h;l\; n~
a IIJ\v exlrat1io ll mtio, aJl(I I)("i n~ o nly 1Il, )(le mldy hOllnd to pla.\rn a and tiSSllt' l'tllllpOllt'llls .
In t.'tmtnlSt, su..h a h i ~h d<'''gn ''t' of \'ariah ilily in t·n0 ·IIl.tlk at1hit)" is cxpt'l.1t"tllll h,· lIl'lskt'C l
in III(' d eaTllllt't' o f a d n l~ h a\i n~ II It i ~h Ilt'pa lit· t'xtl11l1iOll Tlilio, h('C'OlIlSt· dt'am llt.1.· h 'm!.s
III lit, Iw rfusiun Tlllt,. limih"t l aml ll" I"'ltit' h llMKI flow is rt,lali...t'!y t'f.lIlstant ;lIlUlIlg I\('altl.y
illd hit! wlls. MUf(1.J\-N . IIl1lt'sS pl'lsma ;1Ilt! t!sSIll' hil1tli ll~ an' hiF;hly \1Iriah lt·, \111111111' u f
dist rihution, anclllt·I1t1.' eli,' !'lllsilioll kim ·tit'S. of Slll·h a t l n l~ an' IIlllt·1i Ih.. sa ult' for all llt'allhy
jlltlhicluals. TIlis is so for p rnpra uoicil ( F i~ , I:}.....';) a t1 nl~ Ilf hi~h Ilt'pa lk dt'a r;lIl(1.'.
As t1t'S(:ril:M"(1in C hap. 1I , wllt' li t1Il1 sidt'rill~ illtlllt1inli ,lilt! inltihitio n, Chill l ~t 'S ill IIt'l"'llk
t'U0 111e a(1l\il)" n 'su h in \'ari" tiollS in oral hiu;,\'ailahili l)' for a dm~ ....i th a I. i ~h !It'p atk
ext nlt1ioll ralio. An -'u n lillgly, \\i llt sllhst't lllt'llt t1ispnsith m Ilt'ing l'()nl n ,lIt'tl by lit'I~II i<.' pt'r -
fusiun, it st'rit'S of similarly Shll!'Il'l1 ph'imll t1mg t'tmt'('IlIr.ttiun·ti llle p mfill's. bu t n ,.lt·hiug
dilTt' Tt'nt pt.·ak ('Ull<''t.'ut rdlinIlS. should II(' st"t'll 'U I\U1I~ ind i\i d uals \\i llt \lll)il1~ t'1l0 'llIt' at·-
ti\il)' rt't.1.'i\i n~ tilt' S<lIllt' o ml dost, of c1 nJ~. nl is is indt'C 'C1st'('11 \\ith p Rlpr.lIIolol i Fig:. 13--"i).
In l't.lIllr.l'\l, for a t!m g \\i tl. a ItJ\\' 11I'pa lic (·xtr.td ion mlio, slIch as Iht"t'phyllint·, \1lrialioll
ill t'llZ\l na tic ;tt1hit" is f(,III'(1I1.1 Ii... \"arialiun in d t';lrolllt't' (aud hillf-Iift' ) mtllt'r than in oral
hi{J;", ;ilability (and 'm,l'lO illlll lll ptl,'ma <''t llll't'l1tmlio n ), whid l is a1\\"d)"S h igh (F ig:. 13-7).
111t' illll"'ld o f ...ari ah ility in u ral hilJ;I\1Iibhilily , !1('C'llIlst' of a high ~ rst - Pil' S t,fTt'(·l. tll' -
IWllds on tht' inlt 'nd t"tlu\.(' of a dmg. It lllay n'sllit in palit'nt s' 1It"t"t lin ~ difTt'wnt sill",II' oral
 212 CHAP'Tfl! 13

. ';l( - 13-; . Fi" , t..·",h t,~ . " I".·.: h ~, 0:'('(1"..1 3.il l 10

Inl: 1I " ",1o~·1I " ..· ",..ll~·. in ..,ju' " ,,, , 10" ,.I i"; • . 1" 11/:<-
, hIT.·n 'I . .... i n ..u r ..n- " u. I.u' ill ".nl r... , ,.. pn >-
B
I'r.u" oI.d <1" 1: l ~ l , ,I,,· p ~ ( ·IIlnd i.. " . an,;d·
" ....., ilJ.·IIIK-al. ·11......• ,>l ·",..li..'" a ;a' "'1101"'1,,,1 r...
,1,, '(," ,~1Iu .... ;, ,Iml( ..r I. l"l\;.'h.: ,-\' r...1i"" 11M! i~
''''""11,,,,·h· " ""'I"I... li",,,1ill ,I... ti\. -•. " " ri ",trill !)' ill I..•• 6
110011(" "11'-::-""" ..<1"11~· i. mil.n1 f, ,...1 pri",an l:_ ;n . 'aria·
1II,.J.·.or..,tt,,' . a,,,II"·'It'(·I lf·llf.-; lit. , '''11:1.1-('('1-
l "l i l~"
r.·(·,...1 ,-"1,,,,11' .. ( ,Ii. lrihll ti"" " f tl"'''plo},!tin.- h
•
•..Iah"·~- " "",..,,1. (I m l hil\;... -.uI..I,ilily i. (.Jo ..... In UX l'l 4
ill all " ,I'jo'th . ..,..II.............· al"" '] >li,," ' . ... ' m ..IIlII" ·t,
r,..Ito. tI,.." ..1;"'ill.<lil"'.I" ·;'1.n .It'(·nl ....lin " . "'n· . imiL,r.
t:.·10 '~l " h..1 n·r.·!" h. a ,IIIT.'n'nl ' '' ''1''(1. (Dat.. pm.
,...... 11':' S, T' M'''. I- '",,,,al ,~", ·n1l.Ii"" • .l

o B 16 24
Hours

du'>t's In produce - tIll' Sl U III ' I' IT~'(1 , us might 1)(' 1111' ( Mol-'i(' if tilt' tlnl ~ is 101)(' 1I'\('d il-S a _'it"(latin '
Il~l)Uf)lk UT In r~ 'lil '\·t' a IWilllad w, ' h l\\'{'\'{ 'r, if ti lt' d nl ~ ts intt' ndt't! for chrmuc 11M', til('
dt'gn"(' o f \',uiahility ill an'mgt' plateau cooccnmuton sho uld 1I0t 1)(' illlw n '1I11)' diffi-rent
From that whic h ('sish lilr a dnlg uf Inw Ilt'patk d l'armlt'(' am i h a\i ll ~ till' Soillllt' d(~ 't.:' of
v<lriahi lity iu e-nzvmatjc ad h i ty, ( Fi~. 13-9 ). 111is stan-uu-n t is 11,;,1..... '(1 nil tilt' follll\\illg n -a-
'it llli ll~, AI plateau , till' an'ragl' ('UIl('I'llt mtinn (C .. .... > h ¢n'lI I ~'

F 'Dose
c ...OV
• CL· t

wln-n- t is tin- t1l1sil1~ Inn-real. Fo r a dn l~ of high Ilt'patic ch-arancc-, \1lriah ilit)' in C .....-
n,lIl '('h m riilh ility ill 1-1l ~ ' 1ll" adh·it~· thrull~h F: wln-n-as. fn r it dr ug of I(l\v hepatic ch-ar-
alll'l', \1l ri a hi l i l ~- in C...... n -III'(1s variahility ill 1'110111(' lId hit)' t1mmgh C/. (wtt h F Of I), In
hu lll (',lSI'S the- oral ( Iosill~ run- (I)(t'\(o/t ) \m uld m-ed to 1)(' lIdjuslf'(! hy III,' sanu- d ~n"t' to
maintain a eommou C...., wit hin sllhjt'!:1s. Tl us is adlil"\'{'!:! hy adj lls l i ll~ IIIl' doS(' for the
Iti.l!:h.d l'a mll('t' ti nt !!: (a.. h 'llf·lif(, is rt'lati\'dy constant l and pcrhap.. hy a nuxnm- of adjll.s t i n~
do 'it, and dosill!!: lnn-rval (¢ \l'1l Ilml ha lf-lift, \'aril 's) for tln- low -dt'ar"dnl,(' d nl~ . o f major
importmll1' is Ill,' 1lll( II'r1~ill ~ variation in l:"IIZylllt' ';' ll"ti\i ty, whid , t1ifT,'rs Irom o n,' l' nz:,lllC
s)"!'tt-m 10 another. ()h\iomly, In miuimizi- variutjon in pharm ';'ll'llkilwtks . moh -cuk -s 'l'{ l\lld
m-ed to 1)(' 'Yl ,lt'('h,, ! wluch. if IIwtahnl i;r.t'!:1. an' substrat e-s of " IIZ\llU' svstems Ihal show Ihl'
I",lsl va riahility alllOl1~ sllhjt'(1s. Un fortulIatdy, current infon n;;tiu n i.~ ins uffil"i" 111 tn make
tI,i.. st'!('('lio ll.
CHAPTEI113 VAA1A6lUTY
'"
~ A .'l~. 13-Ji. I' i... I..·••hll~ i llhjt-e.1' •.• -1, n-.
0 250 n·i,,~ I I'"~,r.....,j,.1 Lv. (I ll mp;""'r 10 r"ill!>l,..1
~~
ur al l.· (.,., "'10 0" .. ,...nol.. ,1lT'. ..."', . 11..·
~ 100 pl., ,,,,, ..11........lr..tio"·hm.. pnrlil. " "~'n- , ....,'
U
~ " mil.., r..Ik_ inlo: t v. . 1",in i<l"' IIo", V\). 10,,1
0 _
50 , ,,,,,.. ~ I 1..1)(. · .LIT..,, ·...." ". p•• rt k~, l ..rt,., In 1.....1.
~'§, .... K~·" tr..l i1.., .....1 Ace. fo[Io: _;,,1o: <or,.] ...h"ln ·
!>
0_
,,-
~ 25 i, l r..til'n (H). s'K ,I••liIT..n· '''''l''Iln ''''ri"IJil;t> "ill,
e II... hou " ",h" <of ...JIllin i,tnot . ", .... . C".1...-e.1.~1
~
..
fur I' .. ~,,;u ,j," . .. " mli: ,,( IIi¢. ho., ...lic ....I' ''C-
£~
10 Ii'"' v ..n..l oI lil> In 1.., ...liI: rlU}ll'" _ 1I'it}·
.." ....,I.! t h",," "lIp i' 11I,," ift'lt f'(1prim,;arily in ,..,;.
E
~
5 ..hilo t~ i" "na! hit.." ul..hihl} (16-tiO'll. ro.ll..-r
~ 0 2 3 4 5 6 7
dUll ill . hIT.·,, ·....~ ...in d .· itr.....-e ( I I / min) "," it~,
I, r- ·rfll'it .., r..t ,·.li",il.~I. " r I..,.......,,, Io..lf· llf.. ( I
Hours "'11:-'1.• • 3.9 11 \1 ). (1I,..lr_l' from s l...."I. IH : ..
;.;,...1 ,,11•. 1-:. \ 1,. .....1 ();d .'I. J .A.: rLt..,,,u 1'. ...
B 1',....."'" 1... .. 1. ill . 1,,[.., ...111, . 01 .... ......l it.... in
~
0 250 f. .... .-I,i"I .. ·" . (;1i" . I"",r,,_~.I . 11..--.,, 11,112-

~
1;!l:1. 1!J7fJ, lu l'" . I,K...d "'i ll, p,·n niu it.., " f ( :,\ '.
\1",,10:- ,>
~
u 100
~
0 _
~'§, 50
!>,,-
0_
~ 25
e
~

0-
e 10
E~
5
~ 0 1 2 3 4 5 6 7
Hours

l ow Clearance High Clearance " lp;. 13-9. Ear-d ...1 poLa..m.. .Iml:.
•~ .... ~~ 'l llIlit ..\·lirn. · rrufilr" .1"ri,,1t ..
6 6 .11Il'ln~ illk,...,,, ..I st...ad)' ....to· f•.IIt...··
~
a i" " .-ftrtl"k" 0.....1 . Imioi.-t....tit..' o r ;<.
~ .In,l:,; d""" ",.. in 1>t'... lic .. ,l7)' .... _1,,··
E ll~ fur .. . 1011/; <of 10: ....' .. ~lr....1 "", n..lit'
u
~ 4 4 (I.·..u ;<.1...1 hi"" ....It'lIt1l11n ro. ll" (n l:" I).
~
a I" I" ;. ~i ll1 l1lotlk", I..llh dnl!t" ifn' . " h..
'-' ,11";<.1'" f", II...... n..· t'f1T.\11..·. , I..· .....,.
0
~
.~·"I ....I....' rlOl..1 i n t nn~"': do·............) o r
~

C 2 2 ...t,ld, ,...rio.. nh K·r"ltl . lbo · .... ,,1t i~ 10

~ ....m .. ' ...... Ii"K"II.. ·li,j,I"..n..lit .., in tl..·
E~
",• .flIl(t. ....".:. ·"I r"'it..' , Pn...Jk.1 k.., i>
I...."'~I . .., Ih.· ..., -II·.Um...J n.... 10:-1 "fht-
"O
c,
0
4
1..,Iit.· ..I" "i ,,..IiI." .
0 4 6 12 0 6 12
Hours Hours
Dosing Intervals
". CHAl'T E ~ 13

It follows From tilt· ror('goill~ tim! then- i ~ lUI iuhereut n ',L\ UII 10 1I(,li(,\"(' thai a !it'!
variatio n i ll (' !l 0 111t' ;lt1 hily (caused h)' a variation ill ( "Il1ll't'lltmt iulI of t' 1I7.pm·s . Inhil utors,
Of im llll,('rs ) should ('1IIIW a v;n 'aIN i"tmifl( lhitlual variatioll in pharlllitl'uk illl'fic pa r.lIlwlt·rs .
o r in C ...... for a t1 mv; of IliV;h ht'!l;llil' (':\!nK1ioll than fo r Ollt' o f luw ht '!l<t1 k ext raction .

DOSE STRENGTHS
I'mdlll'" an - fn'f I Il('" I I~' markcn-d ,lS uuit do.....·.. uf dd illt'fl sln·II/-.>111. sud . il\ 50 or 100 mv;.
O h\i nus ly. i f tln- t1wmpt·util· ;11111.'\ is s ufTi d t·utly wide-, all !liltit ' nl s can " "('('in ' the sauu-
do">(' stn ·lJ/-.rth " ll1msl irn ·spt'(·ti\'(' of iU I~' diffen-nces in ph 'lOllill"llkillt'til-s alll llll V; ti l(' pu tten t
pu p ulat ion . A narrow tllt'nllx'ulil' index I\('('('ssilalt·s the manufactun- of !it'\'t'ral doS('
sl n' II ~ II , . I Il ,wl'\-N , A lt hllll~J. till' Huaiuumbe-r of , In 'llh1hs t'ho'WlI dl'pl.'lIIls 0 11 1ll,1Il~' pnK'-
tical issues. 11 n lll~h t'!>.lim" It' u f Iht, numbe-r can lit, c alculated ill Ihl' follo....; I1 ~ manner for
t1 n l~' Intended for dm- mk nlaill h'llalll't· IllI.'ntl l)o"
SUPlll l"l' that till' maximum am i miniuuun d l'amlll1' \"alul' s Ihal 1.' 1ll't)lII l);'l"~ 9.'5'1- uf till'
jMlit'l,t Ill'P" I,tti, U1. I lt'si~loI h'( l C l ....... du d Cl ........ n" lll ''(:t in· I~· , di fTt'r by il factor t.f , i' , TIMt
h . C/ ,....., "" fi · C l. ",m. It \" l11 ld then follow Irmn tilt' fami liar f(·latiomh ip

F · Dow
t
- ct . C •. ~
2

tlMI lill" riU'~1' of dm i ll~ rates IIl't '(ll"l l \\1lU ld hI' sh foltl if IlIl' objt'l'l \\~..., 10 obtaill tlU' sanu-
C.. ,... ill all pa tients . In p raet ice-. till' therapeutic imh-x is suffidl'utly \\i dl.' lu allow SUnil'
toh-ram x-. I.l"l an'ra~t' plate-au coucentrattons wi thin :!O% o f the cptunal \"<11111.' lit, al'(:t·pt .
ahh-. "\ (11 )n l i ll ~ly, 11ll' hi~llt's l dusil ,~ m il.' th at ('tm ltl ll(' ~\"t'll 1011 p" til'lll \\i th a d t" \T;Ul('t·
\·alm ' of CI..."" is om' lilill p n lOJ Ul't.·S it e...... tl ml is 1,2 tiIJWS Ilw ..p lillllli ,"111m·; tl w 10"' '1's l
d mill ~ rail' tha t could hL' ¢n'll 10 a pali l'll t witl r 11 dt'i\T;I1l('1' of C l.....u is mu- 111011 pmtlll('1 's
a C••."' Illal h U.S ttnu-s lilt' u pliulill"1llul' , 11.., mn~(' of ,lssnd ah '(l dO!'iin ~ r.111.'!'i (and Iwllt'1'
umounts, if lilt, dtJsill~ intr-rval is h 'p l (1J1lsliml) is fourfold . :'\ow, IIsually. adjal'1'1l1 tlu.S('
s trt '"~" s di ffN b~· a factor of 2 . Tln-refon -, ill IIII.' current ccunph-, if IIII.' slllaIlL·..1 tlOSt'
s t rt · Il ~ 1. is .s(l 1l1~, it would 1)(' n-asouahleto market 11 1n"t, doSt· sln'nj.,tths, ,'j(). III~, 1U1I'1Il ~,
ami 2f.l1l' 1Il~ p mtlll <-1s. whidl wo uld sliffiL'l' for !}''5tl uf tln- populcnon. O f ,hl' uUfs lalldi ll~
St,l,. t!lusc' wit h a pa rti<-11lilrly h i ~h clearance lIIay he 1Il'lllTllIll()(lall'( l with it Iargt'r-Ih all '
IIs' I;I1 matnn-naruv doSt,. (lllllp ri sill~ it (lllllbinitliu ll of th e market ed unit IltN ' strengt hs.
or 1 11I·~· lIlay n'(1'ht' it markelt"C.l do St, sln'Il)..'lh mon- fn'( lllI.'lItly. 111tJSt· \\i th a pilrtklllitrly
Illw l'!I'aTiUI('1' \·011111' 1l 1i1~· II(' ;lL'1'1 l11l1l1tJtI;lh'(! hy t ak jn~ tln- ltJwt'sl il\1lilahlt, dt N ' stn 'lIh'l ll
II'!'iS fn '(IIU'utly Ihall m llal , "t"C.";'IIISt' Ihl' llillf·l ifl' ill Ih is ~n )IJ p is likl'ly to he tI.., Illn~l'sl in
Ihl' Illlpll iitiio li.

ACCOUNTING FOR VARIABILITY

It n 'mains III ht, !it't'll how inf"nllal io ll 1111 \llriah ililY (";.1Il II(' 1J"l'(1 III d l'\i St· all optimal
dtl'oil~I ' n,..rilllt' ll uf 11 d nJ~ for In'"lnl("ut of a tlisl' il"l' in an illllh i tluitl l);,llieut . Oh..i ous ly.
tl u' t1l'sin"C.l " hjed iw \\1mlel ll(' lIIos1 l' ffid ently m:h it" ,'(1 if till' indhi dual's de lSil~l' n '(ltlin'-
lIll' nfs ('1l1lld l)(' <'";.lk11Iah '<-11H.ji'n' fltlm lnhlnt'l/! 1111' tlm!!.. \ \ 11ile Ihi s idt'al <-"allllni he tot ally
nll'l ill pm<-1il1', SC lllll.' ' lIl,('1'SS may II(' adliew"C l hy atlupti ll~ III(' ftllltJ\\ill~ lnll, ' of ilppm.wh.
whiell a ppl ies wllt'll all palil'lIls n'l jllirc.' lI.t' , allll.' (n nhtllllltl) pl.t'ma l'1J1lL't'nlmlio lJ r.1Il ~c .
Tilt · a ppmilc:h is In Illm l ' fmlll till' popll lilliun pha rm iKllkilleti<-' par.IIII1.'I('r lostillla h'!'i 10 the
illtih i tillal palit'n l's \1III1I'S.
CHAPll R 13
'"
111t· firsl sh 'p is III i tlt· lIti ~.. tilt' mos t \-ariabll' pa ra lllt' ll"r within lilt' patieut population.
Va riabili ty ill tln- various pharmacoktnenc parunn-te-rs within Ihl' p' llit·nt populatkm <IiITI·r.;
\\ill(·ly allloll~ d m ~s , as shown ill Tubh- 13-2 for a 1I111 11 1 ~' r of n -pri-se-ntative drugs. Fur
S111111' drugs, such as lli~l\ill alll i p r opranolol. Ihl'n' is suhslanlial variability in aleorptlon.
hut fur drffi-n-nt reuson s. \\'itll diJ.:u.'d n lilt' variahility is caused p rimarily h)' <Iiffl·n·IIl'l.·s ill
plmnn"l'l.·ulil-;tl fllmllll;ltiun . hili \\i !h pr opranolo l it is 1-;IIlSt't1 hy diffen'III' '!> in the 1·~tl'lIt
of first-pass los s. as !Il1'lltinllt"tl p n '\i ullsly ( Fi ~. 13-li). Fur ol lll'f(lm~.., such llSt111'tlphyllim·.
tilt' only sub stantial va riahility is in d l·araml ·. \\'ilh ot lu-rs. am iIJlI.. rune and plu-nvtoin
Included, si",tnifiellllt "lIriahili ly exists in all p;mmlt'lers. Fillilily. fur some, coustdemble var-
iilbi li ~' exis ts ill pl.o mu p mt" in hinl lill~.
n il' 1II'.\ t step is to t ry fu ill'-'tllllll llKl!k . IS much of tlu- variahility :IS pos-sihl" with
mcasuruhle d laI'Hl1l'ri.s!il'S. If tlu- d.dml·tt-risl ic is di slTl'l l' allli iJlllt' llI'm lt' nt, thi s m il Ill'
"dlit'\ l-'C I I,y partililJll ill ~ I l lt~ 11IIpulali till iut o sulll)(lp lllalio lls. Fo r example, us Illustrated fell'
clearuuce- ill FiJ.:. 13- 10. if Ilw d h t:n 'h ' d laraetl'ri sties are IlI'plt!ie di Sl: a_Sl' and smu kill).,t.
tlu-n till' populatkru wll ll l tl l ~· tlhi tll"tl into Iour t-;l ll'J.:o ril·S: thuSt: who s moke alll ilmn' 111 1
I.l'pa lit· t1ist·a<;t·: IhoS{' who sllln!w and haVt· lu·pa lk tIL"";l"" : thost· willi Im\1.· lw plltie d iSt·.t.st·

T.bl. 1 3-2. DetI V.rI...lllty I. tho 0_1 AJ._.,.tI••, DI'p.slt lon_ and
Sp.clflc DI........._ ett-_•••th,. D_g' Wlthl..... Po tl.nt Po pul . tl o ...
lltlJG v a ....
.AmiodofQfllill + ++ + + •
Cyc~ + + +
Dtgo>cin + + • •
~ + +
~onAlo N /A + + ?
- +
Ph&noborbtol +
~n + + + + + .
PJcpolloiol + + + + + + •
Quinidine + + + + +
Salicylic cod + + + + +
~~ ++

Fill; . 13- 10. 11,.. (n" I'" "''''' .li,lnh"u"" n( d.·a r-

..nw " , tlo;" tl..• I"tod ~1i''1, t P''I''',l.otit", ( - -l i ..
f", ..1it." " f II....1."1'" ,,{ tl..· {n .. I' .......,.· .h..tnh"!i '
.. ilhill tl.., , ·..ri<" I' ' lIl,,,, ,,,,l..lit,,,, tlwl '~HlIl'ri .. · tI..·
t"t,,1 p"tit '1I1 p,,"''''litl<l ;1.1,,1111.. n- laU, ... ,i,... "f ......1,
,, " f tI.....· . " I' ''''1" ,l.olit..,"_ In Iht. Iim" I",,;'.., tI,,· , ari·
,
,, ..h!c.,. lin' ~1I1"ki nl: ;llllI l",,... Ik- IIi •. ..,,,,llh.· , ,,I..
1"''P'' I.o' it.... ;In' : ( ••• )--11.....· .. t ,..i ll..·, It;",· I..··
,, r.. li e .I i w" ..• nur '1Il""" (7 N_4 <;t. ). th " tIt .. j ".;I ~' ;
,, (. I"" I...I I:r..~·)--t h ,,-hOI "m"I... I" ,I Io...w ,,,II,,,,,,,,,·
,, ,It..•...,,· ( !Yfl'J,); (. 10 1...1ht...:I.Hht....•...h" haw 1...-
,, . - ... I",t k ,iL........· I',,1,I" ""t ..,,,..... ( 1.6'il); .." . 111.....· " I""
10,,11, . "..,lo· ;u ..1h I..,""it: .li....,..... 1111" , i"f ' "r II..·
,
, y, Lt...t . ul'I"'1".l..lit [. ,,"'. . ..wI! (0,4'1» I" I..· .....·n in
,, , , ',,
, / tI,i, fil:\. .... 1111" ·r~ · ,...I,..., fur dt·"nuK~· in Ih.·
.. .. s ... r.." ... 'I>I"'..II.olit ,,,·n· .. -t '" I. I.,s. O,,s. ""tl ll. 7.~
u"i". n"I" ,," in·~· m" i"!t Ihat . .. ".l.i"l: i' ..·n·.... ..
Clearance (arbitraryscale) •.J, ·a r", ,,~· I ~' in.llId io", "... 111.", .~"t"· i. .... 10.. ~ ..1
in 1" 'P'd k' ,Ii..·"..·.
"6 C HAPTt ~ 13

hu t dn nut M Il Okt, ; ami t11( )'i.t' who Iw itlll' r 11iI\'(' lu-pat k- di.....·; l.w no r slIlokt" 111(" rd ati \"t' si".l.'
and shape o f tilt' distrihulioll l"urvt' of each suhlx )j>ulatiou deterumn- tln- fn 'C lllt·n<.'y distri-
IJIIlio n for the en tire populat ion. If. 0 11 tilt" (ltllt'r hand. tilt' 1II( ·;L~lI rah l(· l'hamdNhtie is
couuuuous. such as il~l'. wt·i ~h t . o r d(·~n"t· of n-nal funct ion . it Illay 1M:' possihle In find a
funct jonal n-latlouship with ( JIl ( ' o r more p ha ml<lI'o killt'lil' pa filllwh· rs. as Sl'C ' II. {'.,g., la-.
tween the renal clea rance of till' cephalosporin. ('t.'ftaYj l!i ll1l' (and 1II ,1Il~' ntlw r d nt~s ) . .uu!
creatinine de;lr.lIwt'. ;1grade dmeasure of n-nal function ( F i~. 13-1 1).
Tn 1' 1l\i~~c lIuw tilt' enti re st rdl11O' would work. (-'ollsidt' r tilt' ,Lit" ill Fi ~, 13- 12 fur 1I
d m~, pa rtly lI11'taboli7.t,<1 ill til(' liver ami p'u1ly t,,"·rt·h... llI lld lan~t ... 1, fur whielt population
pharmacokmcncs are: oral hi()a\~d.i l;lhil ity, O.S2: volume of distrihu tio ll. 10.3 I..; n-nal clear-
1II1l't.', 6./ l AIr; and ht'p'll k dt·ar.uwt', 16.2 l AIr. Ill' p ili "...1 an ' four table-ts , n'pn'S1 'll l i n ~

n It. 13- 11. TI,t' " '1...1 d . ·;<t"oIJK....of till' C'l l'l,;d...
' porin. (·. ,flu id i lt..•• \1tI'Ws i ll ,hO'd p0'l ">rti"n I" 150
('W;otilli," ' dt-1ir-oUK't' in ;0 ItJUltp of 19 ptlil'n ls .. i th •
'....,.i"K.1o'W'..-s of .. .....1 (IIIK1io". I O n frolll tI..·
.Lat. "f "" n I>..L.". It.. Vr>"<', T ,8.. Ilioliln \ . ~ l.. ;0, ..1 •
T..m MIIMI. F..: 1><......" . lju.,t"....,1 (..r('('fluitliu.., ill •
I"' lirf," .. i lll hnpai .... 1n ·na! flllK1i,,'" Eum, J,eli".
11.... n"...u1., » .597..60'). 1w-.6.1 •
•
•
•
••
•
••
r
o
o 50 100 150
CreatinineClearance
(mUmin)

• Weight

• Age

• Renal Function

Oral Volume of Renal Hepatic

Bioavailability Distribution Clearance Clearance

"'x. 13-1 2. Sdll·m;olit.· n 'P"'""""',I;olit", o f ':ariahilit~, ill \';I.rio "l\ p....n na...J.in.1 it.· l'a ".ttll·h·". .., Ihi" " ''''1>11l.otio" ,
n,.. .il~' "f h h.I>I.... i'l n ·Ltt•..! to the .101t..... of ....riahih ty in til,' p;or-./I.. -n-r. nil' ("" rtl"" of ti ll' tal LtI,,·lt..1
"~-i""t . 4/. n r ... rut! f"'K1 ;OIl " ,11,'(1 tiM" fnM.ik''' < of II.... lobI •...n..h; (,~' a<"ln " n t...1 fn r l~' ,·... t, o f tI · f...1"n.
CHAPIE P 13 217

o ra l hioa\"ailah ilily, volunu- of di stri bution. renal d c'a r.lIJt't', an d Ilt'p'll ie ck-aram-e. Tlu- siZt,
of l'ildl lahlt'l is it measure uf \"ariilhilil)' o f l hal parumeter within tln- p auent populalio ll.
Fur Ihh t1 n1~, 0 1',11 hioa \'aibhi hl)' is tln- II'il\1 a ml lll'pa lil' d t'ilfillll 't' is tln- lIlusl \"ari" "I,,.
Slah 'l: l d ilTt' n 'lItly, ,gn'a tl's t l't lllfitll' lIt't, exrsts in ,lssi,gnilll?: Iht" populunou vakn- of oral lao-
il\"ait lhility In Iltt' IMlit'nl ; I" ,lst t'tl1lfidt 'lJ('t,t,dsts in a."si~ l i ll~ lilt' populattou \"alut, lIf1wjl al k
d t'a filll('t' 10 IIIl' patie-n t . \I o n 'o n ' r. as l ilt' pOplllaliull slIlm-' fo r Ilt'p'l tie d l'al'd lll't' is much
,gn'at N than Ihat IIII' n-nal d c'MiUlI't' , \"aria b i lil~' in IOla l d t'a r.UlI't' wit hin li lt' popula tio ll h
also hil-(h .
~ol llllt 's!lt'{:!t'dly , wd~h l at'l'tl,m ts for mo s t of ti lt' \"a riahilil)" in volunn- o f di sl rihulio n
and fur SC llll(' o f tIl(' \"ariilhil i l~' in Ill'pill k ch-u nmce. A,gl', St' pam h'l:l fr om its inlhll'Ilt't' 011
Ilo d y SH'i~ILt , at't 'tlllllt\ for sonu- of l ilt' m rlabi lil)' in lJt"palic d t>a rdllt:t' a nti . 10 a II'sSt' r exn-nt,
in vnluuu of dislri h ulioll . Ht' nal fllll11ioll alsll ac counts for almost all tlu- vuriahilitv in n' na l
d l'a r.lllt'l', Surprisill~I~'I'H:rh"ps, n -ual fUIlt1iull lu-lps to ex plain SClllll' of t he s.uia hilit)· in
Ilt'patit' d t'a l',lIIt't' alltl Hllu lIl" of dis lri llll tiHn, hu l tim !?: d h l rilm tio n a nd md"I Mllislll eau Ill'
aln-n-d iu palit'lIls wil h renal flllletinll Impaimu-ut (St"t' C ha p . 16 ), Xom- o f tln- \.Irla hilily
ill oral hio;wailahi lily is ;11't't1l1ll1c'l1 for h ut. a.s IIlt' ntio llt"tl. il is sma ll a nd il('t't'p la hlc' .
Fil\;l lly, tht, ;Ila hility tn a('t'tlllllt for most of til(' \1lria hility ill IIt'palk- cl.. urun ce "hou ld
Ill' 1U11111, ' l lIl" (If lilt, dlafilt·It'risl it~ illd udt't) t'tlliltl atlt 11l1atd .... account for Ih,' inll,wnl"
of ~t 'ndil's , d is.: ast' , am i 011\1'1' d m;.:s tin this (lOlfillllt'!I' r. Ma rke rs of ~l'lIt'l il' control o f ti m ;.:
IIlt'lahnl is111 !taw Ill'l'lJ t1I'\l'IOIIl'c1 llml he-lp 10 I·,' plain much u f tilt' inllt'rltt'l:l inlt 'rl nl lisiduill
t1i1Tl'rl'Il('('s in hC'piltit' d t'a ralil't ' of ce-rtai n d ",~ (C h;lp, 1,1), Ft··w,1l 0\ \l'\ ·..-r, a rt' I'lllplnyt'tl
d init·aUS'.
HI 't 'l m i ll ~ III till' ill" lili"I'MI IMli" III, t't lm'(1 i n~ tilt' l'H lp'llal io n plllln uat'u khwl il'S for tlu-
pal it'lll 's s\"('iJ.:hl. a1-(t', ami n-nul Iuru-t iou should ~n' w aso llilhlt' imlivnlual t-slima ks of F.
V, a lltl Cl ' H hILt Htt lt· l'tm (jtlt'llt't' in tilt' 1'~ lim alt· of CI. II andlu-ucc totul d t'ar.uK't·, :h tilt'
IOlti'l F/\ ' " l rc lll ~ly illllu t'llt" S ti lt' )waJ.: pl.lsma t"l lllt"t'lItmlio!l aft t'( a si ll~11' dose. n-asonabk-
t't III fid" 1ll't' cnn Ill' I" Ilt't iI'll in I'sl imali llJ' tln- Il;llit"llf S 10.1( linJ' tlost,. if requt n -d. II UWI'H' r,
sillt't, tilt' filtio f /Cl. 1"l llllmls l ilt, aH'fil!-(t· plat eau coucentranon. les s t1mfitlt' nl 't' t' lll Ill'
l's!'N't ·It'l1 ill I'sti ma l illl-( tln- !l;llic'llfs mainlt'!I,lIll 't' tlOSt' n'f!Llil'l' uw nts . If tilt' t1lt'm p,,'u tit'
indt 's o f IIII' t1 nlg: is sllllieicollily l lam'\\", tllt' n ' lIIay hc.' it ( ';l'\t' fo r lII()n i l (l rlll ~ tilt' p lil\ lIl<1
t'tlllt't 'lll lOlliOIl 10 aid in adjll"ti n~ tIll' lIlainlt'll'IllI't' t!osillR fillt' Ih mu!!h fet'(lhat-J.: a.s t1t'-
sl.'lillt' d in C hap . I "i (Co l1('('111ration :\1o nilori IJ~). ~ o llt'l llt' lt'ss, lilt' ('sli ma tl' of lIIainl('II,lIJt't'
,Insc' 1"'''' '11 l UI III,,' inf"lflllalillll p m";,,I"'l:1 iu FiJ.:. 13- 12 ~ III II I ld Ill, lll,ltl' r tllan u"in,glI,t, 1Il1"1Il
l);m urll'lt' r \"a llll'.\ for IILl' wllolt, IlllpulalioTl . C lt'lIrI,.. if til(' d m ~ had just Ill"t'li l'xI'n ' h'( l
lult'h all.Il:C'f1. 1111' pmhabilily of I ll'i ll~ ah lc' tn " sfi malt' tilt' t'tlm't't d us.a!-,w " 1-rimt 'll for 11ll'
patit'lll \n lHltl han ' Ill'" u IIIm ·h h i~l lt , r.
TI ll' appm,;\(' h pn'St'IIIt'f1 a lM,q' fo r pn '( l it'l i ,, ~ an im lh i d ua l's do..aJ.:I' n 'gi lllC'lI Ill,fort,
aollllini'kriul! 11ll' t1nl~ is ha ",'(1 011 lilt' .t\s llln ptio n th"l lilt l.. in!l'rimli\i l illal \1Iriahilil)' in
phan ual"l M I~l la m i l~ ,'sisls. T ilis is not a lwuYl; SC I. Su mt'l illll's, 1II11li1 of Ihl' s'ari ahility in 1'1 "
S('H IIl'\(' is dILl' 10 d i ITI 'n 'n l't '~ ill pharll1at'tM I~l l;uni( ~, A lt lJllu~h J.:lll lS\ill~ tilt' llll'an phanna-
t'tlkilldit' pamlllt · It '~ of till' dnl l-( 1I1;ly 1ll'lplo ,'s plain Ihl' ti lllt' t"l llll""l' in n ";I'M msc', tlll<lll-
li f~in l-( ph an nal'tlJ.:i llt'lil· s'aria h ilily adds Iilll .. 10 lilt' a hilily to prt'tlit1 im lisi lhml dos;'J't'.
~ClI 1t'I Il(' II ' ss , IIIl' hasiI' sll'lllt~' slill holds: 10 d l'lt'nnille tilt' rdati n ' I"l mi rilllltio n o f Illt'a \ ur-
ahll' 1·lIarat1,'rls lil";, sudl ,t\ il.ll:t' am i \\"d~h l , ttl n 'spcmst' \\it hin t ht· ();Itit' nt pUp llt ltiOIl, a nd
111l'1I IISC' tilt' im lis id ual"s dlamt1I' risl il~ to p rt"tlid his or hl' r inil ial dos;I~1' n 'gilll l' lI. Frl"
l l ll l ' ll l (~', IImn '\ ,'r , <I~t', \\l'i!!ht. a mi nl llt'r 1II1',;lSIlI',ihll' dl;II'.l(.'fI' ri."l it~ fail to al't'tlUlll fur mllt'h
o f IIIl' \Ol ri ahi li l ~' in p ha n n at 't M I~lla rnil ~ . Thl'", 1I1I'n' is liull' d Ulil't' hut to start l ilt' imlh i dual
(l;tlil'lll on tllC' 1~1 1il"ll t hKa~1' rq.~ilm 'u , whid l m a~' ht· fa r fm m t hl' illlihidllal's rt'l:luin' mt'IlI,
SUh""ll'lt'lIt adj IlSIUIt'III in till' n 'l-(iIIII'll is mati" l"ISt'l:1 o n n " I'ltlIN ' pn Ml m't'd . II I'n', ,t\ S\i l h
f''l:1Ihat'k h;\SI'(1 o n ph \ llla ('tllll't'llt m!io n, lilt' II.'\\' of a IlIIM]d he lps in doSt, atij uslllWlI1
(C hap . I,', COIII't' nlraliotl \lo llitu rlnl-(l.
211 CHAPTER 13

STUDY PROBLEMS

(An swers 10 Study Problems or e in Append ix II.)

I . a. List tim ..' major SU lI rt't·S o f \-ariah ility i ll rt·spem....• 10 <I m~s .
h. \\11,,1 pbarllliln lkilwl il- paril nw!t·rs val'''' till' 1I10st ill tilt" pillic'n t populatioll (or di-
Kt)xill, pht' II)1oi n, t11l''Ophyllillt', am i ihllp m ft·n ?
2. I )i'Ot'uss l,ric·lIy why 1I1t' lUi plmnnacokim-tic parameters alllil t' art' 110 1 sulncit' nl to cha r-
<I('h ·ri;,.(, llow it dm ~ is ha ndl("(1 in thl" palit'nl populat ion.
3. S\l~t'l't wlJkh pharmacokiru-tk- pa nUllt' ler is mo st likely to {'xplaill tht' va rianon ill the
plat eau ccuccntrattou (If lIo rt rip tylinl' sluM" in Fi,g. 13--2. T he {I m ~ is lipo philic'. stable
ill till' ~;l\ lmill h·sti ll;ll lrd(1 . andlittle i s excn-ted tlJll·h all~{,( 1.
4. By {''Oi ndt!e lll,(', tilt" \\"t"i~h l . a~{·. ami n-nal Iuncnou of ,ht' patient , discus..sed uuder the
'i<t"t1io l\ " Al"tUllll t i ll ~ fur \'ariahi lity" l'o m 'spo lltll, l to tln- p atient population \~a hn-s. Yet..
wln-n tIlt' pharmac oki m-tk-s Hf tilt' d nl~ w as stu t!il't l in ti lt' potk-nt. tjn- \,alul':O; of P.
0 ,·12, alltl \". 22 I.. W('n' l'Ullsid l' rahly diffe n-ut (o utsidt· till' 99% (,(lIIfidt>Il{'(' inte-rvals]
from til(' popula tioll value-s uf F, n.S2, ant! " , 10,3 L. Hril'f1y di scu ss how tlJis (''Uuld
ari sl'.
.5. Lithiu m. IISt'(1 ill till' tn ';lt lllt'll l of p at ients wi th manic depn-scion. is Ul.lmillisteR"t1
d ln lllie;llIy. "I1Lt' IIw ra peul i<.' \\; m low of thi s d nl~ is na rr ow (0 .4 10 IAmillit'(luinlle ntsl
Ll. its fi' is l , its alld t1usa~t' n - quirerm-nts \1 11)' \\;dt·ly a lll(Jll~ patients.
a. \ \ '!lal h a major l-:IIISt' o f tllh \'ari;lbi l i t~' ill dll-.a~( '?
II, \\ 'hat characterisne or a l" ltil' llt should IIt'!p to tai lor lus o r ln-r dOS;I~t, rt''1uin'lIl('llt ?
Ii III a J.:WIlJl of I.t';llth y sllhjl"t.1s, ti lt' a\'t' r-.t~l' p hilnllill11kim 'til' p arameters o f Iht' jl-ad -
r('IIl'!,¢ l' hl (ll'kill~ a~(' lI t alpn'llolnl. whit' '' is t'!illlinak d allllos t t'xcillsi\'d y hy ht'!" il k
lIlt'taboli slll , W('J'(' Iound tn hI' vohune o f dis tri hutjou, :2.10 L: clearance, 1,f16 11111in ;
am i half-life . 2,.5 h r. AfiN Lv. admiuistratkm, vnhu-s uf ti lt'S(' parall wlt 'rs t1ilit' n , llittl t'
wi thiu Ihis V;Wllp ; ) '(' 1. w llt'll the- tl n lV; was i ll~t'sh't1 o ra lly. IMltt. pl'a k pl asm a concen-
tnuton am l /\l'e varied over a fi vefold rd ll~l' , S lIggl 'st why \'a oabj lit~, in the observed
pt LsllIa ccne-ntrunon-tt nw l'1l1',"t' is much ~n'alt'r aflt'r elml than aftt'r i.v. adtni nistra-
I iOIJ.
7, T hl ' rull owin~ data (T " hll' 13-3) wert- obt ail\{'tl ill a siudy o f the pIHlm ml'()kim 'ti<.·
vl,riahility of a d nl~ tl ilit is pn,IOInillantly t' :u'rt,lt't lll nd l llll ~I'tI , fi' = O,W) , TIlt" tl nl~
was illfuS('t1 int mn 'llo11sly ill fin ' slIbj{"t.1s at a consta nt m it' (If 2tl lllgtlir for 41'1 1.1'. T Ilt'
fraction unbcuud "-:L~ fonm l 101M' im!t,!)(,lItltolll o f t1 nl~ coucentrattou hil i di d n u)'
m llell\~ tilt' subject s.

f.It•• 13-3.

"'' ' ' ,

511:.'Odywle ploYTlO co-c e-e once
1
15
1
'0
3
30
4
15
5
13
Img!L]
PO$I,n/v$1QIl 14 4 50 47 00 81
HoK~,1e lh'l
F'OCIIQll ""bound 0 1 015 000 01 0 001

a, t\ naly,.l' tln- dala to id t' ntify tlu- II1m t l\ndl l.t" least vanabh- (use till' rml/!.I'IIIl~ '(/11 as
YUill' illllt'l{ flf \~l ri ahi li ty ) o f tilt' follo\\; I1 ~ p;trlillwh'n:
C lt'ara nl,(' hll.... -d 011 lInlMllllld d nl~ (C 1.,, ), fracti on u nhu und in plasma (fr d . aut l
fr.wtioll liIlIMIIIIlt! ill liss\lt· (fr 1r )' US(, a " nl' of 39 L.
b , D iM'uss b';t,lIy tilt· 11lt' r.II)('lllk' illlp !im tiolls of liteS(' tlata \\; th rt'~artl to tht' rai l' of
;lllaillllll'nt ;Ultl lllainh 'Il;Ull,(' ofa "thl'm lx'utic" l'()IIl"L'nlmtioli ill ti lt' \-:t rio lls sUhjl"t.1s,
OWTE ~ 13 2 ••

!'t. 111t:' u,'i% n mfldl"lwt" Inn-real o f l'!"ara,I(." u f a 1. 1 0l ~ within a patient p upuh&lioll is I..'>
In ; .5 [A ll, a I.lifTt"n 'l1n:, of fin_'fold. Other pharmac:ukindic 1l<lr.l,Ilwlt"n , F and \ ', \ 1U)'
111IK'"1J I,~~ . l1lt"rapt "utic at1i\ i t)' n "Sid,"S I"U:'III ~h,t>ly \\ilh tilt" d rug, alKl lKlt tiM;' md.,h..
n litt"'\. 1>i'>("\I.... lilt" p lt,"ntlal illlp<K1 of thi s \-ari;\hi li l~' ill dl.'aralll't' on tl H' <Ith' mpt In
1.1,'fint " a I.ScN"- W!iPOIIst' n "liti olllohipwit hin a pali t'ul p"pUbliclII. IL~ ill ~ a deloiW1 ill ""hid.
ral i('I1I ~ an- rarKkllnly a.~ ..i~II."(1 11J nm- of three- ~mllp' n"(,..i\ill ~ a lllllhipk:'-tlt:......, n~ .
me-n nf t"itlK'r 50. IUO, or :200 111 ~ {lai l~' of the- d Ol~.
 " 1~

GE NETICS

OBJECTIVES
The reoder will be able 10:
1 Give e...omples of mherifed IIQriobilily in pharmacokinetics and phormocodynomics.
2 . Define the terms; phOfmocogeoetiO. genorype, phenotype, genetiC po/ymofphism. idiosyn-
crasy. allele, homoZ'f9OU$. and hetefOzygClUs
3 DemooslfOIe how pccccrco studiesand sludie$ in twins can be used 10 ind;.cole the eoseoce
01 generic po/ymofphism .
4 Stote undef wha l circumstonce$ pher'lOlype ~lus is 01 therapeutic votoe.
5. Describe alleasl ""-'0 ways. orhet Ihon twin studies. in wnich generIC po/ymofphi!>lTl con be
demon!>lfo!OO and lisl I'M:> examples01 each.

luhe ritance accounts for ;l la~(' part or both lilt' ~ t ri kill~ ,lilt! slIhtll" t1ifTt"n 'Jl('t's alllOll ~
Individuals. illcllldill ~ mu ch o r tlu- vartat inu ill n 'SIXJIlM' to uu admtutsten-d dm~. 1'11(1'"
1!I(/ l'f1/.:I'lIe tlcs is tl u- study of Ilt'rt'tlitary variatums ill d m ~ rt·S p OIlM' . " (·fort, p n K"t't 'tlill l-'( til
t1msidt 'r spl"'l'ific csa mpk-s, sonu- dt ·finitillllS an ' im po rtant 10 all 1I1l(1(' rsl alid ill ~ o f tlU'
.~ ll h~ '(1.
111t" h'LSic hiol(~('1l111 Ilil nflw rt'tlit)' is till' ~(' IlI' . (;nwl Ylw is th e fundamen tul asso muent
of ~l'Ilt'S of all imli\i dual, tlu- bhu-print, wlnh- , l/wll OfYIH' is till' ou tward (:lmral1t'rislit'
l'xprl-'ssioll of 1111 ind i\id llal. 111(' modi' o f iulu-ri tance is r-ithcr lIlm ll ~t 'n k (I I' poIY~t'"it·
dt111'lldi ll ~ UII whetln-r it is trallSlll itl t"l! by a ~PJl(' al a si n~lt· lot'lls or hy ~t' I WS at umltipk-
Iud on tilt" chnIlIlUSOlllt·s. T ah lt·s )+-.I ami 14- 2 list ~t' l \('t ie o uuhttons th ai alTt"l1 rlu-
pt.,tnTl,tl."Ilkillt'l k s and phannal1MI)1l'Uuit'S of some d n l,L,'S. All o f t!.t'st' condmons arl-Otrans-
llIilh"lllll(JIl( ~(,ll il·ally. !Iolall)' an' t·xp l1....st"l1 as POl)ll1l1'llhisllls. utl lt'fS 'lS ran.' pln-uotypes.
C ern-tic polymu rph ism dd ilws Il\ll1llJgt' nie traits tllat exist ill tlu- nor mal pup"latiull ill at
It'ast two pla-notypes. lw itllt'r uf which is m il.' (It'SS tliau 1% ). !Io 1 ()llI ~t' n i mlly t1mtl1.lllt"l1
t"llnd itiulls ure uf'tt·n dt'h"l11"l1 as a drnmatk- anti. nhnormal t l m~ n ·slxlTlst·, that is, tI elmg
Idlw'Yll cm...y, l111'y 111<1) ' also 1M.' t1eh "l1t"ll ill population stullies hy a POIYlllfMlal fn'( llit' lll) '
t1ist rihllliull o f til(' l'hamd t'ristit' ur SOIlIt' 1IIt'.lSIII't· uf it . 1'()ly~t'n it'lIl1y controlk-d \'ariatinm
W\"c rist· to a ununod al fn"<llIt'lIl'Y distnbunon ami all.' " snail)' dt 'h "l'!l'(1 ill slm!it's of twins.
An til/a t, is IIl1t' of two til' mon- difh-n-nt gt'lIt's l1mtaining SIX"li fic inl.t·ritahll· clraruc-
terist ics tha t Ol,('Up)' l'()rn's pullf li n~ positiuns (Iod ) on p aired ch romosonn-s. All alk-h- is
domin ant if it {'xpn'sst's itself and recessive if it does lint , An individual pt)S st'S Si ll~ a pair
IIf identical alh-lr-s. ('itlw r dominant III' n'('l'ssin' is lumw:;y;.!.ou.~ for lilt' gl·!It' . A union u f a
t1nll1imml with it n 'l"l.'ssin' alk-le produces u ljI 1('n ':;ygllfl.~ individual fur tllat dLamt1eri sli{'.
Built homozygous ludtvtduals with do minan t ulk-h-s a llt l l l(' lt · n )/.y~ollS Individuals lila)' sltow
lilt, saUlt' pllt'u lllnx', and hUlI\lrl)l'0llS imli\idllills \'oi tlJ n 'l"l'ssin' alit'll'S may St.I'W ilIlllt lwr,

220
CHAPTH 14 GEr-..fTIC5 221

Tabl . 14- 1. Som. G.n.tlcally D.t.rnllnat.cI Yarlatlonlln Pharmacokln. tJu

,
" ....../
" . •'",'-1: v
" . «, ..~., ~ ;>()')O'
!.; ", ..... A. ,. . . f< ' .. ,',< 'II '.fl.-', i l ,

Pot)< .......vue Il""~ '"'cr" CYfI'2D6 5-1 0% Co<JCo,'O~, Enco'nid.. lIecoonid&

,"'7\0'. ", 3 8\ Bkx" bohoIoI. rimoIoI. co
OQ% O~IO:S de!ne. O'I()I1fi~ine,
I%A,o~ l'Illlklp'oIoI, de.xtr0'

-
melhatpCll'\, spcY'
reine. and perne,o-
.~
P'oor and exlen< Poor '""""'"1OC re ,~ "'0-, CYP2CI18?1 3-5\ CO'.«l\,o<\S

-"
s,~hyd,o""'" ,hO.' .oc-eosed Y' IO%O-'IOI~
ohon oI5-m& -]'::"0"

P'oor and exlell" ~"p.d "'''''';-',10'0<1 ""0, ~ 14% CQl>CO~Kln~

1"0'" 'g' .~. U IkM "'""!tlyIa,oO<'
>w """"""
!lOll 01 &mtor- ..~.~ ..", I"1 ,,,
coploput"'.e
Slow ond loll $-e", " ,.' ,.Io'QI~ ma .. 00% Ccocovoos
~'CW 10'" 'i 1o-zos Or,enlO's
,sonlOZ,d 01
""""''''' and Es.,'"'O!o

s..,...,ol cb-oe-or
~,mmtcQn'
rTIQ(l d'lOIdoo< 1 ..
2500

, ...1.14-2. s.._ o.-tIc.11yhhrM. . . . . V....

if<H1()1> '
.tI_. I.......... """'.1"
'.
Warton" re\lS'
A
,
'.
~t's1 ~lc 'X '" 10 O'
, oagJ!a"
'
"C·W.
'"
""""d~
,'. I;'OJ!"~.

'2 Ialge ped-q-ees

L"'J(.' .......'
" "")1'..'>1
wG'bin
~<, ,..,

eece l' or enzyme ,n

liver witl in-

_I
~ol"nlty
b vikJmln K
~(JVIsm Of d,ve-
ind\ICed he-
rrdyric one-
~moI i l , '" -e
soc-so '0 C","
' " 'I '1''''J'
G<"""""
phole dehyd'O'
...... 1G6PO
Awo "'1"\0 '~ 100
"'11100<' c'teoed
NO'ld occv', ,n
,n
Votiely of d"-'9'. e,9"
ocelonillde, pimo-
~,~
m< hogh lOin, ond chbom-
f'eQlIf'rIC',i
.vh<o<e "'010,'0 's
..",j.""oc 80 bo
.........
c~moColfy d,s' "Cl
"-'VlOl,O"S
Gb<~ AonOt""l' 'eo- Un~r'IOWI'I App' o,, "Xl ~V 5" ~old>
'POn<,/> c) ... USA popo!a"O"
~Txuk:J' C'''\"
""e'c >~O'j

""" ':h,CI
C0 2 . binding
oVolignant h.,.

-~
Ueccoeo l<><i usc
-, bod, ~
:,('''.J'v''' '" t'
..- ApprO> rna~y 1 ,n
a~I">e-
I 5,000
" l~OO'_ls
VOfious aneslhetia,

.....
""""'' hal>
-n~\Cvl.:J"
g;.j ',
 GENfTIC5 CH.\PTH 14

~ I ll rl' thuu Ullt· inlll' ritah lt· dlilnleft'ri slic llIay lit, pn'st'lIt 011 till' same pai r or allel es . For
1·,\1Ullpll', thl' ~,· IIt'S roT h10UII l)llt'S A. n. am i 0 an ' in tilt' "<11Il1' pos ition 0 11 ulh-k-s.

INHUITID VARIATION IN PHARMACOKINETICS

E\1lll1pl" s or illht'ri h"(1 \"aria bilit)- ill p h u n ml(·o kilwt il-s !Ia \"{. hl"('11 a lmost l'xdusi\'t,ly n --
sl n d ''ll 10 d m~ 1I1('la"o lislll _ Henal "xc rl'ti nn or dOl~S diM'S 1I0t apllt' ar til show ~l'lIt'tk
pul)l norphism ; tilt' renal rh-arance- for :my dOl Jt h·lltls 10 1)(' similar in a~l" ami \\1.' i ~h t ­
matched. Iwallhy slIhjl'ds _As a (:umll:uy , t1nt~S Ihat an- pn..:lo m illan lly t'\t·n·tt"(1 uuchauged
n-ml to vhow 1Il1l(:h It·ss illlt'rim ih idllal \~I riahility ill d ispos ition kineti cs than cxtellsi\'t'!)-
IIll'la IMlli:t.t"(1 ()I 1" S. nl" d, ;:n't' 10 wh ich varia bi lity ill t l nt~ uhso rp tiull und di strihlltioll is
under ~t ·1 11 ·tit- contr ol is P(Mlrly d(,hllt"(1. Ct ·rtaillly, there an' st'\\·r.al varian ts or " I-alid
I:lyt"(lpmlt'ill t- xp n-sv-d POI)lIlOl"]lhi l'<llIy, \\itl. ea ch var iant ha \i nJt a d ilTe rent affinity rOT
basic compounds .
~lt 'l ilholi s lll h.ts n-mained 011(' or tilt' la_ \t major unaccouutcd sources o r \'aria bility in
pl.ar m an ll illl'l it'S_ Althnll~h 111I' n ' has long IM'('II a st n l1l ~ awan'llI 'ss or IIIl' illlllll'lJ("l' o r
~( ' lId it'S 011 Illdaho lislll, it is o nly rt"('('n lly, \\ilh ad\"dllt'('S in 1II0 lt'C.lllar hinl l'1t'-, Ihal tilt'
h .lSit' 1Il("('hanislll s involved art- Iwill l: understood.
St'\'( 'ral ~t'l wtit' llt )l)l n0 'l)' l i s ll\s or drug meta bolism have nil'\\"!1t't'1I kk-ntlfied. involving
o\i <bti ou , S'Illt'l hylal it)l), an d ilt't.'t )t tlioll (T ahle 14--- 1), ~ I os l wen- detected b)" a<h-l'N,'
n 'lIt1:ioIlS (It"l'umllg: in a d islim 1: ~WIlP wtthtu lilt' pop ulatioll h'nnt"(1 puor IIId aIM>1i7.t·rs,
rollt)\\ill.l: unfilial dust's or til.. art'h('l)llic tlm JtS _ A Tim ' p lwllol)]lt' is st'('11 with SIK."li llyl-
t'hnlillt' , T )llit'a ll)", mlls<'I(, pilmlpis w t ' urs of]" within minutes or d ist1 111 ti ll lli ll ~ thi s lIt'Uft)-
IIl11st-lIlar hlucki ll ~ al:t'lIl, Ilt,(~.lll st· il is mpidl)" lIyo:.lmlyt.t't1 to inat1:in' products. cholu«- lind
1Il011( ISIlt"l'inyldl(llil1t·, I,y p l:l~ lIla and Iwpalit' pst'lIdo,:holillt'sh'TOlst'S_ In an occasional pa-
m -ut , howt'n 'r . Ilt'u n llllllst'u lar h ltx-katll' 111;1)" 1a.\1 sevr -ml hou rs arh'r s l opp i ll ~ tilt' tnfuslou.
11t't'illlst· hydmlY"iis is lIludl sl()\\"t'r than IIsua l. 11lt, rt':('.OIl is lilt' ('\islt 'Ut"l' or an ill)]lit'ill
t' IIZ)"lI1t' rather Ih.1Il a lower concentration or II\(' typical t'holim ·sh ·rol-st·; lilt' at)Vit'il! cholin-
('slt 'TOl"" h'l\ oulv 1/ )(10111 o r tilt ' usual affinilY for succiuvk-holuu-, am i il 11t·1..I\,t,\ d ilTt'n'nth-
rWTII lin ' l)lllt'ili dl(l!ill('sh'rol-st· tn va rious t:lIZ)l l1t' illh iililur,;_ ~lallY aberra nt rUTlIlS or th~·
('IIZ\"Ill" ure II flW know n 10 e xist, t'il(,h dt'lt·flJlillt..:! hy a di fTt'f( 'nl ~t'IIt· ,

Oxldatiotl
\l osl slIIall lipnphilit, d n l~s aft· sU" jl"(1: tu u\io:latitm by tl.t· t)1od lrt>JI\(, !'-4.')O mixe-d [nne -
ttou n\idatinll S)"Slt' IlI, primarily 10t'ilh '(l wi thin the li\"t'r hul alst) round r-lsewlu-n- sud l a _<;
til(' ~1I 1 wall. T his SUjlt'Tram il)", whid l t11lllp risc.'S lIlallY t·IlZ)-lllt' S. is <li\i <lt"(1 ill 11II1II'lI\.<; intn
Ih rt"(· lllaj(lr t1isl illt1: ralllilit·s, o:It's i ~ lill t"( 1 C Y{t.,.1Ix,h nllll (' )P(4.')()) I, 2 ami 3 , t'lIl"h rurther
t1i\id t"(! int o Sllh ralllilit'S. " I hmll ~h E. Amltlt' nll lllt' mis ilT(' IIst'tl 10 n·rt'r tu illtl i\i d ll;tl
('IlZ)'mt's ( ~t ·llt · pmdm1:s) \\il hin ('il('l1 slIh ramily. 111is 1I0 Illt'lwlaI1irt" is h:Lst'tl 011 tbt' d i\1.·r .
~t' n l t'\ululiOIl o r tilt' ~t'IIt·s , Tht' C1 1'3:\3...') Sllh rlllllily or "II I.)"" \('S, partit'lItlrly CYP3A -I, is
lilt' 1Il0si ahu no:la llt.
Ik h ri.... " llIltlt·. illl all tih)lwrtt 'lIsin' agt'lIt llow Ill) IOllgt' r in list·. 'Ml" th t' firsl d m g Shll\\ll
10 t·\hi hil ~('lI di t' Ilt llYllltl'lJhisllI ill m:itlatioll_l1lt'rt· is a t1..fid (·nt.,.' in Ih(, IIId aholi sm o r
Ihis t1m ~ in ,') 10 10% or C:lll tMol-~ i "lls, \\i th \\;<1.. o:IilTt·rt·J)n 's in otllt'r ('l Illiit' ~rt>lIPS (Tuh lt,
1-1- 1). It is a rt"('('\Sin ' Int il. eoillst'(l by a t1 t'rt 'C.1: 011 a S ill~lt, d lrt)JIlOstlll\(·. Ihal a fTt't.1:s a
IlOlrti ("lIlar H\ ida lin' 1·1IZ)'lIIt·, dt'brist"l uiut· h)l lm \ )t l....' (C n h ,2D6). Sillt't· Ih is di st.."l )\"t'I')-, a
wholl' hos t or t1nl~s, ind uo:lilll-:: TIlt'l opmlol ( Fi~_ 14--1) ami tht' untiarrh) 1:h mit· d n ll-:: t'IK.'llin-
itlt· (T:lhlt, 14-1 ) han ' h''('n rflum l to ht' suhs i rolll's rOT this t'IlZHIlt',
~ bllY dfll~s an ' o:l.\ itliu'(! \\ith \\i ddy difT('rill~ (·llidl·ndl·; hy Iht' d ifTt' Tt'ut ronm o r
t) 1o(-h n llll(' 1'-4,')(111.011 (·,ist in atidi tiull ttl dt' hri stWlnillt· h) t l n>~tl'i(" n it' d('aT;lIIt"l' \lIlu('S
CHAPTEIl 1.1 GlNETlCS 223

a.ssodah"tl \\i tl. tilt" oxidatioll of certain dmgs n lSt~n~att', imliedlillg that thl'Y an- sub-
strales for till' SOUllt' l'1I0 11\(' (Fig. 14---2 ). There is also co nsiderable overlap in tilt" strucm rul
s!)("l'ifid ty u f SOIllt" of tilt'S(' ( ·II ":y IlWS . such tha t a dmg may 1)(· a substrate for mort ' tha n
( lilt> of tln-m. E\itlt 'Il{1.' famring g('nd i(' coutrol of IImny of tilt'S(, p r'Ol't'SSt-'S is gaill("ll from
studh-s \\i t1l twi ns. Fig. I W Illustrates such an ilJ\'('Sligalioli with tilt" antid t'prt'Ssant dr ug
nortripl ~'lillt" Variahility in the plateau pl;l~lIIa Ilort riptylim. concentration after oral ad -
miui stmtioll ilUlllllg Identfcul twi us is mill'll k-ss than among fraternal twins or, ind t't"l l.
alllong auy r..lI1domly St,lt·eh '(l. agl'-maldl('tl gnltlp. Similar data ('xist for otllt'r d m gs. AI·
tbough III,' ,·\itl,' l!('(· pn'Sl.'nh'tl in Figs. 14- 1 alltl 14-3 an ' striking. anal~""ii s !lll"''ti sol,·ly
on 1111' 1II1("hangt'(l dm g ill phlsma IlIay hI' misleading. Consider, for t'X<lmplt•. a dmg that
is d iminah't l hy St'\'l'ml mt'laINllk pathways of wh ich only a minor nlll' is under gt'Jl('til'
control. Examinin g on ly half-lift' or total dt'u r..U1t't' lIlay f,ul 10 d t'lt 't.1: thi s gt' llt'tkaJly con-
tmllt,t! St llln..,' of \~Iri a hi l i ly. Yet, if tilt' uffecn-d ml'taholih' is wry polt'lll or toxic, idt' nli~'ill g
Ihis SC llln ,· of va riutmn lIIay ht' tllt'n1I)('ut it'lllly impo rtant. 111t' m-ed to nu-asure both dmg
and nwtalN llilt's umk-r tllt·S{' dn..·lIIllslam,'s am i 10 calculate- clearance ;t<;StK1ah "ll with for-
mat inn u f .·aell mt'iaholit(, is St,lf-t·\i dt·nl.

Acetylotion
Imlh i dllals \'a r:' \\i dt'ly in their t'limination killt'lil's of tiK' antitube-rcular t1 n lg iso niil7j d .
TIlt' himodalil y uf lilt' frt·ljlwllt·y distribution his!ogmm of the s- hr plasma ifotllliazitl con-
t't'lltratioll follo\\i ng a s i n.~ lt, oral do'i(' (F ig. 14-t) W<l.S taken us t"ideu('t' of polymorphism
umh-r monogemc ('(mi m I. Althou !!,: h subsequent ('\id"I\('t· coufirmed that POI)lll U'lII. i<' iso-
niazid t'limination t'xists. till' use of a singlt, Iimt _point meaxun-ment could han ' ht"l'n
o

misl"ilthng. Om ' dOt's not kno w, a pri ori . wle -tlu-r a low coucentmtion n -Hects poo r bio-
a\"ailallilily. slllw ahStJ'l) tic)I\, \\i 11l l)t·rllaps tilt' conce-ntrat ion still rising. o r raptd elimination.
\\i th till' (" Ilt't·ntr.,!ion r:llling. ~ I nrt'f l\"t'r . if tht' measurements Ilad h('t°ll takr-n at 2 hr .
when II.... ('fII\('(·ntr..,linl1 p rimarily n -Hects uhsorption rathe r than elitninatjon, om- mighl
ha\·,· ohlaillt'fl a unimodal frt'llllt'll('y distrihution nnd t'Xdlldl't lll1ulltJgt'" il' control.

600 "·ill:. I ,J- I. 1>(",. ",.. 1I1t'l"I'" .~ >1 " ""'f'n t rnIMIt'~ af" 'r
.. 'i nfd.· tI"oJ ,...... " f 21 _1 "' Km''f orml..! l;&rtr..t.· ,......
z: ilION'" l,jlQlt'r ill I".,r (0) II,all in , k .,.uw (. J I,~'-
-='"
c
.l n lll~·LI"n " f ''' ·''';''.I"i'It·. H ,.." llN'1"I'",It>l i' ..
.In'K of hi~1 Ilt-p.otk d.·ar...k tI lirr.·"~ K~· I...··
;";; 400 m...·" 1"." ......1 '·~l ..'''r..· nN'1 ..I. ~i h·'" i . '·.p""""..l
in , I..• Lal'):t· .lJrr'·"·IK~· in .. r.tI I.i ",.iJaloilil~· . •1,..· I"
C
~
u
.lJrr.·...·,...~..in fi"'I.f"l" IN,...' it· , n..·,,·rht...I Ii'k'S
c i'kl..:alt· lI ...• " .....L.n! .w,.;.,IMN' (I "'WI. - 3.7 ", .'1 ),
0
u i tk.. lnt\\~1 r"""I .~",,,nl. \l.S.. Sit.". J II .. Fn....'.....·.

~ s .. ",, "' '''y. L.t-:.. T,.. ·ln. GT .. " 'k l W... 1... II.F.:
("MLI "~ p1N·'. ~l"-"'- ", ..jt ... d.'1,·nnilla nl "f .,...-
5-
B " '1," IIt~ IIN'fal• .ti,,,, M! ""'1""-..,..... 1t' 1',;" ,...1loy I" 'r-
~ 200 ",i..I"" nr n... S · EUI:I",1t1 l"u m,.] uf \l ,.. liti,It·.

'"
~ . Jt!7: IM't- IYilI. !lj'):!,)
E
~

~
.
,
0
0 6 12 18 24
Hours
 G{NETICS CHAl'lU 14

houiMjd is prilll ari l~' i!('t,t,.lalt'tl in tilt" liH'r to S -aet1ylisu niMjd , a p n 't'u ('\()r o f a ln-p-
alolo\i(· l'u lIlIX)\lIul; tlifft'I"\'ll l,('s ill III(' 1·limina lio n kim-tics o f lscmiazic] rdlt'l1 po lymor-
ph ism lIf a particular ~ -a('t'tylt rallsft,r:.L'i(' NAT2 , a e:.10';ulic t'IIZ)1I1t'. As sho'l1I ill Ta blt'
14......1. l a ~t ' gt ,1lt,tim ll, · l'tJlllrIJllt'tl t'lhnil' d ifTt' '''IK't.'S t'xist in tilt' di sl rihll liull of ill't'tylalur
sta t us. Moth Ca"('l.L~i ilIlS a nd blacks !la\"(' ap p n n illmtdy t'(l" al nurulx-rs (If slow a nd fast
an·tyla toN, hut in (Irtr-ntal a mi Eskimo populations tilt' Ilt' n.'t'nt of slow ,l('('tylator; is much
small" r. S low 11l1,t,latoN an' ~t'll l't i('all~' !lu lIl0 I)"K0 US 'lith a I't"t.'('ssin' allele pai r, ami 1)(·-
cauw lll't't, latoTsta t us is umll'T mollt ~t'lli c co nt rol, it is IXlssiblt' 10 calcula te the fl't't lllt'IJ(')'
of llt'tl'TU0 Wm s a mi ho mo0~ulI s filst iK't,t" lators From KI'IIl' Frequencies. The results <lis-
pla)"t't l ill Tilbl t ' 1+-3 fur t'lIt:11 d hn il' ~mllp an' c..rk-ulan-d in the- folloY,illK manner: if I'
a mi II art' the frt't! ut"Kit's of two '1Ile lt'S. so that II + II = I , then till' frequenci es of tilt'
Kt'lIutHlt,'S h' lIl s isl i ll ~ o f a l1111lhinatiu ll of tilt' alld t's ) art' ,,2
+ 2,HI , a m i q'l. 111(' Slllll of
tll('st' fO'(llIl'flde... is LO. Fo r example, in tilt' dllta ill T alll" I4--..1 for C;l lI<~as ian s , 11 2 (fo r tilt'
hOllltr0 "Kom slow an.·I)"laton) is 0.,% , so that II = O.;66, that is. ifi.fi% of Cnucastaus haw
01.(' slow acdylatoT alk-h- . I h-nce. tilt' frequency for tilt' fa.st 'K'l·tyla to T.Lllt'lt, is 0.234. \\'h ic h
h-ads to d istrihu lions for h l'lt'ruZ"~flllS ami hOlll tl0~um fast <!('l·tylato r.> of 0 .350 (21 /(/ ) o r
3.'i.9'l a lll i o.oss (f,z>
CIT s.s« . rt'sl)('(1i,'t'iy.

SUBSTRATES:

S-Mephenytoin Desipramine
Niled ipine Dextromelhorphan
Diazepam Erythromycin
Tolbutamide Debnscquine
Cyclosporine
s-wartann Caffeine Chlorzoxazone
Phenytoin Theophylline Ethanol

2C·Meph 3A-3-5 2E-1

Sufphapbenazole Fu rafylline
INHIBITORS: xeteconazoie Quinidine
F i,e:. 1.... 2 . ( :rul'hic: nl' n... ·" IA i.." " f tl lf' ,Mf'·Il·"t ("01" " f l~t"d' "," If ·. I'-&.'il ) k i n' Io'S ) in IUIlU.III' with lIiff,·n·" t
11f,1 ,"'",. ,,,.·.lapp;",, . "I" tl'll'" '''If1 IIn..I,Kt ' I"'fifio.itj,-" 11,,- illf!ic"Io' '; "10:10, "" -,,,J,fJil,- p"tl,.......~.... It,,,..
n....·ll l ati..•.. ,I...l r..h.. " n' 1i.1o'f1"ho..., f"r .....·h " "zy"'''. AI.. , Ih" 'fl " ",·Lith.·!)·...I....tj,., i" l,ihit"n " f th.· '-"1:)1""'"
( Fn Ull ".·ll"f"'1'. 0. "",I Ih ,..;,,,..,.. 1) .Il .: 1101.. of .. ,,' 1n"''''' '1 ,t,,1( 1"" in ,I..· ph"rmo.c.. kinrt ICS " f .Im",: Cun '
...I.·r.d.",,. ,..tI. n"'I"'f1 In "",,,u1 " 10·1•. l'-&.'it) ''1I~'' ''· . .11,,11'""'" c1n,lt"'. I" 11",,,11... 01< "f F.~pt'ri ,,,,·nl..l l"h.or_
l1l;.m lo'l{' . \ ',J. IlU . 11,,,n n.... oI<i'..1it. n( Un ,l(' . E.lih..I I'l.- I· ( :. W.·ltilljl;;<... I I ~ ". 1I"1a,,, . lM·rfin. Sprin,," r.V,~
1I1!H. l't' 2"~'J,.12. )
Ct-WTE ~ 14 ce-ercs 225

Identical Twins Fraternal Twins

80 80
~
5
~~60 60
e
t:
s ~
0 -
Z c
~ .g
E 40 40
""
~
!! ~
e, u

Irn m~~1 ~ ~ ~~~~

~ c
~ 0
~u
20 20

~
~
0 0
HI(. I ~J. 11... mud. "".,II,·r ,,,It''l'.ur \an.."i l'I~· in "1..1.·..,, pt...,,,,.. nIlK" nlntl~ II' or 'K .rt ri pl~~1r"· I>.""... ·n (Ill
iol.·"ti.".,1 I" i'" ,I,.." I"·",..·,, l II I (mh·o ,.,I I"i'" "" 111·;01.... !I,,,I !o:' ·tl"'"" I>I .~ . It "",j" t ... It· i" .1I ....n l'''~Ii , ,,·l'hltt .
,,, l .,,1'1...... F",""I,· I, L,tl " .I" r); n...I,· ( 1l~1 ' 1 ,..Iorl. l t 'n"" ,. .......,.. 10·... ",. It , I'nn ·· t:,"ltJl' . ILo\.. It'K I Sjo'Io(\·" '.
F., " ·.lIh.'I.'I.· I'L.,,,,., 10·",1, II( ' l 'rt nI'I~ I ,, " · III ""in" I"A,,,,. ,,..· ..( 10:" ''''';'' (...1"" ..,..I t1now: 1 1"·n.I'~· ' Il r . \1...1
J. ' 7f>.1 ~7h"'. 1'lh'J )

. l lt. 1-'-4. n hi'III "W ,1."' nl" 'I;'... •J tI,,· I>- I,r
25 pL&-..... ,,,,,,,,,,,,,1 " 1........ in .....1 .,,1'J"'1' ..flrr
s ... fII( 1..w: i<o ...;u.1 ~ ~It. (nwn • • ~t.t...

tl 20 f" ~lt.""".. lII ll nll'.'1. - 7.3 11 \11. ( Ko..l lt (n wn

:5 E' .lm . Il.o\ P.. \I ..... ~ ":..0\ . ;and \I (..:" -\.. \' ..0\ :
~ (:'-"'1..- n ..ln" "I iJl ",i.uitI nll"l..t"oI;,.m in n.... ' fl r ,
15
'" \1...1. J. 2 ......')....&.,1. 19fIl11

" 10
D
;;;
E
~
z
5
0
o 4 8 12
Plasma Isoniazid Concentration (mgIL)

.OW -,
1"-5' .oaT'>1,.-l.TQr5

Soo..I'h Ind-on~ ....'o::Jdn» .J' . 356 54

C~~ .- "~ ,
< 350
, ,~
55
Bloc', <.: • 386 08
f .~
, ":?--J'

, 43 8 45 7

--
C

.... ~-
.. 45 3
408
42 7
282
22. G£NE T1CS CHAPTER 14

Isoniazi d is au ex eept ton. In must (~.l"'-·S tilt" fn "fjl ll" ll l'y of I M:t:ll rn"lIl't " of an alll'll' is linked
wnh o l !Je f Iact nrs . suc h ll~ ~t ·Jl(lt ·r. Also . several sul'l-:rtllips within till' ~t'l lt"ml populutlon
a n ' uflt'n o f a ",rivt'll (·th llidty. TIleS(' dTt'i.:ls ma ke il lIillit-lIlt 10 1~lkll l ak the ~t ' ll ol~l"l('
fn'(jlll"Il I'y . Hnwever, llot\\ilh stml(lil1 ~ tl1l'dillkultit's ill makill~ p n -d o;(' ('<lit-illatio ns, knnwl-
('tl!{l' of the ('x1sh 'IlI't' of lar J!;t· d llllic <lifTe n 'III't's in p ha n mlt"flkint'til-s , stich i t S SI"l'1l with
i<;l llli;uj tl am i sonn- other dmW- illdudill ~ desip nll nim' ("'-'t. Itdo",). is d l'arly im portant for
till' n ptillml n,\(' (If d OlV;S. Thls is ll<u1 k'ula rly mn- for d m j,ts pn'S('rillt'tl \\u rld\\ide or 11M'll
in a Illllltimdal so(,:id y.
Interes t in :Il't·tylal ion POI~lIlO rplJisTII is lint [ust am d l' m il" Poriplwrulneur oputhy. il'i-
sod 'llel l u i t h I'le \1Itl'l l l'olll'('llt rati u lls of isonlaz hl, occu rs ilion ' p n'\'al tollily ill slow al'('ly'
lators uuh-ss a n adjustment is llI,ull' in the d m agt' o f iSllllia"j d or \i la mi n H,; is l,,(JIlI,(llllila lllly
adminis te n -d. AU1Ul'II1'SS of tln- pl1."'lI.l("IIl'l' uf hm no zygous aml llt' It' m :l.)'go lis rapid al'('ly-
lutors nmy ilISI) lit, d i n i eaJl~' relevant, il" lhl'y ap pl' a r til t1ifTNill their s llS('( 'Jlt i hi l it~· to adn'rst'
l1.'lIl"tiollS, sud l ,lS iSllllia"j tl-ind ul,,('1I )lt"p,a til' t LUmlgl" A("( 'I~hlion pol~1Jl( 1I1,h ism ilISl' 11t'('111'S
a mi is important fo r scverul other d nags, SlIl'h its hyd miaz illl' an ti prut~ti lla lll itll' (Ta hlt,
14--2 ). For both d naj.,~ Ihe S ' ,K'('f) '1 t1l'ri\1lliw is the msjor Ill('laho lih '. A S~"'h' llI il' lu p us
t'l')tllt'lIlalosll s -likt, S)l ld ru nll', a gl'lll'm li".l,'l! inUa nllnallll)' f1'SpUIlSt·. run limi t t ht' liSt' of
both t!nags: it de\l'lops mon- ra pid ly in sllIw ruthe-r than rapid ;ll'(·tylators . Tilt' uu-chanistu
n -nuuus o bst'lIf'(', h ul tlOt'S "ppt'ar 10 1>1' ,lsso l:ia h'l! with d t'\"a h 'll pLtsm;t conceut rations of
hytlmlazim' a nd jHlIt'ain alll id t" Hapt d iu'('lyla llJl'S a lsH n 'lluin' higllt'r <IoS{'s of hyd mlazim'
10 control bypertenston.

AdGrtiollaI C1inkal C..lidefations

Sl'\l'ml poinls nr-ed tn lit, llIatll' ill ad dilioll In t hllS{' matll' a ln 'ady. Fi rst , IIII' chnical im-
plicat ion s of gl'lWtil' pol ylIlU'1)hislIl ill d l1.l~ 1llt'lal MllislII d l,)lt'ml nil whe-tlu-r al'li \ity lit'S
\\i l h tilt' a fTedl'l! snhs l rdte o r tilt' IIlt'lal Mllile. RS Wt,lI ilS II.I'" importance of II.... palhwa y tn
ovr-rall r-liruination. Fo r tlnags SII{·I. llS d l'h ri.Sl Ml nim'. al'lhily rt'sitll's p rt'l )mnim llltly wi l l.
the dn l ~. ilm! elmununon is al mos l l'UIlIp!l'I""y via tin- a lft'{1t'l ! path w,ly, In slll' I. l'ilSI'S,
unk-ss lilt' d lls{' is n-duced. 1I10n ' pronouncecl a m) sus num- d l,ffl'l1s lIlay IK"(:lIr ll ~l'I llt' r
\\i l l. po te lli ially mu re frequent a dn 'rst' react ions in I'MMlr nwlaI MIIi".t' rs. A l~ lll i filsti n~ a nd
illh'n'stin~ sit ua tiou is St"(' n wi th l"(M!l'i l1e . Part of its an algl'"sil' al'l i\i ty is due In morphn«-
(u nTIl'll From I'l'M !l'i!1(' hy tlt'b riSlM llIilJ(' hyl! RJ\) -h 'i(' (; \' 1'2 1)6). Al'n mlingly, suIJjt'l '1s tldi -
cieu t in dd lriSl Mluilll' hydmxyhl'il' lIlay d l' rin ' Il'ss ,lIlall-:l'sil' " {'Iwril fm m l'l'MIt'int, . TIl('
l'l'lIl\"l'rsioll of lilt' a nlilllllt'n'lI]a r tlm ~ tlapSl lllt' 10 :-':';lI '(,ty]lbpSlIIll' h y S -at'l"lyltmllsfl' m'i('
l'xhihils l-:t'lw lil- PO I~l l\0'1) lJi slll . 1I0w l"'-I' r, ilS ilt'('lyla tiull is a mino r pa tllway o f <IapSlJllI'
d im inutiull a llll :'\·a{"('ly),b pSlJllt· l'(mt rilmlt's IiUll' to ad hity, or tm,idly, W'lw til- pOI) l l1 nr-
phi slll hilS 110 dil1 il·a] l'l'lIISl'llllt'llt'('. ~l a llY o lllt' r Sl'('llilriOS {, Ill lit, t'll\iSilgl'l l t1l'llt' ntii ng 011
tilt' f'('la li\"l' illlj'Mlrta lll,(' nf l ill' "fTt'{1t'{! palh way to t'li minatilJl1 ami wllt't1l('r tl m g, rnt'lah·
ulill' , o r IMltlJ. l,(lIIlri hull' In lK"thi ly a nd lu, ki ly. SUIIII' o f tilt'S{' Sl'('ll<l rius arl ' sllIlIllla rizl't l
ill T ilhll' 14-1 ,
St'{'{JIltI. part of lilt' la rgt' inh ' rinti hitilial \" ria hil ily in III(' t1t'gf'('1' of tl n l~ illh'fill'l iollS
i ll\nhi lJ~ inh ihil ioll a lltl intllll1io ll (j Ill'n'ilSl'l1 s~' I t l lt'sis ) of dm g 1lU'la IM,Ii".ing t'n :l.)'lws is
tinder gl' IWlil' l'l'mt m l mI(l inl·I1." Lsin~ly p rt'tlil'l ahll'. T illIS, fluillitlillt' is a ptllt 'llt il1hihilor l lf
Ild lriSlMluine hyd m xyl'lsl' alll l lhl'n,ro n ' inhih its Ihl' fOl"lI1alitm of all llw lal ltllitt's Ihat a n '
pnltllll,('li fmm slIbsl mh 's o f th is l' nzy' IW (St'(' Talilt, 1-1-1 ). QlIi nitl illt· I·ffl'(:t in·ly l~ lI\\t'rt S
a nonuillly ('lI.ft'nsiH' mt'l aho li".t'r 10 a n a ppa n 'l1tly t·n;,'Ylllt,.c1t·fit-it·1l1 lIlII' (llfM,r IIlt'l aIMlli".t' r ),
\\i t h lilt' :tlh 'llda nl O llt(~J lIl t'S .
l"lSI, ge m' lic IMJIYll10 rp his lll lJ:lS ill1 p lil'aliolls ill di ll il~I! lri a ls tl uring tlnlg t1t'\'I'!opnwul.
HI'latin ·ly f(",,, suhjl"t,t.'i an' stlld il't! in till' t'a rly phllSl'S of di n il'al l'\'a lna tion llf .1poft'nl ia lly
11t'W IIlt'mpt' uli l' a~I'Ilt. :k (,{ lrtiingly. if llll' ff'('/jUt'lll'y o f all illllMlrt,UII tlm g-n w laI M,Ii"j ng
l·n:l.)·lI1t' d t,fjt; l·lll;'· is \'(' 1')' low , all ill1 jlflrta nt Slllln..'{· u f inh-rpatit' ut \ '-i1 riah ility in p hilrma -
CHAPIEI1 l A GENETICS 221

cokinc-tics, ami rt '~ I)( II l\(" may Ill:' lI\isSl,'(1 unt il tilt· dm~ 1)('('()JIws \\idt'ly prescribed. wit h
polt'lltially St'riUIIS (,( ll\St'C IIll'Il('t'S, Fortu nately, \\ith the.' illl'rc."L~ill~ amilah ilit), o f pun ' hu -
man t1mg-I1lt' laholi zill!-! t'1I0 111t·S, prodnccdustng hiol ('('hnolo!(\', prt'('linim l i " dtm S{'n.'(' I1~
art' hq~illllin ~ 10 1M.' I I.~t'(l l o e.,haradt>ril.l' lilt> 1'1l1.)1111'S primarily n 'spollSihll' for nwtahoJjsllI
(If a d m g. If tlu- l"nzyll lt' invulved is one- known to d isp lay gt'l ll'tk POIPllUlVh islll, tilt' dmg
ranl x- evaluated ill a pn-seb-cn-d ~n lll p o f suhjt'(1s \\i I1l Ihe t'1I7)111t' dl'fi l'il'III'y to ecunuu-
whetlu-r St·rillllS pmhlt,tIIs migh l ari'\(, duri ng its sub'\('(!1Il'1I1 use .

INHERITED VARIATION IN PHARMACODYNAMICS

:\ ~ p n"\'i l)Il ~ly 1I0!t'i.1. palit'n ls n ll'Y in Iht' dllSllgl' n-qutrcmcnts o f warfarin 11('('(lt'(l to pm-
(hll't, atlt" ILlalt' anli('(lagulant control. At IIImt, till' variation in d{)S:I~I' n-quln-meuts is five-
fold , In sr-veralnn-mbe-rs of Sl, 1I11t" famil it's, however, lIIiL\.sin ' closes of wa rfa rin an' 11I,('11t'(l
10 ;(l'hit"\l' a 111t'r.lpt'ul k ft'SPOIIW. Figurt· 14-,5 Illustrates tln- Hudmgs ill h m familit,s. III
('{ lIl1JlLOII \\i lll rulu-r ~t' llt" t k traits. warfarin rt'~ ist a n('(' is not found ill all kindred. Anal)",is
o f tilt' frt" lllt'Jl('y o f ti lt' n-sistancv in Sl,...e ral ~t' Ilt" r.lt i(Jn s i nd ic.~dh's that Iht, n 'sistmll't' is a
domiuaut d laral"lt-ristk t r.ln~rnillt'd in a single gt·llt·, A normal phanmll"llkillt'lk pmfilt· o f
warfarin in tilt' n -sb tant sllhjt'(1s points to a phanna('()(I)lla miC'illly !J;l....'(1 fesistall(,(·. A
p rnba lll{· Illt'l.'!Mll islll is irwn.'ll<;('(1affinily or tilt, n ,('t'ptof for vitamin K. with which warfarin

Table 14-4. Potential Conseq uences of Generic Polymorphism Invotving Drug and
Metabolite for Poor Metabolize,.-

'-
~ aled reponse, PQIllI"IliaI
lOxicity

..........

o
• D
M

o M

I
 C HAPTE ~ 14

F I". I ~, H... hM1i"n "f 11.. , ,....'.,t" W" rn ll lln ll'"

hin ild i.ih' Ian h "f ""lit~t;&,,,Ld>ihh' l fn ll n n I..
4!'l I,r, "ft,,~ .." ur"! , " f 1.5 mJVl<K I,;"" w" ,.(ari" .
ro... .' )lj ,nt'", I.., "f ~ ,.(..,; " .n i' I""1 kiu,ln..l..
n ..· tI,IlI<..1lu n 1'n ·nl tlM' !N'l ( ,li'''·1K.. li",ih
f.., II.., n"'l""" '" i,, :;n 1 n"a1."I>,...1. Ki" 'I1 II..· ~" ...
,10:..... n ..· 3-1 nM·ml ...· "f IltJlI, ldndn'tl, ilh II " ",.
nl;l] n .. I"..'.......... il.. lil I... II-.:-' tiM' .... ~' il .. I ,..I 2.'j o
" f Ih. ' 26 I1M·ml ..· -uh " Il"\i.lillli 1l"I!"m ,,· illl" iu- 100 80 60 40 20 o
,1;,;...1,.. 11-.:-, tiM' ,,010 11....... ( Ho.. lr Tl f,u", ( rH"il ~'. Percent Reduction 01Prothrombin
11.:\ .: S~~"I ...i" '" "n pllillTt,..... 'l(' ·' lit.. , G'·...1i<.' f......
Activity at 48 Hours
I" ... in 11M' n"'I"""" lu II..· ur..! .."I;,;.t;&K',Ltnl ,Iml:' in
I"," w , ~·'''1it'S. I>TtI. ' ....lin~ "f tI..• ",,,,rt"
Inlt-no,,·
ti... 1;l] O:..tpo'M of lI " m"" G''TM-tit... 11Ih·rrul.hllllill
C'''lK"'''' So·n.... 2',0 , :I,m.to·" L" n. E""'1 Jt;< ~1 .. lklt,
1972. PI' . .f2.\ -ll \.l

l'OllI(X'k s 10 produce Its ant it'll<l~u l<l ll t t·ff('(:t. Ti ll' iU<lhility of appm\i lll at d~' 3()~ of c.UJ-
('ll~iam 10 tusn- certain dnlW' sud l 'L~ prupyltlJionradl, which contains a Ihiot) "llnate ~mu p ,
illuslrak s how ~I'llt'l iC'S also t'lmlri hult' s to \1tria h i li t~· in tlu- 'W II<;t.'S .
Other l'l:uupll's of gt',wt kally dl'tt' nnilll'li variation in pha rlll at'l K I~l l ,lI l1 it'S are ¢\'t'll in
T ah lt, 1-1--2. Although the number of exampl es is t'u frt'll lly small, tln- Importance of such
sou n -es of \ll riah ility in ft~SPOUst' should uot h,' U'\l'rloo kt·d .

PHINOTYPING
Phcno l~pi ng: patients for a p articular IIIl'1al Kllk pal hway, sud l ,to; a('(·tylation Of oxidation.
prior to d m R administration has been p mpost'll ll<t">t'(l lll'ltlll til t' m ho of dr ug an d Ilwt a!ltllih '
conceru rauons in urin e follcMing a si n~lt, tl Ost' of a markt'r. SIIIEllllt't! 'azilll'!Ht<; 111.'1'11 II ~ ..I
to p lw nolypt· for slow 'K'l·tylalion; ;11lt1 spa rkillt', for slow oxidation i,m ,l\ing:dt'hristKluilll'
11)'tln nyl;tst'. 111is app ma{·h aims to lx-rn-r antieipa h' lhe c1osa gt' rq?;illlt'll of a dmg: n-qnlred
in an iudivklual. Its appt.·aJ is gn'a l('SI ill Ih,lSt' situations ill whk-h: Ihl' therapeutic iudex of
tilt' d n lg: is luw; thl' aual~~'s o f dmg am ] its meta bolites in p l.t<;mil an ' c1illk ult ; till' tnarkr-r
is relauwly s afe. t'a')' to measure. and its pl lt'llolyp k d litnlt1t'ristit· is h ighly com-lated \\it h
thai of tilt' d n lg:.
» t'sp itt, its llppl·al. IIwtalltllit, pllt' lIol~l)i llg is 1101 \\i dd~' t'llIpIO~l'( l in di nk' ll p ractice,
for lIlany reaso ns. Om' is tilt, mconvenk-nce a<;~)(:ia lt'( l with tllking of lilt' ma rke-r and
lulll'<.1 ing uri llt'; anor lu-r is ;t<;s.a)' t~)S ts ; am i ~l't unot lu-r is ti l(' Ilt)Ssihilily of faist, positin's
thai an' elm' 10 otllt' r tl lm ·ntly adm inisten'll dmgs, such us cl" inid int' , inlti!ailing: tilt' en-
0 11W. (;t'u ot)llillg. luee-d Oil D S A .tnlllysis of a small ~u Jl rl (' of " Il u l or all )' other IiSSUt',
holds IIII' promtse of pn l\iding a ilion' direct approach toward pft't.l il1ing: 1J1I'1'lho!it, plu-.
Iltltn ll·. Curren tly, D ~A tests have pn-dicn-d lite pln-notcpes for IKIlh :-:; ·at.'('lylalion and
dt'h ristIClllilW h)'(IRJx~""ll i(J n in 9.'5 III 97.5% nf llt'ultlJy volun teers. wh id l d t'ur ly ind it';th"S
the importance of ~t' l lt'tit..'S a.o; tilt' major sn u ft.'(' n f '~dri ah i lit~· l lt'n· , TIlt' .lpplim linll of pbe-no-
typi ll~ to pn-dtct d(J~lgt· dept'ntls till lilt' n 'latin' t1111trih u tion u f otlu-r factors. such .t~
t1i.st·ast' and concurrent dnl ~s , to lilt' overal l vari ahilily in d nl ~ uu-tabohsm in tilt' p ark-nt
population.

STUDY PROILIMS
IAn ~wef$ 10 Study Problems ore in Appendix II).
I. G in· twu t'xmnplt"S t'udl nf inhcnn- d variation in pl mn tlat'llkinl'l k'li am i ph arlllac.'lKly.
namics .
CHAPTER 14 GlNEOCS 22'1

2. I>dilw lin- terms: ~l'nntn)(" , ph ellol)lll', and j:;l'lll"tk poly morphism.

3 . Discuss brit,fl)" how lUI inht"rih"ll SOlln '(' of variation ill ph an n,K"Ilkiul'fics lW .U1 he idt'n ·
tifit"lI ....1thin till" !);ilil'nt populat km.
4. A <Img: <!I'\l'IUI)l"l1 for \\-lIrllr.\idl· u....' is Ilwtaholi...t"ll h)" :o.; .an·I)"ltrallSfl'f;l'it" \ \ 1l:lt an'
thepotential im plications of this fi ndi n~?
S, SlIhjl't1s p!Jt"lIol)l )l't1 a('c:urt li n~ Itlllll'ir (lehrist llluillt' OxilLlion status (11l1l1r or t>xtt'min'
llwla!lllli7..t'rs) inv;t"stt't l uue l,f llit' follO\\-11lV; fuur Jl-adrt,Ilt'Q.,ric hllll.'king d m gs: iltl'llUl()I ,
lIlt"lo p ru lul. pmpr-dllulol, und tauolol . Tahll' 14-5 list s the 1Ill",1II \1111ll'Ji of va riou s pha r-
llIal"llkindic paranu-n-rs for l'ad l d n lV; am i wllt't lu'r till' ('orn,btin ll ....-ith debrtsoqnnn-
slatlls was weak or stmnV;. l>iq:11SShrit'fly IXtssih ll" n'usons for lilt"(l1>""'l'\l"(l corre-lations.

' ..... 14-5.

a
"'", , 3
50 38
63 0 2Q() 0 .0
50 0 280 <03
31 0 150 4.7

fl. a. G in' h \ll esampk-s. ill ad d ition to lIlt'topmlol ami tillluiol. of dmv;s that an' m.idi 7.t't1
and that f'xlaih il V;I'l\I,tie polymorp hb m in the-ir clearance.
h . li lit'fly diS(1lsS each of til(' fullo'\1nv; stan-nu-uts:
L F h-camkh-, an au ttarrythmic aV;l'ut (ff' "" 0.4 3 1. is" suhs tmtt' for Ik h risollllil1l'
h),lmX)-la.st' (C YP2 Dfl), }l't nnly in IMtie nls '\i lll seven- n-nal d)'sfulll1illll is V;t'-
nettc POI}l llOrphisllI in dl'<U"lllll't' n'ad ily appan'lli.
2. D apso nt' and llldl'illl' an' I....ll examples of dnJv;.~ that fnnn m inor nw lalllllih's \ia
palhwap llial (.'xlJihit ~t 'lll't il· polymorphism. hUI nnly fur lull'im' is there a pn-
h 'lIlial ll ll' mpl'ntic im plil-,Ition .
3 . Q llinidi Jll" converts t'stellsin ' mt'l alll)!i7.t'f'S o f substrates of dt'hristlllUilll' hvdr ox-
Y!<L"f' 10 pnor mdahol i..a-rs.
•, Ti lt" fn "( IIll'lIl')' within ti lt" population of an .tllt·lt' .Lssol:iah"(l ....t th slow oddanon of a
d m~ is O,I S, If slllw o\idi 7.l'rs .m - hOl1lm:yv;ous \\-ill l a n"(.'t's~in' aUdt, pai r, whal a n · the
t'\lll"(.1('(1 frt"(lllt'nl1t's of slow <Inti fa, t nxid i7..t'rs in tilt" po pu lation? ASSUlllt' lli at ll\icla-
tion status is und er 11l1111(~l'llk l'(mlml uud that " II tilt' ' 1Iriah i!ity in ol:itla tio ll wit hiu
tilt' populat ion is of v;ellt'ti l' oli¢ n.
 ,_' 15

AGE AND WEIGHT

OBIICTlYIS
The leader will be able 10:
1. Desermire eose drugs for which Iooding dose. normalized for body weigh1 , is likely b be
independenl of age, given the volume of distribulion and fraction unbound
2. Cesaibe the likely changes in the pharmoce*ineliCS of a drug Pfedominonrly excreted un-
changed. from neonate 10 elderly polienrs
3 Adjur.t. based on age and weighr , the csool adult dosage reg,men for on individual oIdef
than one year of age.

A ~II ~. chsracn-rta-d bypcnods of WtM1h , t!t...·(·lnp lllt'ul. ,lilt! '\(·lIt·S(...-ncv, is a n additiona l

souro- of varia bility in d n 'g rt'slxmS(' and . ;L~ a res ult, tilt' usllal ad ult t10S<I~t· rt1.rinw ll llIay
I\l'('(1 10 l)to modified. pa rtkularly in t ht· Y()II I1~ alltl tilt" old. if opt imal tln-mpv is to be
achieved . Furthermore. it is the- n 'I)' ) 'OII Il R and IIIl' ag:c'(! wiln IIftt' ll an" in 11I1)';1 cri tical
Ilt't'tl of d rugs. It is a~aillSl th is 1);,l('Kg:rolll ul ill whkh un atte mp t is mad t • ill this cha pter 10
dt"\"t·lop a [rann-werk for lIlal.i ll~ do~ge adj ustll lt'llts fur il~t'.
Th e life o f a hu man is eonnuoulj di\i dl'tl into various sta~t'S , III th is bo ok tilt" various
sta~t~ nre t!t·filw(1 ali follows: neonate , up to om- mon th I Hld IIIl' m ; in/ mit , 11(' 1\"('( '11 tilt'
a~('s of OIl(' month and 1\' " )'('a rs; ciukl, 11('1\1.' '( '1\ I\1.l 1)'l'ars and 12 )'('ars of a,gt'; m/o/f'!o'C('llt ,
he l\vt"{'n the a~t~ of 13 ami 19 years: mil/It, ht'I\n'(' n 20 and ';'0 }"{',Irs; and eMI''', ,,1<lN than
';'0 )"'-~.lrs of a~t'. It is rt,(1~l ii'.l,(1. h{}\\l'H' r. that this stmHfi tMdtiun o f human lift, is arhi lrary.
L fe is a coutiuuo us prt K'{'SS with the dhtillt1iou h('I\"I"('n 0 111' period and the next oftt'n ill-
defined . It is alliU n,(1~li zt'( l thai d lnlll olu¢ t, a~t' dot's not Ilt'("{'ssarily define fUIlt'tional
a,gt', and lIt'{'t)f(li n~I)'. state ments made in tlJis d l<lptN pertain ttl tht' a\'{"Til~t' pt'rson wu hiu
tilt" a~l' b racket rather than to tilt' ind i\idual,
Expt'tli('IIt., ' and pr.td it'lility didalt' ag;unst tilt' \\i tll' UM' o f IOllwtllllinal stlltlies III indi -
vtdual s to examtnc Ill(' influ('II(_'(' of a~,' o n pllannatl 1kim 'tit'S, Hather, singlt· OhM'n.'lltlOIlS
an- mildl' in individuals o f difft'ring agt's, The infnnnation ohtailll'(l then-fon- pertain s tu
the population ami doe s not 1II't.1.'SSllril,. n-llect how an imlhi d uill may d l;lngl' wil l. agt'.

A POINT 01 RIIIRINCI
T lmm glJolit this dmplt'T n -fen-ncr- is made to tilt' "( usual] adu lt dnsag,· n'¢ IIll'Il,- I~'fon'
procecdtng. this ph m_'i(' needs to 1)(' ddillt'tl. TIlt' word at/lilt refe rs lu-n- ttl ti l" typical ad ult
patilont\\i tll ti ll' disease or condition n't illi ri u~ tilt, d r ug. n it, "( u sual] ad ult dO~I~e rcg tnu-n"
is dt'f1llt--d as that rt'¢IIll'1I wlJk h when W\l.'l1 to th is f)llk'i,l p atient O!t'hit°\"(·s t!le r.ll)(·utk
S llt:t.'(-s..~ . Clearly, the charact e ristics of tilt' adult patit'llt population d ifTer with til(' t1i'i(';L'i('
IM'i n~ treated. AgtOis t'(ortlti lily om- of tllt'S(° characteristics .

230
CHAPTf ll 15
'"
111t'(Lito, in Fi~. 15-1 , !l I M I diffen-nt a~e trends for tht· II ~ ' of hm d rugs. 11111\. p"lti" IIIS
lakin ~ di ~()1(ill . IISl"(1 to treat l-an lill<.· disorders, are ~l'll(' r.ally nld" r th an those takin~ nitro-
fUrd.nlo in . 11...... . 1 to In 'al urinary tract infN.-tiolls. a condi tion m" n ' ''''' '111)' alT('<.-tin" JX.....p ll·
(If all a~, .,. . l'atit>llb "'i tl. in('fmlin t·IK"l.· an' V;(·lwr.ally '...·1· 11 ohk-r, 70 to Ml )'f.·ars. than IhoS('
with cardiae disorders . IIfM, ...·N. there art" ft·..... tlm~s fo r which t·,h ·usi...... Ilhan nal"ukiTll'l ic
data a n- uhtailll.....1 al the mean a~,· o f t t.(' ad ult pa tit' nl po pu l.d iull. S i IK 't" O K...I patien ts
takin v; dmj..~ It·lltll" hi· middle-aged . fo r Ihl' PUrpt N 'S of sllh....... IIIt·1I1 ('".".It'-Illations. all ad ult
a/o:t · uf 5..') wars is iLSSlllllt....1.
The- tlaia in T alllt· 15-1 illustrate a point ahem! a~t· and tli...·a.....-. Li,tt-d an' t'Sti lllaft'S "f
tl.t· p" pulati o n rhanmtl·oki'll'tit.'s (If lli ~(ltill in a ~JCJp uf )1Mlnv; 111",,1111)' a<lulh ant i in a

Nitrofurantoin t·l lt. I S_I . .' C" tI•• lnh u l lOn fir
50 tlruc ...... . umpUon . UutpaU..n ll In
I.... IUln~' "(Jlml l.ntl. S..... ~"I>. I.d. ­
I~ Ihcu.. n an' ~. oIo.l.·r ltwl
th,"" t. h nc nilrofur. nloin. I,' lt-
40 , trat'lr tl fr om Borlhiu• . <: ..nd
S,....;d. ' c.: I), .... .ntl cJ,~ lulri"
,.,J. <I( ,ln~mnoI ......".... ..,.J
30 ph.um"""lo:.inrhc pli nctp lr,. elm .
PIl.u m u nl . Tll rr.• 2 "25.\ -2~3 .
IU7'l )

20

15-59 6lHi9 70-79 , 70

Digoxin

30

20

10

o
15-59 6lHi9 70-79 , 70
veers
232 ACt: AND I/VElGHT CHAI'T£i 15

,.ltJ. 15-1 . hp.I.tI_ PIIa,..__kl_tl. h_ rs .. DI••• I.I_ Y__• H_....y

....Iem ..... l.. petI..... With ....... C.....HI•• c. c•• UUN

Young heolr+.y
SUbJe.:::tI" 2B 71 40-70 7t/J 85 J5
InPciloenb , -..ere
"""""~ ceooc
10..... 54 68 476 3.5 14

""rnmll uf i llpa til'Il t5 rt,(" i\;I1~ d i ~lJ\ i ll for tn-atun-nt IIf s('w n.' l111l~('st iH' e.m lial' [ailun-.
l\'ntit" ,!It" di lTt·fClIl't·S in till" values of tilt' ('sti malt's , [l'util1ll;arly fm n-na l dt·ar.lIll...-. ht··
IWt't'n lilt" two ~rllllps . E\i dt·utly. t'stim :lIt's ill till:' )lll lllK Iwahhy Kmlljl an' of littl,· tln-ra-
PI·uti<.' value.
Part o f Ihl' difTt'n'!w(' ill renal ch-arauce of t1ig,nx ill h t'! WI't ' 1l tltt· !\\11 g,ruups is ill'(."l, llIl1ll'd
for h~' the t1ist.' lL'it' , Pa rt . h OWI'\'N . is al1.1)IJ nlt 't l for 1Iy aj.!;t', O il(' ohjt'C.1iw of thi .s d ,aptt'r ls
to SllAAt's l IIwan s o f 1''OTTt't'tillj.!; \"alut,s of phann,wokhll'!i(: 1)<Ir.u l1l'Il ' r; for a g,t' , 111(" int ent
tl lt'rt'by is tu permit a la -tt er estimak to ht' madl' of tilt' initial tllI<;;l~t' n-quin-d tn tn'<It a
t1iSt';lSt' in ;11I indhidll.tl pati t'n t or in a patie-nt poplll<ttioll whllSt, it~l' d ifft'o suhs tillltially
from till' 1Ilt'<I1I a~t' of til(' Ililtil' llt populat io n in which ti lt' usua l adult t1t lSi1~I' rq~i n ll' n was
es tablis hed. TIlt' intlm-ucc of all other fil('to rs- su dl as diSt'll'it' I x'i n ~ tre-ated. e uuurrent
d iSt';l'it-'S, and other d m J"r s-.tlTl phan nill'()kinl't k s are assunn-d to lit' indepe ndt'llt of a/.:t', or
it is il'iSnlllt'{l th at tilt' i1~t'-rt' lah'tl t'ffl't1s ('lUI lit, ucoumted for illdt'pl'Ill!I'ntly,

PHARMACODYNAMICS
l1mmghont this chapter. tilt' m ngl' of unbound plusmu d nl ~ conwnt nuious ;t'iStll.'iah't ! wi th
s lll,('t'5sfll l t l l<' mp~' is assumed to hi' indcp-nch-nt of a~t' , Fur alltie pilt'pti<' dnl ~'i alll! t li~o,'(i n ,
l' fft't1i\'t" plasma d nl~ t'UI\('t'ntm tiuIIs aplx'a r to hi' the SiUlI<' in Iltlth chtkln-n and ad ults,
alt h(l\ l~h cluhln-n "PIIt'iU tu tulerute a " i ~l ll' r c unvntra non of tilt'st, dmgs lx-fon - ;Ul~' tone
mamfestanons IX't'(IIll(' ilPllilrt'nt , Difft'n '/lt'('s in n 'sptJllst' with iI~{' an ' likt'ly tn (''(ist fur
certain drugs. Fur example, th e ohst'r\'t"d inl'J'('il'it'{! st' llsiti\ity o f t'ltIt'rly Ililtit'llh to tilt'
ceut ralue....'(J\lS (,fTl't:1:S of be -nzodluzepim-s cannot 1)(, expl.uno c l 011 ti lt' hil'iis of di ITen'lIt't....
ill pharmacoktnetics of this ~n lU p of d n l~' ,

ABSORPTION
D n l~ absorpnon dllt'S nol ilppt'iU to dl a n~t' dmlll"ti('lilly «tth i1~(' . :\'llIw tllt'l(,ss, all tilt'
fadoo tIiSl'lls'it't1 in Chap. 9 that aITt'(1: dm~ ahsorpttou, indud ing ~,l'i l ric p i I, ~il"t ril' 1'1II1l-
I)ill ~, iute-snnal lIIoti lity. and hlood f1 uw, do d l<lll~t· with a1-:('. Thus. ill till' ncouan-, a
('(mtlition of n-hniw adllorll)-dria persists for till' Ho t week (If lifl', and u nly aftN 3 ~'('ars
o f a!-:e titit'S ,g<l\tril' alit! sec ret ion appmad l IIIl" "tlult value. (;;.."tril' (, lU pt~ill ~ is alstl p m-
lougt't:! and pt'risla lsis is irn,.,l br during till' (,ilrly months of lif(,. s k(,lditI Il1 IlSl,I(' llIil'iS is
,,1st! IIlllch n 't:lul,('t:1, and 1II11s<:·I(' (,mtr-dt1: ions, which It'nd to p m mlllt' hoth "'"ol l llo\\' ;1IIt!
sprl'mli n~ o r an intr.ulllIsl'lIlarly ;ulminislt' n't ) dnl!-:, art ' rt'!a!i\'I'ly rt't·hlt'. An t']t'\ll lt't ! g,l'it riC
p it. a tlday ill ~a'il ri(' ('U1pl)ill~, ;mtl lltith d iminisll('t:1 inlt'sti llal lllolilily and hlollti llow an.'
alst! st'l'n ill till' t'ldt'rly. J)ifft'n 'Il('('s ill t1 nJ!-: ah"" 'lltio ll a lll(Jll ~ ad ults, tIll' \'1'1')' )Ull ll~ ilm l
the t'ld NI)', an.' thl'n'fo n ' I'XI)('(1:('(1. (;l' llemlly, dl'IIl~('S ill nllt' mtl lt'r than ill exte nt o f
ahsorption an' found . 111l'St' dlilll~("S telld to he It'sS apparl'n t ill tilt· ,·Idl'r ly than in till'
 AGE ANDWElGHl 233

n 'ry yo ung. Clnldn-n "rtt'n app,r-ar to a h:-Clrb d rugs il-~ t"l,Jlllpll'lt'!y uud. if an~t t.ill g , mnn-
ra pid ly than adults, At1:'o rtlingly, in subsequent calculations of tlosagt', e xtent of absorption
is ;I-~s u med not 10 va ry \\i til agt'" A major exce-p tion is for souu- high fjf'i l- P;I-~s dmgs ~ n 'n
III till' ,.Idt·rly. II t'Tt, ural hin<availahi lity increases \\i l h agt·.

BODY WIIGHT
Om- ,l-sp,'t"1 of a~n.l: is IMKly wt·ight. \\"t'i gh t, 3.5 kg at hi rt h, illl·n"I-St.'s rapidly in l·!Ii1d luKltl
and atlo l" s(1' nl1' und tln-n d t·I:lint·s slow ly in tlw t·ld t·rly ( Fig, 15--2), HI'(.~ l lISt'I M lt ly «un-r
' 1);111's, musck- mass. o~all IIllM ltl llow , a nd organ [unction art' related to h'ltly \H·ight. so
too sho ul.1 volume- of tlist rih lltioll . clea nmce. allll ltt,!w(' d nsag<.' n~lI lt'lI S uf dm,gs. (}.\i ng
to Ia~,' \"aliahilily, !towt'wr, a \\'t'ight adjustllwnt is ~ellt'rally thou gh t 1I<''(.'t'SS<try (lilly if tilt'
wt'ig hl of an intli\i tlual tlifTt,f'i by more tha n 30% Ir om tilt' a\w:'I~I' ad ult wI'i!?:ltt (70 k~) "
In prat1 il't' , then. mljllstlllt"lIts for wt'i ,ght an' ma de o llly for th .. (·!Iild a nd for tilt' ad ult who
is pe-tit e-, l'lJlat'iatt 'd . h ig. o r ullt,St,.

LOADING DOSE
Cli ll i(·<all~ . (1IrTt't'ting the' <ad ult huling dose proporttonally for Iltltly wt'i~h t appt'a no n-u-
s.f lllah lt·. The vuluuu- (If t1isl rih ulinll 11,1-\1,<1O il unbound dn lg. \ ''' ' is fn 'qllt'ntly IMlth din'l.1ly
pn lport iun al to Iltltly wt' i~hl a nti il1Clpllt' ndc'nt o f agl·. hilt no t alwaYli so . ~ l lldl t1t·(lt'llds n il
til,' ph~ ... i( ,.c.'I ll'lIli(~11 PruIM'rti c's tlf tilt' dmg and Oil tln- n'usou for IIIl' di!Tt·rt.·Jj('t· ill w<.,igltl.
Show n ill Tah ll' 1,')- 2 an.' valm's for d t1'"'1' u f plasma pmh·in hill cli n ~. vnlunu- uf d i.\ tli -
111IIioll (V). IIl1lMlllllcl \ ohunr- of e1isl rthution (\'11 ), a nd percent o f drug in tln-litltly unbound,
for u 111111111(' 1' o f tlm,go. in m-ouates and adult s. 111(' h st 1\\ 1) Ilill"d Tlll't <.· rs w e-rr- calculan-d

70

60

50

"
"-
E
40

.~ 30
;:
20

10

o
o 2 4 6 8 10 12 14 16 18 0 10 20 30 40 50 60 70 80 90
Age (years)

FlK· 1.'5-2, \'. n"I,,", in "",r"I:" " " il:l,1" illo "1.'<'. fmlll II.., ,..'" ,\a !o' In II", ,·I,Ie·r, WMId,1 ilM-n·.... ~ rdrmU~' in tI..,
~' '''''I:, l"uhc.ll ld~,[" nlll( II.., fi n l ~" "r Ilf lif.·. ..", I,IunJlI( p',I...~·. It ' Ie....ti"..... Ie",,,,,·..fce·r ."jll ~" iU"'I ul" "1(' " ( 1).. 1..
fmlll' U-2t1~ ";Cf'i. I " "-~ ",,,," I .. (;' ·h~...-. ,'!1f t, E,I.. Ii " -l. K;cfJ(l'r, I~. J'I'. 2.'5."j....2.~: 2tj...~ ~,·;cn, 2nd ~ ..li" ,,'" 1I"altl,
,,",1;\ Ulnlin" E' atnin.,Ii.." S"rw'o'. I!f.'fi---.'ll l, ~1 ;c -LIIl' 1. U ,S. ~ ..liu..'" (;"nCo'r fur 1I,·;c.h l, St.ti. lil's: 7S-~ 'o'~'on .
cue 11"",I\... ol" f , ..,nli,,,, in till' ,\ \t<..1 EcI'I,..l i~ a.n. Wal" "I, t1urilL.. CIlI: I'n~,. I ~. p, I ~.) ,
 CHAPTE R15

T.It•• 1 2. Pl._ Pretel. ai_I....... DI.....ItwtI_ D.t. .... s._ ~ .

I. N A41."'-

ceo
.
1'>fON.loH
"'"
,o..,t()N.>.ll.
"'" ~" "'"'0 r-.l0\lA1E
"'"5.
Phenobo<bolal
SuNiso_ozole
068
0 .32
0 53
0 16 to 3.
0 ,55
0 .16
1.4
1.2 1.0 1,56es72 5.

-"
SuWa~az,ne 0 ,43 0 38 0 .47 0 24 1.1 063 02
Digo-,n 0.80
02
0 .70
010 t1.3'O 7.0
0 63 is
65
10
6.3 t 12'2 6
0

from III am i \' ( ~'(' Chap. 10), As co mmo nly Found. plasma binding is lower ill neonates
than adults. Yet , for tilt" first tlm'(' dmg.s, plu-nobarlutul ami tilt" two sulfouamides . \ '11 .
corr ected for hod,. \n'i~hl, is the same IN.''(~,llI~' must of Ilw d m~ is unbouud in Ilw Il(xl,..
Clearly, for tllt'~, <lm!!:s;a \\1.'i~h l ·n(J nn:lli7J.'(1 do~' produces the S<U1 lt" unbo u"d d m~ l'(JII-
ce ntranon in both neonates an ti adults o r in any otln-r a!!:(' !!:nmp. In l.'(mlr;l..I,Ii IlIl.' of either
di~oxin or ph t'1l)1oin is unbou nd in thl' blxly. Even MI, a d i!T('n'lll.'f' ill "indi n~ ( 111). lK'CIIr'S
to plas ma protein n 'll is virtually tilt" same]. and SCI a \\1.·i ~b t-(,( l rn '(1 ('( l lo'lI l i ll~ dose, if
n-qni n-d. should sufTk t,.
Du rin g adulthood the \"alue of Iu n-maius uuchauged or tends to ri w fur thl lSf' d m ~s
hou nd 10 albumin. tlu- couceutnmon of which falls sli!!:htly wit h ad\"a nti ll!!: year... 111('
dlan!!:e in hi nd illK is Keller.tll)" too small. however, 10 warrant au,. conskh-ration of dosc"
adj ustll lt"lIl.
Body composition is important. :\ du~' corre-ction must lit, conskle-n-d for t' lIladalt.,1
anti oll('S(' Il:ltiI'IlIS, 11w tIiITt'n'ul."· in loatli n~ tIuS(' ilia)" uot lx- ,l" gn'at as anl idp,a!t"tl from
hntl)' wd~llt alone. IItM'eH 'r , as wit h a!!:l.' ·n'!al('(1d lllu!!:es ill dist rthunon. 1I111eh dt,pt'IJ(L..
on the physil.'(x'l1('mic:a1 properties o f the d m~. Di~oxi ll am i polar t!nlgs, for example, do
1101 part ition well Into fat, Al.'('(mli ll~I)", fo r IheS(' dru gs. \ 'u co rrelates b~..tter with lean body
mass. which is similar in nlN.·S(' anti a\ 1.'ra~t· pt'fSUIiS o f III(' S<U ll(' ht'i ~h t and Frame, tha n
....tth total body wt'i~1lt.

DISPOSITION KINETICS
Fi!!:llrt" 15-3 shows d J:lIIK('S with aKe in half-life ami dt':lnUll,(' (If l.' n '<llinillt' t'xpn's~'( 1 pt'f
kilug fUm of body w('i!!:ht. Creunnim- distrihllh "l; into total body water sp.u.'('s, is lltogliWllly
bound to ttssue or pl'l'ima l.'(mstiluents, is d imil1alt'(l almost enttn-ly 11)' n-nal excn-tton.
am i h,l" a d('amnt'(' equal to IIU' ~IOIne mlar Hhra non mit'. 11lt, t'~llIpl(' o f c reatiuiue is
chosen 1 1("t.·a\l~' dmTl!!:t's in tola l lickly water ami glomerular filtratkm r ate ....t th a!!:(' an' well
understood . To the extent Ihat creatinine mnmcs ot her d nl ~s, Ihe data di spla~1..,1 ill Fi~ ,
15-3 furt her our lIlIdt'r..tandillR o f a~l.·- n'l:a lt"tl ch,lrl!!:l's in phannacekine-rics and 5 11~esl a
means of illd i\i d llali7j ug dClSa!!:e r'l.-Wllwns for age. Let us l.'u nsid('r tilt' va rious parts of Fi~.
15-3 ill some detail.
Clearance, if no n n:ali7.l"t1 for l'N kl)' wt'ighl, is dc'pn'ss("ti in tilt' IJt'(lJIatt·, blll irll.'n 'a'it'S
r.tpitU,. 10 l1'aeh a maximulII ...altw at 6 mOJlth s, wlll'1l it is almns l I\\i <'(, Iha l in tilt' :u llllt.
TIw n 'aftN, wt'i~ht· norlllalin'(l dt'amnl.1.' falls h ut still n ' llIaim, th nlll ghollt d lild hcJlI(J. l.'On-
sidl.'mllly al)(J\'(' IIll.' :adult m ille . Also , an nftt' n forgott ell l'N linl is that t1lmuglullit ,ulliltlu l(Jl.l
man )' flllK1ions dl.,:n·'l'i(' (FiR, 15--H. TIlis is l.,,·rtaillly st) for e n 'ulilliut' dt'ard ul'" ( ~l mJ1(' n l ­
lar fittmlio n mtt·), whidl di min ishes al a mh' of al'Nl1ll I II pe'r )'t';ar.
Taki ll~ inlo accou nt di!T('rt"Ill.1.'SOhst'fV('t1 iUlllalt's and ft'males.l llt"dlangt· in ('n 'alinhw
dt'lar.lIIt'(' IX')lI ut! 20 ~'('ur.. (If aJ.::t' l.'all II(' llpp ruxima h., 1 by
CHAPTH 15 AGE AND I;'oI£IGHl 23S

(Maintenance Dosing Ratelkg)/

(Maintenance Dosing Ratelkg in Adult, Age 55)
or
Hatf·lifel(HaIHifein Adult. Age 55) (Clearancelkg)/(Clearancelkg in Adull. Age 55)
( ..... ) (- )
2.0 2.5
,
,,
r

1.5
,
,
r 2.0

, ,,
1 / 1.5
1.0
,, y'
, , , 1
, " 1.0
iI _ _ -- - -
>)"
0.5 ,------ 0.5

o 0
o 2 3 4 5 6 7 8 9 10 20 30 40 50 60 70 80 90 100
Age (years)

Infant Child Adult Elder

I~

Neonate
Hit. 1$-3. " " Iwlf·lir.. (I.·r, ..",I." da."N'tlli,... 1 a'Hl lHllIo d"a r"'I(~ ' "'HI "';4i"h ·n..,...~ · '....ing nil.. (IiW'1 ...",1.'.
n"',"" l lind ..f lnlR miw,l "1U)" ..i ll, "l(l' . n H' "',.]' M" ..... n · .",10,,1.... ..1 rno", .I..t.. "n •·n-;dini'M'. 11M' , In,~ lik.·
.T<"1Olirn '... . ,1" l nl." I... inlo I", .,] IH"~' .. ;aI,·r. i_ 'H" IH""HI ill pL._"... n r Ii.." " , 1 is ,·litnlflllt,..I ,·nli~~· I~' n ·n.,]
.-uTrli"n ..i l h .. d.......... '''1''..1 ,,, tI... ~" tH ·mL.r liltr..li" n nah-. Ib lf·llf.· i po I ... .. rnM.'tin.. 01 11..· a r.. I,"·
,,.\.... f" r a ~pK"\ .').'>-~...a r..,j' lllIlu h 1", Iil-nl; II ~ . ..'!tin....' i• •...k~'I ..I I ..n 'lIl1inR lhat It... d.-D....I ·T'lOI:'·
pl"I""" unl. ,,,tHl n.u·ntr..liI" main...."' . :",..i<.... llut. I......" ..· " f p""" r.·na l flllH:ti"n,
11 th"' '' 'RIH",1 lir.>
.·limi' WIH >1l i• .I.M' ill tI,,· ,...." ,.., 1" ,1 i"'p"' ., r"l"' Uy ,".-h 11,.1. loy I ~,·ar. h..lf.M.. i. ill ' , lwIf I...· .. I"h
, ,.\,.... n" n nR d'il.lI 1;4.,,1 10"'.,...........·. II ha lr.lif.. I... ~"tH.. I<"' R.·r I u..• d....nt1 ..'t' fttt 1iort tlf s..rf...~·
......... in. ·n· " ...m · ." ~' with lQ'....lI, t!w , .1.".. ".I"n..· tlf d i.llih.. liI,n f", ...1"'''' "f I " ,,~' ~1 . All"'''' ¢>
I", ,,~' .. ~-iRl '1 1tl...n ·f" ",I ..",.· "f ,li,lli],lIh"" d nl...· ""J:.' .1iRl,tly 1..~""t1 .1U ~~."",. h:alf.lif.. I' 1<"'I:"r i" II..·
"l(l"1. I. ".,,, · n ·,...1 f",..
i i.." ..,..I tI..·,...f" '1.•..,...., p n ",n...I"'''· .Iiminhl. , H~' \:I.") ~.""" h:alf·lif.. it twk't' II...
~l'ioU 1,,11 ,,.\..... n....,.- d .....I«'f. ill d.~..n ~·ltl .. I " .· id ,l wilh "lot.· .'~p"'in .. hy ,1M ' nlOlin,,·f\lU I.... r bl<",r;4tt'
lOr Ix,,~- ·ld.t i\ hiRl"'r in Ih.· d ..kllU..1k ~·r in I h II · ,.........I t· .. ,.. I II..· ..1, 1II",,, in I • l"lt ,
n Ltl.. 01 1in I...· .Olk~ ll ..t"'.." .. . ·n · <" ..,uIl<..I f,.t" "I: IIa!f-lif.·_ ..c al I..I'..1 f" .." ~'''llnM'' "f di.l rihllti<..,
...",1.·k nt1, lI ..1f.lir.· i" lUI "''''''Jo(l' ...Iull. 55 ~"..n . i• .'i ij hr. \ '"1",,..· " f .h . ,ril"lli<..,- TaL 711:'1- " f I.,,~'
,",MRi'1 ..t "'rth. !'i, '1- "f I.. ,,~" .. ... W.,<It fi n ... . ths. ", 1 fil l'l "f I.... ~· .. ... W,l tl..·n· ..rh·r i Fril. · II ~..·tt. H,: Ch....Jo(l...
in I ",,~' ""ltl.., ''''''I''''J'I"...
''h ,I" rinl: RR ....i lo _A.i .. I' h;dr.. (S" p".) Iff" l -ffl. lij.'">fi ). CI....rantT-Mi hirt h, t;J..."
.... inu lin <4<...".,....... 3 ", I) m;" (\ \·MlI. W,H.; n ..· "\'",Ii"" of "" f"'''1it", in inf..,.., · anti m l1tll 1 .'u" . J.
,-"..I. Sd.. 229:6'~ . 1ij.').5); I ~ ..·n fi """,tI" ..,.. I 20 ~~ k"lL.h.. II~· mullip~i nK Ini · d.· , -.
120 rtrl/ml'Vpl'" I." "I''''~ nld "R III . " ...~.~. , I...... h h~'. ~ •• m~ 1.. 11 " f 21-29 ~""n. hy I ~" " .rf.,.'1' '"
I" ......~ ..·n 31101,,,1W ~.~" ..... t"",·"rnm , t 1...1.. " f Sitonl"" ·It.:"io:·I...·n (Sit·n ],ao:·It· S i..l...... K.• 11"' , 1. ' _M .• K"''' I>-
m..nn . J , 1 Kri" ...I,,·n. M,: futpio: l ,.\ " .. tio: II' " f ..... ~"I"' i ...· d'~"""'K't'. 1 ,....1 . 1:1133- 113-1. lij'j ll. s "rf......
An...__Cal d..I•..J f" .." I."i;.- ......Jo:hl " .,jnl: 1...· n-1..1"'''''''ip: Surf"''t' ..,.... 1./'1 "lit"'" nlf't..n · [Wl"iKt,1 ilt)tll
,01'" .
 '36 CHAPTU 15

Mo les
. Weight
Cr&Qt iolM Clearance (mVminl - 11 40 - Agel " 70

Females
. . Weight
Creotinlne Clearonce (mVmln) - (1040 - Ag e) " 8S 2

when- a~t· h cxp n -sv -d ill )"l'ars und .... l·i~h l i ll k~ , 11m..., ill an lIn 'raKe UO.~'{'ar ..old. fin. k~
adult , ck-arunce-s (4.'1 m l J min. mall' s; ;}.'5 TJl IJmin. (('malt's ) art' ()"'5 tlnu-s those o f tlu- tn}iu tl
5.')-yt'ar+(,1d !);Ilit' n ls. wh ile t lu- VU]II('S ill a 20.p.·iar.old, iO.kJ' ad ult ( 120 mlimin . malt's :
!02 1111 J ll li n , ((' malt's ) un- I A tum-s tllt ·S(>values . Mon- Kluha l rt'latinm hi ps that Incorporate
scrruu cre-atumu-, 11 rt,1I1'1..10r o f hotl. l'rt';d iu irw p rod ul"lioll a m i n-nal excretion . i LS wd l a.s
a~(· . " ('ilotht, anti ~1· lIdt· r. ar t' WVloll ill C ha p . 16.
BI'l'iIIlSl' to ta l lMMly ' S111N a-s II percem o f hody \\'(' i!-th l. und lu-ncc d isl rilllltioll. dmll!-ttos
rt-Iatin-Iy Iitt l,' t1Urilll-t lift' , Iht, I,:h;Ull-tl' in cn-at lui m- half-lift, i ll\'(, rst:' I~' rt'fI'"(.1s lilt' dl;lIl ~(,
ill d .'ar'lIIll.'. That Is. tln- Imlf-lifl' is shortest unnux] I )l 'ar o f a~t'; il is 101l ~t'st in hoth
11' '''\'''0 01 alld ,' ltlN I)' p anents . Altholl).':h t'xli'llsi\'(' d ata an' lal·ki ll ~. simila r ago-n-lan-d
dl,IIl ~" S ill di sposition uf d Olj.,"" st't ' lll In (){'1.'U T.
In ,m'"wI"'" m-wlsorus, creatinun- d("lr.Ulll.' is ('\"( ' 11 IIInn' depres sed per l';I()~ralll o f
hu(ly wt'i~h l Ih;t11 ill fllll-lenn Ilt'tll mli's. C n'a linim' dear-lIll't' aplx ';ITli 10 increase l'xIXlII('n·
tial'" bva f,l(1n r of S !It'tWt't'li V; ,Ulcl 40 \\'('t'k.., ;•.'; s1l1l\\1I ill Fi ~, 15 -...·, . 1111' d;lhl in dicate
t1lal l'~'alinil\(' d earalll't' dllrin~ Ill<' first few weeks aftN birth is pn'1.!il1t'tIIl)· comx-ptlonal

100

-~
p
~
~
> 80
"-
p
~
2
.~

2
~

"'j;'
60 - ,
,
-
Cardiac index
Glomerular
filtration rate
Vital capacity
~
~

" 40
e,
E
e
~

~
e,
- •
Renal plasma flow
Maximal breathing capacity

20
0 1"
0 30 50 70 90
Age (years)
t"i!t. I ~ . \t ~,,~· pt .~,io.J. 'l"<· r'''.di..,,_• •L", i"iu , ""tI. illt-n-,,-.i ,,~ ;&~. dllrin\( ...1,,1,11 1 (" ....ph ...1 (ru," SI.. It-~ .
sw., :"j(" d liUl!o:''' ill p11~"')O:oIo ~"'] rllllt-t io.." . ill , I..· 1,,(;0] ;&ni ul;&]; n l<' rule· . ,r Ii." t-..bh'l.l I ~' B IR Sl rd )!.'r .
n .., hio.... '1{\ "f ;t(itl'o(, Wll-.I'i l~ '''' . (l ,c. , .-,,,,It'ric...tI I". hl,," · <lr llio. oI"l(ic.,.] SC...·IIt~ 111H1. 1'1'. 2.'i4 l-~ )
 231

a~l". (finn - sinn ' l'Ulll't·ptiu u). I)usill l{ requirements for a d",~ that is primarily excreted
1I1ll'hangl'tl d l\ ri ll~ thi s period lllay be approximated Imm knowledge o f the conceptional
al{t'; hul IIIl' n-quin-ments. RS rt'll('<.'tl't! hy creatinine clearance, an' rapidly (:h a ll ¢ ll~ and
must IN.' (111\tillually updated.
:'\(' xl, ("llllsitlt' r th(' duta 011 diazepam , a d m~ IIll"taboli1.t't1 p rimari ly in the live r. As S('C-'II
in Fi~. I.'>-fi. diazepam half-Ii fl' is If)II~('st in the neonate, particularly within the first few
da~~ . ami ill adults older th an .55 yl'a rs of a~l·. Infants eliminate tilt' drug most rap idly. With
cn-annhu-, tilt' Inll!!: half-lift· in tilt' neonate is caused by depressed renal (UIIl1101l. which

100
• • . '111;_ 15-.5. Cwa tini,
IUrTt"l-1...d
d,.;ln",('1.' ,
k.. llln'<i t;,d ) ... w..I u n ·
('()u .-ct''l l (o IM' n hla('k circlesl for
IMIt I} ' ''''(;ON' "n·... p lulI• ...J ~' .. n tl .
('("It~'fIti.. nal aJo:l'. n... li'lI'S "'P"'-
" 'nt Ih. · h..., fit of ;,/d, ""I""...."lial
10 o ''<Iualiun to till" .L I;/,. f"or tlx- liN""
;",.1k",,·r ." ...."5. t .......I....linn. ..n-
00 CL..( m lJminfl. 73 ", I ) • 0.37 3
o ..0 Il l ' "«' a nd C I.... ( m l.lm in} _
IU MH fi2 .. 0 1111 . " . ' , rt"s!"-clin" >'.
t:...· n ..f,.., (",uN1;" !: for . " rf;oc.'t"
all'll, clo:'ll flUl("l' i. jtTl.... J:,' tl.l'n ....J
in ....."'''IM. "'p'..:;;"II" tI" ...· cor r-
Ii e r ('<"'('< 'p h" " al "It" , R.'(,..lI lh",
l......hnillt· d .." r.ux., (m m 6 11"",11••
' n 2U ' ,,".of' l. ;d U ll 120 mlJminll .i3
0.1 ml , (AtLql'l ...1 (n" " AI·Il.."'....,,_ J.,
28 32 36 40 44 " "J""l('k. G .8 .. C hant 1,·., C o, <1", 1
Conceptional Age (weeks) Stim",J.·r, I ~ , Sl.limn I" M'.....I".; ' in
,..n n Iln d prt1t·nn ,,,,\,,,,,1<,,,, An"h.
Dis . Chilo!., .'io'L]'1.~2. 19'13.)

80

60

20

o
Premature
Newborn
Full-term
Newborn
(3-30 days) (3-30 days)
~
Infant
(H O
months)
I
Child
(2-11 years)
Adult
(20-55
Years)
Adult
(5H O
years)
H lt. 1l\-6. 1I ~l f·li f, · " I',h"",'Jl;<lU i\ , IM'r1."\1 in tiM' inf"ut ....111 kIC1~"\t in tilt' ,_ h" m "llCl lh.. ~ ..1. (Ad,"pl,..1
I'rmu tiM' ,L.t" Ill' \ 1" ",, ·111. " .L : !>nll!: !>L\p"' iti"n !>llrinj( 1>..",,101''''' ',,1. ~I"" Yorio:.. Sp' ..:.1 n ll" !>uhlil...li".... 1977.
PI' , 3 11_lfilh 'lI l l'_-&.')6; ;1,,111 rn"" II.., ,L.l;l, of Kk>l7. U.. .... " •.111. G.R., " '~lm l p" . .'\ .. Sd ll '" lw r. S.. 1100 W ilkin.. ", .
'II'
( ; .R.: n ..· ,·1T...1 or '"!-" . ;I,'lI l liwr IIi......." · II,,,I..
till' Ui' I" " i til '" li min,,tk,,, or ,Iianl"'m in ",Inll "'li n, 1- ( ;I;n ,
In" "\t ... 'i.S : 3-& ';'~1.'iij. HI,;,:,>,'
231

lalt,!, "<"'t'ml IlIlIllths In mature. \ \'ill . t1ia7.t',l<UIl thl" km~ 1.;(I(·li ((· ill tilt' IIt 'OIlOl!t· rt·flt"(1s
;III 1I1111,"\\·101'("() clnl lt-lIlt·t... holi;rju!t ;K1hit)'. Md ahol it· ;K1i\it~· llla~' t"k" lIIon l h~ 10 rn alu l"t' ;
Iht, t i llit' n'clllin '(! (ur Iull matu ranon varies " itIJ tilt" (·II ~lIlt· \) 1;11'11I. That ti lt' pn-mnnm-
!It'ClIMh' 11;,-, tilt' km!tc"",t h;lIf·lif(· of diazepam is flul s u rpris i ll ~ and :'> In"".....,. a point 1II'lllt,
(';arlit'r: dlR lllul(~k a m i flllK1icma i a!tc' must Ill:' t lisfinJ:uhllt'tl. t""pt'liall)' ill Ilt"Ollah-s.
111l" shnrt N h.llf-li(,· (If tlia:t.t'pa lll in tlK' infant than ill tilt" 20· In 55-)l 'ar-uld ad ult n-llects
dHTc·n·nn.... in dC-anIl K'l' pt'f lilll).,1T".Ull. h,,"('".I.IISt., \ullllli(' uf dhtrihu HolI of th is d n l~ is ap""
p m \ illlillt·!y tht· SdIlK' 0 .2 lAJU in 1.0111 Wf" lps . 111(' further prokm!talilJlI ill half-lift' in tilt'
11l1)',t t·MI·rly ~ml l p , dl·:.l.rly !lIIIMl l to l it-, ege- n -Iate-d ( Fi~. 15-i). requires !>C)IIlI' Ih!>l-m~tOIl .
C I,'ardIK't' n ' lIli1i ll~ t'S"'l'llt iaJly constant . and \ulUIIlt, uf tli!>t ril mliu u h ilK"n'a"'l"(1 ",ilt. a~'
from 20 In MI ~"iln, bill nll l~' IJt'("auV:" of tiM' 1t"lJ(It'IK, ' for KM't' r plasm a himlinJit of dnJ!'t.
l)i.w.1l;lIn i.. admit Of KM'I"'ltrM:iiull and lary:" \'oIUlllt' IIf I li ~t rihu tic lU , aIKllx"t. its d l'ar.uK."'('
<llKl \ 1111111)1" IIf I li~t ri hl)hol1 art" dt-pt'mlt'nt o n pmh'in hill(lin~ . 1111' IIl1lxM.lUd \tllulIW' uf
I li ~lri lolll iull dl;lIl ~I 'S n ,bti\t,~, httl" ",ith a~t·. IIcM'(."\'(.'r, tl K' all -important IInholllKl ck -ar-
a un' is " "(111("("(1 (Fi~. 15--JoS), prohah~' J't>At"t1 inJ: dilllini slK'tI C'".lp<K.i t~· for 1It'Ilatic ult1;1.IJt)-
li\lIl . ","ic·1IIll")" Ilrim.tril~· hy o \ icb tion .
.\ cll"(·o 'a.ow' ill IIl1lxM UKI nlt1a holi<.· d t'ar.ult"t'in the e k....rI~· (lalit'nl h.u ht"('n tK'mollst rolt('cl
li,r.t11 i nln';l\i ll~ numbr-r o f tl m~ . t'Spt'rialI~' t1KlSt' e hn unan-d prilKil)all>'I ~' m .idatiou. For
t''-I lIIpll'. thl' d t'ar,lll(,,(' ( P""(lc ll ll i nan t ~· nn-tabohc} o f lIntiP:oTiIK' , a nKJtld t't)lIIptJIIIKI Il_ 1
tn a.~\ol"'!> lI,t' ..tat u, tlf o, icL ti\1.' IIwt al. )h...m in tlK' hve-r, tlt"{"'rt' il.<iot'S hy app rn u ul<Ift>I>' 1%
l"M"r >l ~.tr ( Fi ~. I5-H). II cJ'.'1"\1'r, tiM;' n\ '(.' rolll \1lriahilif)' in U1I;kl l tiw d C'il.roUK't' o f I l n l ~ i~
lI\u.llI> LlIl~t" :11I11 a., \\it1l all t i l"~Ti IIt', ~t' ma~' C"dpt u n ' nll l~· a s mall pt ' n't"nt o f tilt' hltal
\Olri.;U K't' ill d l'am.lIl't'. Ctmju!:tidht, l-olpadf)' also dec n -ases hill I~' a It"!>.'\t'r 1'\lI'nt than mt -
Ilatiw l'4lp,lli t~·. 111t'S(, dlan Kt"S llIi1.y 1)(,' a5..'i()(.i a h "(I, in part , \'oilt. Iht , t1 t"(·n.·a.\<.' ill tht.' StJ'.(' o f
tilt' live-r. a.\ a p",pnrtinll nfl:XJtly \\1.'i~h t , from 2.5'1 in the >' )111I).: aclnlt lu I.6 'l ilt 00 ~l'an
uf a~. ,.
Fur \( ,11I1' lI\('t.tlx,liJ'-I't.1 tlnJ~ . no d ';lII~t" ill dt'ardlK't' or hal f·lift' ";t~ he-t'n nh~ 'I'l'( l in
t h., dtl,·rly. Unlil lIIun' data hC"('OIUt, il\'a itahl(" tilt' I Jt~t current I"l't.lk-tion ts that I1It1ilh-
ohsm is I,itllt'r dt '(:n 'il-\("(! or nc" dlaIl RI"(! in tiM' t'1dl'rI ~" Tn he' nil th" n )IJ!iI' I'1Iti\t' ~ille uud

. '1([. 1:5-1. n lt·lwJ(·!lf.. ,,( [1;_ ,...... illI""lI-'l ~ .. ,11,

•
"1<:1'. ("'''' 2u 1 1~1·"". (CC ltll, I.· ,LI.. fn.", I .~ 120
KI"" . lJ nl. Gil.. "'~1" n, A . s..-IIt·"t..·,. s.. •
"'I(I Wi l ~ i " " ,. ( ; H., The· '· fT....1' , M" ~' ..,:xl Ii..., ,b••
........ "" 11M' .1"1.... ;lio '" ..,"I .·I" " I,,"'io lt' of diu~i"' rn
•
•
;n ...Inll 1m", J eli" 1" ' ...'5.h'H7~1'1j. l ij;~: (,..I· • ••
.. "'CII~,,.... nit·.." "'MIr.."" ).... Cn'C'C,I>L.l1 . IlJ., .\ lle·...
\ 1 n.. lI ..n "..I ~.. J s . "'MISh..ttc.... R l : I>i..,.,..u" ,b•.
-e.. 80
•
•
pt .. It,,,,, .1.·..·. "" " .."1•. 1.:1 1". l'h .. r", .. ('C ,I. TI... r . .
ZJ,.31 1 1 ~1 1 2. 11j';'U, (OI- M..·tc... 1. S M.. <:,tc... I I <:..
IIo·" t.:'·r1. II . 1..,1. t' 1 So·ltc·" . F: . ~ I . : AK'" "'KI
K"·,"It·,....L h..I.t.fTr n·,:x,,, i " ,1,_, ...", ph;m"....li.
,..1..... J ( :1", 11....,.,... >1 . J~ I .'i- lij. U,iY, ,. 1--
\t..·U,....·. \ t·.. H..u1'N I. \t o J ' N O . ..,:xl R...... b,u .
\1 n.:n l(' ..fT.'Ci ,M" ....... " " II pI m•••,,, oliflC1k"to of
,11UC'w," e lm . :'id .. S!i .f7lf-4 'l3. lIN).)

o
o 20 40 60 eo 100
Age (yea,,)
 "9
i L'a nm~b approxinmt km. tln- t!t't:lillt' fur IlUhllilll<llllt'talx llic d t'a nlm.'t' \\il t. a~c should h('
t' llI, il!t'r1"t llo 1)(' lilt' Sa 1l11' as that fnr n-nal clea rance, III P" r annum.
:'\1'\1 (umid!"r till' ilwn ';L, i ll~ ratio IIf platt·au ptL\lll<l couce-nt ranou In do<;ill~ r.llt' pt -r
kilol-!:r.tlll. t1c·!t'rllli llt"t1 alit·r ch rome oral t1( l'S in ~ of S(...erel anlil' pilt'pl ie d m ~ with i ll('rt';l<; i n~
;!!!:t' in childn-n ( Fi~. 15-1)), All till'S(' 11m!!:, an- compk-tcly hio;l\";"la"I(, and since

c.......
3
IDo../ kglh

it follows lila' tht, \ \ '(·igh l-t."lITn '1:1:l't ! d l';lr.lIll't' llIust lit" higlll'r in a )l Jtl n~(' r and smalk-r
child . All lh('~· alllit'pilt'ptil' IImgs an' (·\tl"llSh-t 'ly 1I1(·taIXllii".('(1. allt! in 110 11(' studk-d tlc ..-s
pr otein himlin!!: appt'ar to dian!!:!' \ uhs l;Ultililly ht"tw('t'!l th e d ifTe n 'nt age J?:n mps. G n-ater
I.t'll;ltie Illd aho li(o ("I Il<ldt~ ' Ill'r uuit hnd y Wt'iv;ht is tln-refon- im plim t("<! in tilt' YOllllj.,'C'r
g;m llp .
Finalh' . tln-n - is <;I11 1ll' l'\itll 'Il('(' t ha t hor mouul statu s ill wnmun muv al<;ll inl1l1t'lIl,(', or
1)(· a l'tlll ;pOlll' llt o f, d l<lllg" S ill t1n1g killl'lil'S with ag;(·. Fi~lrt· 15- 1lI sht;'w'S tilt' rd at ioll slJip
1)( ' 1\ \'1 "1' 11 p la.'im <l ck-arance o f <llft·u ta ni!. ;\ po tt' nt optoid. and age . A SiWlifk a llt t1t·(;n ·a."t· in

Young Elderly tilt. I S-It, n., 11I,1."",,1(-!o·" r..r.. '(· " f ,Ii"", ,,,m
(13-37years) (61-84 years) ""'iI..
i. ..,,1,.......1in " IeIc'rI:-' 'I. ,'O,",,,,,..,,1"'i lh ~"" ")(

'"E 8070
~
~
•
•
;O[I Il1t~. !>iIT.....·,..'(...a1"" ,...ht I..>fv,.'(·" m........ ar.. t f...
n", It.. , n,.. .."h..H I " nl... ,"' I ......ar...... • i. II..· pri.
mar)' .. ·a."m for il pn ..... ~ ..1half.Iif,· " f .1""0"1"''''
E ·,,"LI1.
ill II", •·... It·rIy IlooI.h.·"I. ~ 1I ...Ir..",,'(, fn'''' (;,....
60 •• n J.... Ikoll. \ t o .. 1I.m"..tz, J.S.• ill,,1 sl......·r. IU. :
~
U
c
• I>i_"..m ,1i"!.. ..,,;l it.., ' ..-i......"i f1llflh C lin l'ha n n" .
50 11."..
'"
~
.e
<..> 40
• ••
•
« 01. n,.., ., 2,:30 1~,) I Z. 1!:H1.
Ini"it", " f C .\". M".I"...l
"1,,..,,1 "'i l h I"'"

u
c •
0
~
30
----:r- iY
••
D
c
•• •• •
:::> 10 b ••
• -1L
E
~
~
10 ,=. ••
~

.~ Male Female Male Female

c 0

flit. I ~. n,.. d'·llr..'''~ of .."Ii~-n, ..·. ..n .....

80 Io·M;".·~' n,,-ial...Iilt...1,Im~ ......1i.".. 1..,1 "'llf'JCin.
aiI:-' wilh II!:, ' ",l""l 010..10...1in .107 I"-,"h l,,. ."I,jt'l-i"
.....1, "f ",1."0 "",,'("i\.... 1 1 II: ;""l il~1iIlt· 1.\'. ,,~. "" •
.." ",t. f,w lillie- tI( tI... ' "IlriJJlihl)' in d "OIr.Ulotl·
"'illli" ,Iii. p"p"l..ti .",. (A,la pl ,.. 1f,. >ln \' ,'. 1011.
R.t:., ~ ,,"b, ,\ .11 .• Tnlli". J-Il., C"I,,·n. B II..
s tu :!.. S ,W.. aI..1 A,..ln.. . R.: A nli!'~Ti ' ..· n,,-i.J ..
"Ii.", in "'..." I " R.......... " f ~. llk"'.. ~ . r .Jf.-i.... .
ant) on."'i"ll:, eli". 11",nna<l.l , n ....... 11l':42>-
o 4.12. UI':"S .)

o 10 40 60 80 100
Age (years)
, .. AGf: A!'IO WE IGHT CHAP1EI! 15

Jo"I.It. I ~ I O. 1'6.. ",,, ....·ar..,I(~· of 35

..Jf,·nl;t"il ,10."," ';0.,,"\ will, "1:1', 11..,
,1o."l'Tt'''''. ' i. ",,,n' l.n" '''''' I<~''l1 in f,·,
30 •
• ••
",..it'S k" I"....1cin-J.-sl ,1,;<" in 110;01...
(" " '11 hLot'" cin,I. ..). TI,,' ,10.....•....• in
(.." oak... "l;I~· I n ·L.I...1In l".-i, 1'....
. " 1....I " M.. "'1 "~ . l;at" • . I fU..J""""
25 • •
~ 20
("' Mil (;,,,t.o,,,,,", I. E .. ;uKI 110·,,, "1 , . 0 o
~ 0 o
1-1':.: ~"'I" '1"'''''': l1.... n".... "':-. ..."' .

...., .
it., ;tn,1 r/...n ll * "a,in.1it .". E,p. ( ;'·r·
~
u 0
•,,11,,1..2!i:4.1 '-H-1. l~ Will> I,,"r·
c
e 15 • • it> -,
~
mj" jo," (}n~ 'ldl '''' 'd rmm ~
~ 0
IA'm"IC'''o, 111\1.• Ii" n ,,_ .-\ <;,1- ,
IIo·nni. , I'.J-. (;!.ltLllt'S, \U' I' .lt .
.....1 Bl..;lI. J.C:.: Ino...·'....· ur ~,. ,>I,
" 10 0
~

tl..• I'llMIn.....olin... iol., .J ;olf'''' '''01il,

G,-".),-, dilT.·....K 't'. eli". 11...n n" . 5
...>I<it".... l fl,-l I6-l 22, 191111,) •
0
0 20 40 60 80
Agein Years

<:!1·;lr.III('(· occurs ill " 1mW Il h ut lI o l ill nu-n. 11 1(' dt'("n ';l'i(' in women lIlay l it, rdakt l to Illt'ir
1II1·noll;.lm,a l sial us . Furt her \~~ Jrk is 1I1"l'111"11Io t!e1e n nillt· l ilt' inll.l('lIn· of ho rlll lllJ('s ami
otlwr f'lC.1l1rs O il tln- !!:1'lwm l h ·m lt·lJl·y fur mdahlllislll to <!t'1'n·; L'il.' wit h a!-tp.

MAINTENANCE DOSE THERAPY

Adult

For musl 1l;.ltit ·uls, then- is g:t'lIt'mll)" 1111 m-edto adjusl t111s a!-tt· fo r ag:' ·' A 11(" '1l lllay ,·, isl
when Ilu- d ifTt·n·!H.,\· helw("l'n t hl' indlviduul a nd tilt' l)lli(:aI path-ut t·\(~ '1"l L\ 211 yt' ars, fur
('x,;lmpIl' , in )lIu n~ ad ults k-ss than 3.5 )'t'a rs o f a!-tl' a nd ill Ihost' im!i\itlllals hl ') l md i5 )'l'a rs
o f a~l', wln-n tIlt' I)pil'lll p,llit'lIl is 5.5 )'t'ars o ld .
(:.c·mor.dly, {\(lSitlol;P is lIut dm lllol;'''l! ha'il.'11 em ~t· lld.' r . Th.· "us ual" ad ult d u'il.° is d t' ri\l"lI
from dinil'ill silld it's in a lIlist"ll popula tielll. CClIl.sicI" nlt illu of adj ll\ti n~ for ~t' Ilt It'f IM'l'tII1lI' \
ilion' important ;lllhl' ext re mes, i.e., fu r ddt·rly wumen and )'l ll lll~ 1111'11 . As \I.(I\~l1 in T ,thlt,
15-.1 . l'f('atillilJ(' clearances of mall' a lit! ft' umll' .').')-) l 'llr-o ltl p,ll i" lIlS a n ' fair l)" 1'1 0\1' , bill a
9().\l'a r-old woman a nd a 20·\l'ar·old ma n tlilT" r 11\' threefold in tl u-ir t'n'atini m' d t·'lflllll 't'S.
A 2<).)'l'a r-nld woman , !I0\ \·;...-e r, tlifft,rs nnly t\~~.. fold Imm t hill of a ~j(I-YI'ilro(,ltl mnn.
\\'t'i~ht is aIS() a fat10 r he n ', ,LX lilt' awr;I!!:I' 20-yl"tfo()ltl man may Ill' do\( ' 10 7n k~ in \\l'ij.,(hl,
wt.iIt, 111I' a\·,' nlJ.:t· 9().y to aro( lld wnuum is p mhahly on ly 6(1 kJ.: in si;r.('. TI l(' di ITt,ft'n n ' lIlay

, ..... 15-3. • • pecte4 e-.tI.l_ a ...... M.I• • n '••• 1. 70.kl Ad.lts

.. "..... ........ A. . . .

20 120 102
55 85 n
Q() 50 43
CHAPIH 15 AGE ANO Vv'EIGHI 2.,
111t'1l Ill,' ('\('11 g:n 'ilIN than llo!t'(1 in Tab lt· I.'}-.·l Thus. add(>(! atte ntion lIlig:hl h(' wn'n 10
n "t!Ilt.'ing: Illaillh 'mlll{"t· do~aw' in t·ldt·rly \\UIIlt' 1l and Increasing dosagt' in )'Hung 11\('11 .
Dm ag;t' ill olll,'M' and t'lIIild ah "t1 patients must also hI' adjusted to ma int ain 11ll' sanu -
an'raw' IInlll, llInti ph\lIIil o uuvru mnon. Usua lly. d nJg:di min at ion (t'.g:.• re na l clearance) is
lIot illl,,"t',l"It>(IIII,'t'iIllM' o f add{'(! ad i po~>(" tissue. All exception may Ix' in t1 n lg:s \Imlt'fg:Hing:
g:llI{'n runid atioll, ill whidl l'il-....· rln-re is an inen·il-....• wi th nlx·sit)'. People wi th lar-,;:t·r body
lrunu-s (Il('ig:l.t and luuld} prohahly ha\'t' h i~lt'r clearan ces. T o a first apprm illliitinn (h,l"'t'(!
0 11 IlI'ig:ht alo!lt·) ~tld l illl·Wa.....·S ran Ill,' t's tilllitlt>(1from Idnll lJ( /(ly It.'dJ!,ld . kk-ul htll,ly wdg:ht
in kilng:rams (fr om lift, insurance actuarial stud it'S) ca n he eslimalt'tl From the following:
r{ · b tion~hi ps \\i th I Il,M I~' Ilt'ig:ht.

Ideol body weight lmenl = 50 ... 0.9 1 (height in em - 1521

Ideal body weight lwomenl = 45 + 0.9 1 lheighl in em - 1521

T Ilt' 1'\ 1)(>('11'(1d t·:lr.lIlt'(· of t-n-atiniue can t111'n lit' calculated Irom Eqs . I and 2 for ad ults.
Fo r t' IlMda h'(l pal it'nts, estnnat ton of dosa!!:t· n 'fl" in 'Illt'UISis ev t-n mo re compk-x. Dos -
011-:. ' n-quin-nu-ut s dqx'nd ou lilt' t'ill\\(' of III(' emaciation. ~t al nnll ri s h nlt'n t am l va rious
t1iWil<;t· stun-s lIlay alTt -c·1 n-nal and Ilt'pillic elnulnation. In most of slld l palit'nts, howr-vr-r,
dnsag:l' rt 'l l lli n 'Il\( 'IlI ~ an ' uot (,(IIllIllt'nSl.ratt'ly reduo-d with IMMI)' \\·t'i~h t . Jdt 'aII MII,!y Wt'ig:h t
may tln-n Ill,' a Ix,ltt'r app roximat ion u f unbound ch-a runce andmaiun-nancc d( r.o;in~ rate.
C lt'a dy , umn- dd ini li\l' Iufonuatkm is 1ll'('tlt'(l for both nlx ·S(· and emuciated palit·n ts.

Neonate
TIlt' lark of maturation o f renal am! he palic funct ton m ccssltates thai tilt' ran- of udnuu-
i\l raliu ll of d Olf.:s to IMlth neonates an d yu ung: infants he Tl'(IUl'l,(1. cwn 0 11 iI hody wt'i~hl
l"lSis, if to\(itil)" i ~ to Ix' avoided. Unfol1l1nal d y, dJan ~.'S occur so rapidly ill tlu-se t'arl~'
sta1-:t's of lift· Ihal il is imfMM iblt· to pn'tlid \\i th l'(mfidelll'(-' clearance and hence tilt'
n - qnt red dOsagl' rt,,.,rinlt'n. Cauti on mus t dt'arly Ix' exerci sed in adm i ll i sh' ri ll~ drugs In this
1"'lit'1I1 IXlpublion . Ut'sitlt's l'a n ·fully not ing: n'spon~. II1nllil(l rin ~ o f tilt' p lasm a ('(II\('('U-
trutiou of dnlg5 with a narrow therapeutic lndex should 1)(· helpful.
In passi ug. 1I0It'\\ '0I1hy ln-n- is the intidt'nlal t'xp'lSun ' of h-tus and slll"kling; Infant 10
d Olg:\ . For Iho'O(' d Olg:s Ihat ( ".1Il 1l:I-SS till' pla(,(,llla . Ihe unbound plalt"lll concentr ation in
tlu' fl"lus is likt'ly to eq ua l that in ti lt' p n 'g:lIa nt mo llll' r in ch rome therapy. W Ht. dimi nati n.l!:
(':ll);lt'i~' g{'Il('m ll)' l)fll,lfly t1t·\l.,lolx'(l. Ihe fet us ac ts for tlu- most 1l:111 as an addilional - lisslle-
of t1istrihulion . \\i th half-life in tln- fet us IX'ing: the same as th ai ill till' mot her. :\ drastic
d .'llI ~t· {M.'('1Ir'S, hm\ 't"\'('r, on t1t·li\l' ry . Dt·pri\l.'(! of alU'SS to tilt' fully dt,,\·(,lolx '(! dimi naling:
orga ns of lilt' motllt'r, {·lim inaliull o f dOl!!: frolll Ihe Ilt,\\'!)fJnl dlild m n Ix' w ry slow indt'('(1.
11It, slll,k!ing infan l is t'Xllt ISl'(1 to th ost· d m g.s takl:"n hy th e IIml llt'f. As sUl·kling: Ol1:lIr'S
rl'~lIla rly. uf { 'U II{'f ' m art ' .'\ l 'nh ..I pialellll. 111t' ri.de' an' ~rt>ah'st for d nl ~s . pal1il'lIlarly
Hpophilil' OUI'S. thai l'(IT1('('ntmll' ill hn "I-\t milk. thai an ' poorly d ('aft'(l by tilt' infali t. illill
that ha\"(' <l nam l\\' tht'm(>t'litit- index.

111t' ('vit!{'Il('(' in Fig:s. lS.....'3 and 15-1 1 SII~I'S tS IlJilt a mainlt'llanl'(' R~ n1t'n . m lclllalt'( l hy
(,(lm't1illg: tilt' ad ull dOSilge for Ixxly \\'('i~h l , m m ld pn )\'{'inad('(paale for childn'll . Mpt'tially
for tilt' wry Yll1l1lg:. IXJSiI!?:t' R'(llIin ·nlt'llts. l'ilrtlia<.· oUlp ut, Ilt'patic and n 'nal h!{)fxl flow,
ant! .~ IOl llt· m 1a r riltmtioll mil' in d lild n'u and in you n~ ad ults of \\i ddy dilTl'ri ll ~ si7.t·s haw
Ix't'n found 10 t'(,m·tatl' hd lt'r \\i th IJ( /(Iy .\ ,(' 1"(I ("t' (1 " (/ th an IXlIl)"wl·i ~h t. Bt't'illlst· d t·ard.Il('(·
rl·b lt·s t1llSill.l!: mi l' 10 plall'a u pJ.tsma (,(IIlt'('lItmticlIl am ! lx't~AUst· w llal dt'a nlll('(' is pmlx ,r-
,., C HAf'T £ ~ IS

Carbamazepine Valproic Acid

0.8 3

2.5
0.6
2
0.4 1.5

1
0.2
0.5
o o
6-12 13-1 5 1&-48 2-7 8-1 1 12-15 16-20

Ethosuximide Phenobarbital
10

2.5 7.5
2
5

2.5
0.5

o o
2-7 6-11 12-1 51 6-20 <2 2-7 8-11 12-15 >15

Age Group (years)

nil:. 1.5--1 1. n M' ""'It.. " r l;<>m" d rul( <~ ""~", I h,,... " f .......no! "''' 11<,,,1., '11' -,In ,1t' "' " ..•.., ,, ,,.. 1",fl" r d, n.uic..
fI..oJ ""..Iit·..li< .. in . ....ilo.l An !1ll....,... ..J d ",}('I" r"" ~llr ~.. m ,,( lu ly "" "10:1'1 1'1041" . tI ..• 10"........li" "I"
(...........,lr..lk.., In .W~ .10: J-" 1dlo w ol'" in ,",' )' MlI1",...t d ,;I.In-n. IA,Lapl...1 Imm II..• .1..1.. ..f ~l "rwlli . ".I A:
. ."Ii.,.... l"k' .Imt'_I" Urut, l>i' P'''';li'''' Dllring 1>' ''' '\''111111'111, ~:'I1" ..I I~ 1' 1. \I" ",,·IIi, s."", '·<>r~ . SI"'(1n""
rt ,hlit-..t ic" ... 11:1';"';', CI...., II . 1'1' J I I-.1hlI.)

tloual to ~IOI llt'n11ltr fil tration run - (St"t.· Fi~. 13-11 l. the <:hoi<,-' uf sunat'l' an-a owr w(' i ~h l
a.~ tilt.' IlH.'thud o f (~.tk·lI lal i ll~ maiutenancetlu-ra py 1Ia.\ SOliI(' j ustificat ioll. Takill ~ II ,5 5'yl'ar·
old as the typkal patient n"(-'l 'i\iIlR till' dm ~. the dt"lImllt'l' expc.'l1t'(! for a 7()-k ~, 20->t'ar -
olt! is 1.4 tunes that for till' reference p atient (Ell_2 ). Al'l:()nlin~ to this concept ,I d lild's
maintenance dOS;I~t' is calculated [mm the fonullla :

s' rnxe cm2

rec 01<h;ld]
Child' ~ • 14. 1 ) . Typical adult
maintenance dosoge '
[ 1.8 m2 maintenance dosoge
4

when- US 111 2 L\ tilt' surface an-a of an a\/t'm~t" 7()-k~ ad ult. 111l' surfan ' an 'a of a clnhl can
CHAPTH 1.5 243

Ill,' ddc'Tlllitwd [n uu its hClI,ly \\"(' i ~ll tusi ll~ the OI)S('I"\Ollio ll th at surface urea is p rop ort ional
10 I M lC. I~' \\"( 'i ~ht til tilt' II., IMI\\"('r ( wt'i ~h t n.). Us ill~ this Llst n-lanonslnp. Eft. .. may ht·
n-wri ttr-u as

W eight of Child] 0 7
Child's _ 14 . (kgl • Typical cdclt
ma intenance dosage · [ 70 kg ma intena nce dosage
5

To illustra!c' till' lI SC' of tilt, n-lutionship t'.\ p rt'sst'tl ill Eq. .s. (:onsidt' r ti lt' example of tilt'
anti hiolil' t o h ra l1l~ 'C.·i ll : tlu- usual adult tnaintt-nnmx- dCN' is 3IIlWkv: clail)' P\'(' IJ in th ree
d i\iclc'tl clost's. QlIt'stio l1: \\1m! is th e daily tC)hm lll~·'C.'i 1l dosa v;c.' 1iC't'tlt'tl in a 15-kv: d lilcl?
:\l1s\\"('r: 1lI0 1Il~ c1aik Th is ,lIls" "t'r 1~..11\ I...., c's timalt'tl Irom the mtio of surface areas Ies ti-
male'tl fWIIl IM~ly w"t:i~ll t ) lISill~ E/). 5.

15 )0 7
Child's dcsoqe of lobromycin ., 1..4 x ( 70 . 70 kg x 3 mg/kg

• 100 mg/ doy

:\ol k t· that the- wt'i J.tl l l - llon ll a1i "~'t 1 dail)' c1c}S(' of tol mull)'d n ill till' child . 6., mW1v:. is
nun-h luglu-r than tltat in tilt' aclult, TlIC' n-ason is tha t cleanuux- is proportionaltu sm fan '
un-a ami sur fuo- an-u pt·r l.i lcl)?;r.II11 ;lIcn'fl.\C' \ clisp m pu rtion ate'l)' with dC'('n'asill~ \\'('iV;ht.
Tln- nc't'C 1 for a hiv;llt' r Tllainlc'Il,\Il('(' d(}S(· pC'r kilc'1--rr.un lxx ly w"t'iv;llt. ti lt' smalh-r an d hr-nce
usuall y tlu- )ll ll1lV;t'r the- c·h ilcl, is sc't'n in FiV;. 15--3 for chtldn-n hd w'C."t'n 6 mouths and 12
yc'ars. :'1:011 ' tilt' l11111p lt' IIlC'utal'7-' c1t'1:rt':lSt' in tilt' llalf· lift' wtth dC'('rl':Lsin ~ size.' alltl a~(' . Thus.
no t oul y Illay a l -~'('ar-ol cl ehihl n-quin- a I:lrv;t' r matnn-nance c11}S(' pc'r kilc'h'T:un I x x l~· wt'i~hl
than an adult. hut ht "t.~IllSt, of a shnrtN hal f-lif(" till' d rug lIlay also need to hc' p\l'n mon-
frc"l l' lc'utly. T his is c'slx"t.' ially so if the dOl!?: h ,l~ a low therapeutic index am llafj?;(· 1I11l1uatitJlls
am llllCl lh c' :1\·t' r.i~C' plateau ('()IJ('('lJ!r.ifinn an- tn ht, :l\uidt"tl.

The Elder
The d elt·r1y ('(ms!illl lC' an i ll (' rt·:~,iliJ.tI~· gn-un-r p mpn rtinn nf th e total pnpulati uu .l1lt')' ,JSt)
('(lIiSUIllt' mort ' pn-scription dm).,~ I....-r cupitu tha n do pt."llplt' af any orlu-r a~{' . As a hm;l(!
V;t'Ilt'r.cl i "~llinu . c1C1S:I~t· sllCllIlcl llI,' n-duced ill dclc'rly pa tk -ut s. rt'f1t"t1 inv; the ~t'Il('r.tl c1t"t.·linc'
ill Ixxly l um-tion witll a~c' ( F i~. I,H). A reduction in dOs.;I~C' is 1Il"t'tlc'C l pa rtie'u lar ly in tilt'
weuk am i in firm c ·lclc 'rl~' !l:ltit·lIl. Such a pali t'II1 oftc'n su!Tc'rs [nun a -vr-rul dist,it-St's. n-celves
multiple c1rtl~ lIlt' r.IP)'. ,mcl h ,~s Ixxly Functions tha t ha\l' dt'(,rt',LSt"t1sharply with acl\":Ull'i n ~
vears .
( :('rt ainl y. tllc' IIlarkt'tl mlc l pn ~rt's si\'l' dc'C,rt"lS(' in n -nul funct ion illlplit·s tha i tln- c lns:t~t'
ft'h';nwHs of clrtll:S that an- p n 'tlo millan tly ex("rt,tc"tlllll ("han~t'Cl should I...., ft,lul'C't1 in tilt'
t·ldt'rly populalio n. For c'x:lIllplt', an .';()-)t'a r-old pa lit'nt n-quln-s. on an 'mv;e , cml)· ,()Ik of
thr- 1I' ual ad ult cln,<:ll-:c' C'\prc'sst'Cl rt'lat i\l' to ,() kg of Ixx!y weiv;ht. The c1c}S(' n' luin>tlma)'
Ill,' C"'PH It,SS I x"t~ lll st' tilt' elclc'r1y p atient is, un a\l'ra~c' , l i ~h IN , A dt'p rt's.St'C 1 dc ·ar.cn('('
\\i thnu! clust· ,uljm lnll'll l pmhahl y t'xp lains, in Il:Irt, tilt' in('n ':l'it"t! fn"tlut'lIl'y and c1t-gn 't· o f
adw rst' clm~ t'!T("t.·!s oltl'lI no!c"t! in ddN ly pat it'llts.

General Equation
Tel rd um 10 tile' ('\am plc' of ('n'al illim ' autl similarly hanellc"tl c1mv;s, fmlll I )l'ar to 2U)t ':trs
of a~c ', tllC' rc·la!innship Ix'lwc"t'1l n 'nal dt':U,\lll't' allC l ll~t· is c"pn'ssc"tl in E(l. 5 : IM')'tlllcl211
 CHAPTE R 15

)l.·al'li, this rl'1alionslJip is expn's'>t"tl in Eels. 1 aml.'i Bt'<wN'I!lI' vulur- of I ·Ul-A ~t· (hlll~t ·s
Iilt lt· IM.·lwt"t·1I I antl2n ) t',11'li of a~t·. these - t~ lllati(Jll s (..Ill 1M.' combim-d to ¢\l' tilt' ~t' l l('m l
t"tl" atiu n:

Ma intena nce [140 - Age (yea rs)] . [We ight Ikglf)7 U5l.~1 a dult
1660 . ma intena nce 6
do""", dosage
thai !:M.·nnih IIII' nJ1l~h appru\illlalioll of ,LlIIaill!t"Il;lIIU ' tlo"L~t · Il ll' .1 1l.tli' ·lLl lIf all)' ;I!-:I',
ex cept tilt' Infant amll ht· neouate-, wln-u mainlell;ln et· of tilt' Sitll W an 'm!-:t' unlM. lu llIl plah';111
conceutration i.s needed. :"0 chsn nction in ~(' IlI IN n 'fjllin 'lIlt'lIls is madt,. Tlu- \, IIUt, (If lilt'
tlt 'numinatu r, )661:1, in Ell. 6 is lilt' pmtlud uf lilt' a~t'-rt'lah"tl ",'(·Iim' ill n-nul ck -arance
for a ,'j.S.yt·ar-old: SoS ( l oin - ,'j.S) an d iti )';' or IU.5.
Fi ~m' 15-12 suuunanzes tl.t· dOSit~I' dtilll~l'S with a~t· hl')lJlld ) )l 'ar n-qutred tu main-
lain tilt' Sim I(' a\"(·r'.t~t· nnl M.lIl11d (1)lt('t'lIl mlioll. Tln- nuunn-uaucc dosin~ run- Increases ul-
most lilwarly between I and 12 )1.·al'li of agp . 111t'S(, pn"tlit1ions a n - bused on dmll ~I 's in
hotly surfao- an-a .... tth a~I' . which art ' I'slimah "tl fnull a \, ·r.t!-:t· w, ·i~ll t S , alltll 11l' ~t'" Nal
correlation (Ib~'n.·t'l IIM. ,"\"("t·1l dt·ar,II1I"t· al)(l l)(M.I) slIrfaet · an-a in childre-n. I\I"(';IIIM' clear-
alll't' tncn-ases up ttl 20 ) t'i1rs (If a~l' alld tllt' ll dt'(·lil\t·s tln-reafter , then- ;Irt· pairs of a~t'
values for whit-Ii tilt' satm- rate of adllli llislnllion is n-qui n-d. Fur examph-, U ll a\'(·r.tj,(t', a
4 '~1·ar.ultl chik l (16 k~) n'i l' li rl'~ til(' S;t lll!' rate tlf drug ..dmillisl ntl itJIl a.~ a UO')l ·.lr-tllti
IWJ'S(m (60 k~)_ Similarly, iI 12-yt'ar-ul d d lild (:39 k~ ) rt'illli rt '~ lilt' SaJllI ' daily doS(' us tln-
n -fen-nce iO-k~ lliltit'ul. naull' I)', tilt' usual majnn-nam-e <lost· .
11U'~· l'fpmtions cau st'I'" 10 fad lita h' and imp r ove- 1111' initi al t'~l i ll1 a lt ' uf tilt' dusa~I'
n";lIlt·u Ilt't"tlt"tl for a lliltit'n l of any a~I ' 1M.·)1I1111 1 ), ·ar . In ~' · l1I· ral. a corn-ct ion ill lilt'

A B
1.4
~
;;
~
;;
'" 0
~
1.2
a: ':g
0 0
~

':g ~ 1.0
0 ~
~

~
~
~
~ 0.8
~

.i!!. :i''5"
'" -a ~
~
=>
0.6

0.4
12 4 6 8 10 12 14 16 18 0 10 20 30 40 50 60 70 80 90
Age (years)

.·IK_ IS-1 2. \"~ri,dio,," ill II,,· mai ,,"''''''''~· ,I" , ml: rat.. ....pn.....~ I .., a fr...1"M' ,,r II,,· m.•iIl1 ,·, ~n " . · ,~"i n~ rdl, · in
~ ~"'\1'Ar-4lk l Jilluh (.Iut" "! Il·rtir.-..l lil,,'1..' ~ flllll1io.N. nf ~ ' . (nnll 1 W.tl" 1,, !J1\I'm . -' uti' liN' ..InN'" IUN';a)"
t."'
iI K"" ~"" in "..unk""'K~· ,~ "i"l: 1'.. 11' " i ll...",· fm", I ,,, 12 ~1'''''' l. ;I,' ·.1.II'~ l l'ri,,''''ri~· " i ll, ..n ;110...· ;1,...• in 1..1:-
U/~', .. ,,,l lh.. ..rn,,'" lin..... ' ~"t1i".· 1.""" '11 .10 ..,.. I \JU ~";'I' au. a' ;;oI.. II' ri' n..ri l~· ",11, ,lillli "hl,, ~ 1 "n,:;o"
(" ••1io N' ",11, . t.",.;nj( " ' ;0... . .",1.., 'IO N" II..., tl. · ,~"i"l: It ....';o f", 1io." ..f "1:" ,IiIT,-r 10·.. I. ' "••n· II"", ..I• • ,t
2.5,f,>Ic1 {nolll 110.· "" ...1~ I"lt , ~ "i lll: r..I<' . \ ·.. 1,.... ..n' .".1 ,1..1<.1" ,i " l: ":'1 f> ..,,,I Ih,' "'''I:I,;.f"•.~...· n·I<.IIio",.I" I"
gi\1'11 in '-;11. 1 ~2.
CHAPrE ~ 15 AGE AND 'M:lGH1 2"

IISII,II adult dosa~l' is \mrtllwhile wln-n adm inistt'ri ng d r ugs to the n-ry}UlI lIg, to t he (-luld.
alld 10 rlu- agel!. :\ correct ion is also worthwhile m cmeciated and ohe S(' patie nts.
:\ fina l no ll' is ill onb-r \\;111 reg ard 10 changes in phrsi{)l~c pa r.Ulll't ers co ncermng
a~l' . Phys iolo¢ e parameters such us cardiac Olltp ut , hepatic blood blow, renal blood How.
a lld ~lo rne: ' OI l a r filtmti(lIl mi t' c:!e:"<.'rt"Lst.' with a~e ( FiR, 15-4 ). 11\(' values mos t \\idely quot ed,
e: ' .~. , ~lnl1ll' OIlar filtmlillll rate = 120 mlJmin, and hepati c blood How = 1.3.'5 L'nun. art'
t~Vieill fo r ~u" ng Iwahh)" ad ults, uot 1111' typical patien t wh o may If{' 5.'i o r 70 )'l'ars of aRt'.
\\1 Wllt,\'l'f compari sons a rt' made in l)l)il~d.! pa ti('lIls lilt,)" should 1)(' d une c..m 'fully. For
t'XiUllplt' , a n Ilt'pal il' bloe:xl clea rance o f 0.7 I1min fo r a drug may indicate hiWI Ilt'pal ic
extraction in a 70-year-old pancut po pulatio n ill whom the hepatic hloe:xl flow lIIay If{' 0.8
L'mtn inslc:'ad (If 1.3.'> I1min . Simil arly, a renal d e a mnt1.1 fu of 70 mllmin 1I1i1) ' 1)(, e:'li llitl 10
til(' GFH of an t'ldt 'r1y patien t po pulation .

STUDY PROBllMS

IAnswers 10 Study Problems ore in Appendix 11.1

I. Comment o n wl l('t1lt'r pach o f th e fo llC:J\\i ng statements is true or false. Qu,t1if)' )uur

answer whe n )u " tbtnk it appropriate.
u. O ral hio:l\"ililahi lit)· increases \\i lh i nl'n'a.~i llg Ixxly \\"t' ight.
h. \'ul lln l(' of c:Iistri lmtio n va ries in di rt"<.1 p roportion 10 hod)' wt'i~h l ,
e. In cluldn-n. dt'<lf' U1t1.'/ hoe:ly \lo'l'ig ht dec reases with incrt'a.~in g age.
d. Hl'~unc:l 20 yt'a rs o f agt', renal function dec reases h)' app ro:\i lllatt'l~' 0 .311 P" )"t'ar.
e-. The:' half-lifl' of a d m g is sho rtes t in ) u ung ad ults.
2, Shnous " I al. sl uc:lie:'tl til(' phar macokinet ics of lilt, antihistamine dipllt'nhye:lmminc:' in
cluldn-u am i holh ~l ll lll~ a lld dde:' rly ad ults after i.v. udnnulstmtiou. Their find inw; an'
hSh'll ill T ahl e 15-4 .

T.bl. 1 5-4. Aw._•• D. . . ._phl• • 1HII ............IcI.etI. IkIta

,_ Dlph••h.,... ,..r..-

~ lyeoJJ 8Q 32 6Q
We<g'" {kgl 32 70 71
Cleorooce IVII'1 Q3 Q8 50
Volume 01 d '~II 'bJc: lO'l III 6QO 1223 Q66
~~ood"""'~, ~ J W<Nso 1" ._lJ, Il..e.~C atd!-ono,fE ' ~ Pto••,..<.,1"..... o atd~
.. odooIy~ """'1/_ <rd,~"" ... J co"
~ 30665-671 .1 990

a. Arc:' t he:' dilTI·rt'n l't's in volume of d istri butioll ac ross th e aRt' ~n lU ps Ihc:lS(' t'xpt'(1t'tl ?
h. Art' lilt' c:litT('n' un,'s ill clearance acros s lilt, age gro u ps those t'xpt"<.1ec:..l?
3. 111e:' us ua l adult dosa g(, regr rm-n of a drug is 20 mg once a day, \\11al darly dose would
)l JU n-conum-nd fnr a 3-) l 'a r-n ld . IO-kg dl ild ?
~ , Cakll la!t, a mai n!t'uam:t' c:Ios.agt' rt'Wlllell of geutan ud n 10 treat a seven- infection
t',IIIS1'l1by r.~ I·"dOlllmw.~ tl/ ' m gillOsa wi th tln- o bje:"<.1in· of ma.inta.ining tile:' salli e a\1.'mg('
coucent rution in :
a . A cluld. OI1-:t' ~ ~'t'a rs , \wight 15 kg, wit h normal renal Iuncttou fo r its age.
246 AGE f#) W'EIGHT O W TE 91 5

20 •
•• •• •
•
15 • • • •
E • •
;;
• • •
.' .... •
.e.,.. .. .,..
~
c
• • • •
E 10
'" • . '1-· •
E-
~
u
0
e
•
• •
• ·• .-. .:• •••
•••••
•
..,
~
5 • •
'-'
'i •••
•
o
-0 9 days 5 months 2 years 6.5 years 16 years 33 years 61years 104 years
Age
t'I". 1.5- 13. C"·Mr..,.. ~· ..( ('<·(trY,I..,.,,' III.,, 1.;''('(1 frulll I tl..~ tll !:t2 ~" ;lO ..r ~'. t:.-h .~ tll l • .1 "1m ...·Ilt- .. \ ;01",-
iU;ln illoli"iol".J . S uI<' tlo.- ,,-.do:. ru, "" hio:b i!. 4,'" r..; ....I,.. thr p""" ' r ,,( UZ,> ( :o.~." rll. ( ",.. 1. ;1\0,11 (rulll " ~ t' " '.
W_ I ~ ;",,1St,n-l<..1. " ., :\~;&'''' ''-iat I .-h.ut~-S i ll n ·ftri;lu....· I" ';tm ' tr........., C:Ii" . 11"," " ...ol.;,.. 1 .• 11,7n -M ,
I!M 1I.1 1n.1"....1wilh 1,,·nniI.UOIII Ur .\ DIS P........... ".trk . la J't:-' U mit 1.)

h . All ebk-rly f"ul<ile p ath-ut. il~(' S'j yt'ars, Wt'i ~h l 6.1 l/-t. with nor ma] n-nnl flllldiull
for her a~I· .
c. :\ p rl 'mah ln' infant of ("Il11('t 'p t icJllal "~I' 3fi wl't,h.
TIU' adult dust· of ~t'll ta lll id n 1lS1Ially 1"(,,(,(ll1llllt'fl(lt'l:! (fur a I)pi(;al s,'},p·ar.oltl, 70-k~
palit-nl ) is I mWk~ adm inistl' n '(l i n l ra m "<;('lI la fl~' I"\l ·r;.' S hr. This antihioli (' is allllllSl
('o ll1 p le! l'Iy renally (·x(·n· h'l.IIlIl t'han.gI,(1.
.'), Fi~ m' 15-1 3 Sh' IW~ tln- va r iatkm in dl'ar,lll('(' ('ll'r ~ l lIan.· uu-te-r (u lf ) Il f I MII I~' sUffa('('
an-a of 1111.' ('('ph;J ' lSpo n u alllihintk' ('t·ft ria.\l JIII· ill ind i\i dll als [rum ) Illy tu 92 }l.'ars
of ilJ.:I'. He ual ;lIlt! hiliary excn-uou an' a bout ('(lua Uy ilJ\-ulw '(l in tlu- t<Jimillal ion of Ihi s
dm" in normal ad ults .
a. Dist11SS bri('lI~' Iht' dlilll ~I'S Obst'f\'(,(1.
h . (-;iw II Ihal IIH dl;lIlKI'ill dm ~ di slrihutinn with a~e ' is nhSl'fY(,(1.SlIj'll'rimpnS(' on IIIl'
ri ~urt' 11.(' ('xI'll'('I('(1 t n-m] of ha lf-lift' \\ith a~l' .
c. \\ 11at an- tilt" ~t' l w ral implicanous o f tilt' filll l ill~ for til(" admillhlmlioll o f ceft riux-
Hlil'?
6. Blydwrt l.'I al. stud it'(l til(" phan llill.,(lkilld i('SHf the- ('"d l d ll lll illlla j,(ollht ft·llld ip illto, IlSl"(1
in ti ll' lIIilllil"l'lIwnl of h)l'll'I1t'n siHII, in a ""IIIP of 14f) slIbjt '(·ts . All suhjt '('Is n'('('iw"((
I·it hl ·f 5 or 10 1II ~ om lly twi ce- Ib ily f OT fi 10 30 days. Fortv-t w n of 1(.1'11\ also n '('('i\"("(1
tilt' d nl~ inl nl\l 'Unllsly (eitln-r 1I.c~ IIr I .S Tn,,:). Tl n- suhjl'(1s wen- IIhi dl '(l into tlm'('
a" t' ,," mps: 20 10 3 H }l·a rs . .In 10 5~J )l·ars. nne] fiO 10 Ml }l'ars. Tahh- IS-.....'5 sunuua ri..~ 'S
till' d(' lJIl~mp"i l' tliia am i p!l;tml'\(''Okilll"lit' fiIUlillj.(S. Ch-a r a~(' <!e!'ll'lIIlelll."i(·s in ACe .
(l) til 12 hr ), dt" ardlll,(' and hiM· life an' \( ,('11 .
 AGE AN[) 'NElGHT 2.7

"'- 1_S-,.
,_ M_.. De • .,_pkl. D.-. _IHI •••M.pl••
......... ,-_..ten _IHI M __,.,-
""
,- ,"<G'"
......
.a"",
..,....
Q
... " ' " OO>NG
10-12101"
""" """. ""
"~, " DOS!
'OIl .l,(,.CM
.",'"
70 26 76 17 0 82 0.Q28
2~ 3Q
4~5Q
60-80
30
40
52
68
88
77
12
13
0 64
0 45
"
24
2Q
0 041
0 052
"'~"""'''''''''8Iv<_
Jl 1~]4 lQ\ll
t
,_, ,..., 0 "" ...... I A~ ....... ~ .... ~ -. ~ ~ a J CJ,n ~01
"A!.C '*'"' to....'''''"..,,, ID-<j "'''' . <b'vo<oI <loM

III ,iIIswI ' ri n ~ IIIl" IIUI'shullS below, tln- cleunmcc values t"Stimaft'1! from till' t.v. Illta ill
lilt' Ilm 't' su l~n m ps ap ply In all lhoS(' in r-ach of lilt' n -spcctlve ill!:t' WOUp".
a, \\'illl ad hity rt'sid ill!!: in rlu- IMrt'lll lim!!:. comment Oil tilt' 1lt'1'11 10 adjusl rlu- doS('
o f fl·lollipilll· for a,e;t',
h. CUlIlIIIl'I1t 1111 wlw lht'r till' d istrihutiull of fd ollupim' vum-s wil l. a,e;l',
e. Eslim<lh' till' l'Ilrrt 'SI'M lmliu!!: oral hilJ;I\1l.iJ.lhil ilit"S fm ('ad . ,e;rtlllp.
d . Ci\'I'1I thut Iitt ll' fl']odop illt' is found ill urin e after i.v. admiuistrutkm a mi that till'
t1 m ,e; un tla,e;lIl;'s t-'xh'n sh'l;' hq )illi(' metabolism, comment OU tlll' 1ikt'1y n-ason fur 111I'
oml hi ll;.\~l i lahili t \' values .
1' . \\1 Iid . parann-n-r. For Cl. , II1nst likd~' exp lain s lltl' ill(:rt';l'il' ill AL'C.. (O to 121tr)
with iucrt'llsin ,e; a!!:l'?
f. \\1lal ll1t·t,'h anislllllli.c:h t I'xpl.lin ~"lIr ,IllSWN to p art ~l'~?
7. \ \ 111'11 atllll in ish'rill,e; t1 m ~s 10 ol'M'St-' p atu-nt s, a ('1111(1'm ('xisls whet he r u r nol duS('
sho uld hc' \\"t· i ,e;ht -{~ lm't.'tI'11. Table 15--ii lists mforrnanon o n till' \~111I 1Il(' of di stri llllt iull
u f t hn-e- t1m~s ill <~ m l ml and nl)('S!, 1);llit'lIts; an iudi\idllal was d;lssifi(''ll ;IS ol)(,S(, if his
or her \\'('i,e;ht fur llt'i ~liI wa s in t'U1"SS of 150% of idt'all'MM: ~· wt'i!?:lIt. :\"t'illlt'r t111'1lpI1o
yllilll' nnr t1i!-:o\ill. n ·laliwly polar dmgs, "hlJ\\"l"'l1 it t1ifTt'n'II<1' in till' \,O]Ullll' of dis trt -
lmtjcm 1)('I\\·c"'l '1I 110nlMI und ol)(,S!, Individuals. tilt' wc'i~h t -{'llm't.'tt'1l values wt,rt'lnw('f
in IIII' nl'M'S(' illlli\itl ua k In contrast. IIII' \lIl11111t' o f dist ribution of t1ill7.1.'p;.UIl, a nonpola r
dm).t. W;lS mu d l ~n ';II('f ill tln- " Ill'S(' ,e;ruup. cwn afh-r <1Im't.'tin,e; for t1ifT('f{'llt1'S in
bl Kly wl'i!!:ht, :\" CI Si ~ l i fi l'<1l1 1 di fT('ft' nt'(' in plll'illla btndtng of tlwSt, Ih rt"'l' t1m~s IIRs 1)(1'n
fou nd lx-tweeu olll'S(' a nd normal \\'('ight slIhjt"'l'ts.

">'!MGt 1I:"" 0 0l' WEIGH!

TOOfAl. llCO'f WE01lI'\l

29 27 032 0.47 165 91

981 937 107 143 16 2 98
2Q2 91 281 153 164 95

<I. \\1mt t"plains till' t1i fTt'n ' nn ' in IIlt't'fTt"'l't of ol)("Sity on 1111' volunn- of di st ributioll
lilT ('(It'll Ilf tlu- clm,e;s?
h . Wlt at illljl;\C't tin suc h fimli n,e;s 1m\'(' 1111 lhl' dl),>;l,e;t, rt'hrinll'IIS uf these t1 mh>"S'~
 ~ 16

DISEASE

OB JlCTlVIS
The leader win beable 10:
I list a! leasr Sill deecses in which the phom'oOCokine41O 01 drug~ is knQlNTl to be cbe-ed
2. usr and brieRy discuss the phorrnoc:okineric pOfOmetefs rhol ore chen cseed inpotlefllS With
hepatic and renal disea!l8S.
3, Judge, using phormocokineliC principles, on when oltefOlion of drug odrmntsncnoe should
be cOMidered 101 patients with becotc Of renal d'secses .
4 , Estimate !he creatinine clearance of a patient hom the pcneors age. weight, gender, and
serum creonntre.
5. Esrimote how much the clearance of a drug of known froc.tion eltcreted unchanged is de-
oecsed in 0 PJ1ient With known renal functton.
6 . Eslobli!>h, from phormocokinehC principles. a dosoge regimen !Of the pot,ent in objec-
rive S.
7 . Sketch /he OrTlQUfll in ee body with lime loIlowing the do$oge 'egimen fecommended in
objeo"", 6 .
8 . list the O$$UmplIOflS thor undEKlie the application 01 renol h..nchon rests in d<»oge regimen
odjU$lmenI for patients with renal insufficiency

l>iSl· a.<;t· is a major source- of \~d.riahilily in dmj,t rt:'sp, mM·. For lIlan y (LM"a."t.'S thi s \1lriahility
is tim ' primarily 10 d ilTt'n'III'C's ill pharmacokineti cs , tilt" an -a uf prillt'iral Focus in this
chapter. " It' chapter hegi nli with a ~t'Ilt' rdl di M.1ISsiull o f t IiSl'iL<;l'S known 10 arret_'t dnl~
killt'til'S anti l'Olld \l{lt'S " i ll. t'rt(' nsi\'(' rh-tatls 0 11 atljll ~till ~ t1n1 ~ :l( llTIini ~tr".Il i()n in patients
wnh renal in sllffidell l ')',

DISEASE STATES
The pharmacokinetics, a.~ we ll as th l • pharnl;l('Od~,mlll i('S . of SOIl1(' t1n1~S has la -en s llm\ ' 1
10 1)(· illlhll'lIn't1 hy tht, pn>Sl-'lIl't' of concurrent diseases othe r than till' O lll' fur wlnch a
drug is IIst·.1 Examples o f co ncu rrent diseases that illl' n ·ll...• vart..hility ill dnl~ rt'spoll Sl' are
ltsted ill T ahlt, 16- 1. 111t' subsequent dtscussjon centers on Iht' first tlmO(' ~n )lIps o f t1i<;l'IL<;l'
listed, mlllwly !Jt·Il<ltic . cardiovascular. ami n -nul d iSl·il...· S.
Then- an' oc casions when Ihe plnmnacokus-ncs of a tlm ~ is altt' n 'tl ill 11ll" di Sl'll<;l' for
which it is IISl't1. An example is illllllUlI1>v;loblllin, 11-"''''11 in IMlIlt' marrow trunspl ant p auents
for Ihl' prevention o f cyt omcgalcvtrus ccmphcanons. In lh l'S(· Il<lti,·nt.'i tln- ha lf-lif(· is :lIM Ill!

..
6 .2 days. whi l(' in normal subj ects it is 22 clays .

,
CHAPTI P 16 1)5£"" , ..
Taltl••
wi'" c._.~ DI. . ._ S..... ..
6--,. . . . .pl.... IneNaNtl Va,....lIlty I. Dr.••••pe.... Auecl.....
V ~tCNN

"""""'0 """"",0
eeoc
C<;lI\OI IC:l'< C>SS Q65EVoi"'tCN "''0
""""'" CQMWN'S

~·co.>eO""
c."~l "-"",~ '"""""',.... Sb.o..-IaI irl pkw.o
000 "* .-.atIOl1
• Cleoto<>ce ,ed....::~ ,
,..due" do>oge 10

-"
~IO><'C'''Y
I\c..-e .. rot W"rb,n
'"-" ,~
•
....... "
""""""'
'
PecL:e dcoage 10 leo.-.
,,""01hemorrhage
Ca<d'(M}"'"lar d,,,,,,,...
Coogo>"~
=d~
todoc",ne
.,..
AA!>O'¥m" ,...........
COiOti"""""ak.
• C""'onc" o.-.l...oLrn. 01
d,,.rbuban "'""nlol>ecl.
h I;.""
""" ....... 'ed.o:e dosogt 10
Io.uen ,,"" cllO><iC"Y
Pe"'<J: 'h ''''''''
~~. GenIOmO<:ln G<o~ ... hc>t!o>ed 1Ol<iC'ly
"",;, usual dr:.ogt
• Penal cleo<anr.e
dnt>boo/lC doml",~ . 'edo::"
doI.dgt 10 ~ ,,'"

~~. Th_ " "'""'"'" ................ ./- •

oIlO>.o<:,1y
Pe<:ko do>e 10<MlKl
e><CeW>'e !Joop.ng lime
Gd,"",~""" na d '""''''''
C.~
d,_

C, .,t,nl
.~.
--
FoMJOC cod """1::0::.....001
"9"'"

"'x'"
---
,........... •
""' ....... •
....---.
,...........
..... .... NS
Booo-o,labMv'no;,1IOlolld
ond/(J// dl!l(JIIO"ICe

..........
d,m j",~

"'bor.::l,"9. eIoMJle,d lI ,·

-----
~ oc.d~~n

~
-~
onIv In. 0Cfr>0e

' ''>pm""" d ""~""l

..... ...
_ •
Toll:o.r1Om";" Hwogfve""''' M:xe <opod IaI in
"'"'~

,.""'""" IW>rph,ne
-<--
"9""

....
CCII\OIO-=-oOtl
roeo-l sensilivlly NS N'
~'"
~educet dose 10d,ml"''''
,,"" 01 ""P'fO'OtY

""""""'
........ "
•... ceec-ce
..... "'" --
C>",<
!,b<OS>l
Doc lo.-oc,l,n ""boo< Reduced(J//........ •

-
t"'d<X' ...... <i '""'<c
~,~ Bronch;,d,laO' ----
,........... • ~o;
oeoeosed.
dearance
,educ"
dc»e 10 \e$wll~ rJ
10><0<:'''''

n.,.""
d.--.",
(),go,,"
.,..
Cor d >OOC!l "" [),,,,,,,,lh«I~
",~,m;
• AdjU$l do»oge <XC<JI/d'''9
10Ihyfood OC!'''''''

,~
""'-'
....... -
...,.....
Qv, n,...., kT>"'Ola''d1
"9""
.......
cJ
~-
Ovg eIe.oed.
• N' !Mpa"ed fhelOboI'vn
~, rna,.--:l
d_
..............
-.... 10 'ed.o:edo::-> ,n
_ " lob ,1or loI<JIM

• ....t.i,,Noej ""'"". 01 ,.".ooboI~,

- ""~".." "",«>" ..., "",.......d doe to d ......
NS ~..,.,
25. CHAP1£R 16

Hepalk Disorders
Ik(~Ul Sf.· thl' [iver is the- major sill' for d nJ~ lIll'tilho!iSIlI. all imp res sion p n '\ "ltils thai special
care slulIIlti ht' tal('11 ill atllllinistt'fin~ drugs to !);.llit' lIls v.i lh di M'iL\(' stat es lI K )(li f)i n ~ Iw-
1'I<ltk (111111ioll . Ohjl'1.1in· data. whi lt' ~t'lw nllly SlIpportill.\o: this impn-ssjon. an' Ol"l'a.sionally
ill t'Clll flid .
(}IIt· n-usou fur rlu- ('(mllk-! arist·s Irnm an attl'mpt to d 'l..s i~\' lwpatic-di ..o nk-rs lL' II sillJ'lt'
entitv. II tJ\\ '('\ 'N . disonlt'rs of tilt' her-r. It ll..11 or d ifTlIS(' , an' caused bv manv di st ' il'i(' S; each
diS('"~W afTed s various ]('\"t,I, o f Iwpa ti(' ory!;ani7.dtioll to a diffcn-nt ('x·!t·nl. '\'ilh few l'Xl'('Il-
lion s, tln- bepatic- clearance o f d n lJ!;s is, O il a\"l·t;l~(· . d('{· n:·a.~'t l in ci rrhosis. III contrast, in
at'uft ' virul ln-patttts. Iht'n:' appt'ars to be a f.url~' (...-en tlhision h('lwet'lI Iho~' d m~ for
whid l dearallt't· is rk-cn-ased. or hal f· lift, p mltll l~t'tl , and th uS(' for whkh 110 eha ng:t' is
den-en- d. E, is li ll~ data S U~('st tha t dmg: cliuuuanou is tlim iu isht't l in ohstm(1:i\"(' ja ulltlil't·,
11 1t, t·tTt't:1 is t'XI)('t.1:t'tl 10 1)(' mort' t'\h'lISi\"(' for t1mS(' tim"'.... d im ina h 'tl pn:'tllllnillanily hy
h ili;u)" excrettou.
Anotlu-r potenttal pitfall is to t'fIliait' prul(Jl1~ati(Jn of Imlf·Jife- \\ith t1i miuntion o f ht'!);llic
tlm~. nlt't ahol i zi ll~ act ivity. Half-lift' is (:onl",lIt't l hy I)(JII. lola l ck-arano- and volume o f
tlb t rilllllio lJ, h\11 lud ep-ndcnt pa rall lt't t'rs (C hap . II ). To a.~st'SS clearance and volunu- o f
t1istrillll tion, the- dm ~ sho uld ht: ~ivt'll illt m\·t·mlUsly 10 t'IISUn:' co mph-te bio.a vailahility,
\\llt'n "'J stlltlit'tl. lilt' vnlunn-s of d ist ribu tion of some d m g:s remain unal n-n-d in 1lt'1);ltic
tliSt·'L<;.t·. hut Ihu~ ' of ot ht·1"'i are incn-ased. An lucn-ase in VUIIlIlIt' o f distnbution is found
pa rt k llbrly wi th d r ugs bouud to alhumtn in p attents wit h d rr hus is. Tlu- explanatkm lit's in
rlu- dt'pn:'l;S('t1 s}ll tllt'sis of alb um in allt l Ill an~' protetus, ind udi ng: variuu s t' n0 1lWs and
dollin~ fa(1:ul"'i , i ll l l lt·~ · p atu-nts . TI ll' n-sultant fall in alhu m in concentrat ion is n-sponsible
fnr a dt'f:rt';l'i('tl plastnu h imli ng:, an ;l\ sul1alt'tl increase ill volunn- of distrtlmtkru , and an
;l~ ...- )(:i alt 't l i!l('n',l'>t' in d l'ar.IIIl't' for a t1 nl g o f low extraction. A fall in hepauc t' 1l0 'l1t·s is
n-sponsibh-, in la rgt' pa rt , for a duninisln-d ln-panc 1I1l1 )(Jlmd dt'anUll't· tlf IImny dnl ~ .
(hitli......d dm~s appt:ar 10 he ilio n ' afTt't.1:t't l th an tlltlSt· t'!im illillt't l hy ("l.lIlj ll~i1ti (JlI .
T Ilt' illlllle m "{' of lu-patl c-d i.'>t·'L'>t' o n d m~ ahso rp tion is I)()(lrly understood. 111l' pmhlt'lJl
is 1"l.J1llp lim lt'tl h~' li lt' IIt'('(! In <;{'I);lmtt' t1iSI)( lSitinn From al}<;{lrp lioll when allalp·jll~ p l,l..ma
(,(l!I('('ntm tioll-linw d ata . It is likt'I)·. thnll ~h . th at tilt' orul h ioavailahility o f tim"'rs lJi ~hly
t',tr:\("It't1 hy ti lt' lin 'r is iJwl"t';l<;{'t1 in d rr t.osis , t· .~ . , Fig:. 16- 1. 11lt' rt· art' tv.u n '<l-'itlllS for
Ihi.. iIlNt ·,N·. Ont· is a d imini.sht'tl firsf -l);lSS ht'pal k Ins s d llt, tCI tlt'p n 'sSt'(! lwpato('('lIula r
a(1hit}'. T ht· ot llN is Ihat lIIan y drrhotil' patit'lll s dt'wlop 1)(lrtal hyp ,l'>S, a l'(lIld itio li ill
whit'h a sig:llirit'allt fr.l(1:inTl o f tilt' I)(Jrtal hlt)()( 1 b~l );l'>St·s pa rt'l lt'h~llIal lissllt' in till' livt'r o r
t'Illt'1"'i t1in't:tly into tilt· Supt'rio r \"('na (';Iva \ia l'Stlphagt'a l \,tril'(·S. TIll'St· I)(Jrtal ,l\'al sln mls
l'all g("('a ll}' illt'n· il'>t· oml biuavllilahility: an illl'n'll<;{' of gn 'atN than :21111~ h;Ls hl't'n rt'I)(lrtt'tl
for Slllllt' t1m~s \\ith t·\!t'nsht, first -l);l'>S 1I1(>1;11)( llislII.
F m rn th t· furt' goinv; t1iSt'ussiun, il is appa n:'nl tl mt t1m g dUS;I~t' may Jlt't't llo 1)(' ("('1111('('11
ill palit'nls \\i lh ht' I);ltie fum1:ioll in1lMimwIlt il~ a rt'Slllt of 1)(ltlJ d t't' rt';l'it"l.1 dt'amnl'(' ant!
im '("('il<;{'(1 oral h iua milahility, All adjll stllll'1l1 ill t1tlSOlgt' is pa rt il'l.Ilarly warranlt'tl w il('li Ihe
usu al n 'WI1WIl n:'slllts ill lh t' lI11htll llltl t1 m g l'UlIl'(·utr.t1 iu lI at p);'lt'all apprn'Il-l.i n~ or t'X'
l't't '(!illg th t' IIPI)('r lim it of tilt' Illl' m l)('lIlil' l,(lIIw ntmtion \\intlow. This l'(llltiitinll mist,s
wllc'l1 Iht' d t'ar.lIIl,(' lIa.<;.( '(1 o n unl )( llInti dnl~ is ,>uhstalliially dt ·p ("('l;<;{'t l. 1)("(,t1N ' it is l h i.~
d t·aroUll't· thai t,(lIltmls Iht' 1l1l1)( lllIIti dm ~ l"l.lIll'(·nlmtitJII OIl pl;llt'all (Sl't' ( ;haps. I I an ti 12).
II t'IMtie t1ys fllllt1:ion is a g:rm lt'(l pht'110llWIIUlI . am! Iht'tm 'lit"'llly a t"tl rrt'!al itJl\ should
t'\ isl !)('hn't'11dlall ~t·s ill tht· phannal"l.lkindil' I);lr.U1It'h'rs o f dOlg:S, t'SI)("(1,,II)' ht'l);ttit"dt·ar·
a1 ll,(', alltl ,Ill appnlpriatt· 1Ilt';L\ Un ' tlf 11t'I);tlie fU lldioll. Atlt'mpts to t's tahl ish SlIl'II n '!atio n-
sh ips, ,,1t 11U1I~h t'lIl'()ur.t~ng:, h,,\(· nu l 1)("('11 It)(J SIl(1.'(·s.\ful. 111is failurt· prtlhahly ariSl-'s
1)('(."mN'. u nlike d Ol~ t' x('n'lio ll. tht ' f"(> an' llllllWn JilS 1);lth\\"lI~ "S of t1 m g 1llt'lal)( IIi ~ Ill , ('adl
\\i th a dHTN t·..t st:1 of ('tJfadur n 'q uin 'mt'nts al u! t'adl alTl't1:t'(! to a di lTN t'ut c!t'g:n't' in
OWTEII16 251

ls-pa ric drsonlc rs. TIll' ccutrtlmhon u( ( 'ile" lliltll\\'a' · to tota l dnJ~ elhninatkm illSiI \1ln ('s
with th e d rug. Thls \1lriahilit,· is ilppun'nl (""1l tilt' act ivities of (nuT ht"Jll,tic ('Il7),m's n-.
spn nsibll' fo r l,mj ll~lli io n n-acnous ( Fi ~. 16-2). 111t" ( ' II/lUll" activitie-s wen- T1l('ll~lIn'll in
)j\'t' r samples ohlaillt'l! h,·hiop \.,·. G lm1Jnlllyltmns(t'r"'\f" app('ars to ))(' unaffecn-d byl n-panc
di M'il'it' . Sup port ing this observatio n, till' phannaco ktre-tics of ti lt' ))(·!lIJJtlilUA.· pilll' U\alJ'-
pam, wh ich is r-ltnnnan-d al mnst t'lllin·ly hy glm.11n1llidalillll. is 1IIlafTr'l1t'll ill Ilt'jla t k d is-
e;L\C. It is also app;lrt'll t that w hil(' tll(· uct ivitu-s o ( the otla-r th ree l'IlZpnl's arc Oil an·ragt·
dccn-ascd. the re an.' sonn- iml h idmtls with normal ;1l·li,i l\" and others in whom \ 1.'T'\. litth-
11l1h i l) n-nuuus. Alteredmetabolism in chrome persisteut ill'llillili\. dlnlllic .tl1iw Ilt'lliltitis.
alll i drrho~is ts llw n '(()n ' a funct ion of tjn- (·1\7.\1nt· in\'nl \"('ll. IIII' slIhs lmlt·. a nd ti lt' aet jvitv
n'lIlilining In tjn- indi,idllal palit·n t. . .
In drrhosis. a com-Iation 1)('I\\1'(' n tilt' sew n tv of tilt' condition and till ' Iikt'l illOtJtI o (
d-p n -sv -d metabolism by uxida lhl' und su nil' ('~lljugatlf)n reucrious h;ls n (tt'n lx-en re-
ported. In M,\·t·rt' cirrhosis, siWlifit'll by tjn- (,OIllhillatioll of a I(,..\, albumin (less than 3 Wd l ,).
au clec a n -d c1()lti n~ u mc (p mth m lllh in umc ~n.·al l· r than 130 11 u ( 1I0nlla1), and till' prt·s-
l'lIl" of l·Ill't·p ll,,!upat l.il·s. tl m~ metabolrsm is ofh-u t!t'l."n·;L\('l1. Th e <It'l.· Tl-' a.'it't.i metabohsm
fn 'fillt'n lly requires n'lllll"ill~ 11.(· clost' and 1lI()lIiturin~ lilt' pa!it'nl fur !d.,lvt·N' reactions.

Control Cirrhosis
700 700

~
400 400
~ c _
~ ·QE
g~ c 200 200
1
~H " 'l" '" 1......
_ cco ·-
Q.>
_
c
0
~$E t·l ·····f
~ 5~ 8. 100 ······1
100
c
~ ······1 1
c
0
<.> 40 40
~c 300 300
T
'-"
0
0
Q.
200 200
1
g 100 100
a; ,,~
o.=, 50 50

o 2 4 6 B o 2 4 6 B
Hours Hours
t1K. 16- 1. In <im ." . i_. tl... "r.J hin lIit..hiht:o' of ['n" nu.,I,,1 i. "",,idly incn ·.......t ... f"\idnon..l l~ n " " f'o',.;...."
,,( II. · I''' u l t, • • , ·.d l'll.ti"" ,,( .."U. · I ,lnlK .. f",. '>r.. t ", lrnin;~ n.h"n (t........,..j !inoe) "";Ih 1""'1 ,Ii 1";1;',1...1 , Im l/,
..ft... I,... ",Im; n;""nth,,,, (, 1. , 1hL.--l!i "cl . r"I i "K. ;"'u1l..",.... I. ,"·h· n ni" ..lio:"lu( til<" 1o:1......in n( pn.p,....' "
<Iu";"Kth. · .. .. . ·nl h ,1".i" lit In -..I ..( ...I " no!,Ii I" , inK 1'1~ " "'n i ll 1l•• JOna! ."hjrt;1_ an,I7 !""'Iit' nl ' ...11h d rrl ..
(""'IU' :!: SE ). (I "'WI. - .1.9 ,, \11 jR... ln•••", fn..n W, I..\J-J., t.:,, "'h.., ·, . I) .M.• Wilkin ",. G H., s h.. ,.1.
1),(; " 18r.."d,. H..\ " 11..· InA " ..• " f dm "" ." ~·.•I..l'. 1>10...1 , K-'M'lrall< 'm ,Ii ""1 ,,,,1[' n.I'''''' '' ol. ''
"fl"r ;4) ", 1",;ni" ,...01;''' ' . CIi'I, 11, "''' n 'lti' '' 3: -4 , 'I-_ 7. Ill" H<1"'. h" II')'· I"·rm i-.. ;,lfl uf .\ Il I<; I'ft"'• .\ u. ·
Ir.J.a..,J." I,,· U llnh , 1.l
252 ~"' AS! CHAPTU! 16

Blucumnyl- Sulfo- Acetyl- Glutathione

transferase transferase transferase transferase

I
(2.5)
0;-
.~ 20 • 1.2 • 8 8
• •
-
~
~

• • • •
0
E 15
, 0.8
, 6 •• 6 •
~

:!l
,. • • • • I
•

t l...,
A
c
·e 10
,..• &
•
.,• 4
~• 4
...
•
~
0
E
§. 5 .'t'- '1: 0.4
2 A

-
• ~
c,
2 -,• ""
:(
-e:
0
• e 0 0
i 0 3
n K. 1S-2. Ad i itM-S ur tl..· m nj"lI:alilll: ""~11""S, ~'K, ,",,,~llr..,,\f.·r.N ·. \ " If"lr..,,\ f..r....·. .... '~ ll r. "r'·r.." · ".1
~"I. l h~ II'" Ir 'r..roL... . in "" n " a1 (hl. "kl ;0".1 ..h"" n n;u (., ole,,) Io""'an I;,." "" ' -;01)' "'llt.·~· . S'",,,,. ,;n"Io ar,,1
lrUl1l1:lo.,. ",r" r 10 h'uf"i 1 wmpIM fnlln p;oh...." ...., 110 d,n",i(' 1"" "";""'" 1"'P"l iti•. dm,nil: ;1(1;\1' h. pat ihs, ..,,0:1
dnt,,,. ;. , ""'1.....1i....ly. n sulr<t"" '" "toll": 2.nal'lIt"..1 rolf .":IoK'ln" '~ 1tfll".f, ·r....• alld ,,, If,,lnu,,f,·IlI...-: p-atlli,",I>.
r "71';': .,.;,.1fn. ;I<'~~l r..."r..r-.......; ,,,"11,,...,,1(',, lp:oTt',..·.4.5..."'ic ..• for II:lub'II'i"'''' Iran, f,·....." ,. I" n ",tr.\..l,,, tI..•"till"
''''~llll'' , Ith""In ",~'Ilr.ul. f,' r~..· d",.. 1M" ;<J'I" 'lll' 1.. 1,,· ;JT' '''1...II~· ",,~· ..f tiM' IM,"'I" · " " "Ll" "". ,~.l... "1'1......101 i.
n,,·
" \; 11,,,,1 1... 1 "f ....1;"; I)o·,,f tI" , k,l llm.., ,' "..,...,,,.. in ' " " ''' I"'Iic'" h . irnl'lie"l ic"" (ur ,1m", l.ri ll"'ril~,.'I; "'ir"'I,..1
hy tlM· t.,"j"It"'ic"' l"'dl....~"an' " .. ·,,1 (A,L.pl ...1fn" ll P..o" lV..t C .M .•" .....I. A . fo'r......·I,L M , Soc" k ri" i. S . T"Inillilli,
:\ ., Gi"lw'i. I~ , "-,,,I ( ;;.r,...u. M.: C.M 'j"~ic." p;.>11,.. "~,, in li.... r ' Ii..." ..·. Hr. J,eli ", P1 wn""onL 3f,lA 2';'- -l"l."i. 19'1lJ.l

IlIdpt ....!. mn- lIt....-ds to conshk-r if all t'Xtl'lls iH'!\" ll1t'tllIM ,liZt'(1d mJ!; is truly 1It'('(lt'(l or if lUI
altemutiw (n 'nally excreted) dm~ is a\<lilahlt','

Oreulatory Disorders
Circulatory t1isonl. ·rs. wJ.id l illd udt· shock . ma liJ'lIall! h~lx·rtt' llSi()lI . .md lu nJ't'slin ' ('a n liat·
failu re, an' "t'lwmlly d lar'1l1t·rii".t....1 by d illlinist.t'(l \·<&-"t:lll"r pt'rfusillll til n nt' Ill' ilion' parts
of tln- hod y. Slm1.· hlootillow limy illllm'lIn' d m~ ahMI'lltioll . disiri hutillll, and dilllinillioll .
i t is 1101 sll rprisi ll~ thai tilt" pJlanll,l(tlkindks of dm~s llIay 1M.' nln-n.. . 1ill d rt.'u lalury tli'>l lr-
ders .
A d iminis llt.... 1 pt'rfusioll of absorption sitt's . t' . ~ .. ~,lslmint t'stillal lr.j(1 and muscle. with
all ,lS'>I )(:i"I<'(1 pmtr.u.1t...1 am i . 'rmtlt' dm~ absorption. n-nds to Ill' se-e-n ill pa lit'llls with
dt·p n·sSl....l l1lnlin\",l'i(·ular stall's; it lllay 1)(· nt'l't·sSiU')" to ¢ n ' tln- drug inlm\t'llll11sly if a
pllllllpt n'SIXlllst· ts t1t'sin'(l. Ilowt·n ·r. ill tln-se t'Ollditilins Iht, kiuetu-s of d istrihllt iull is also
arTt"t.1. ... 1. with perfusion In lllallY n~;tlIs dim inisht.... L EX('t'p tiolls an ' tilt' hraiu sud tilt'
lIl~ucilnl i lllll . .....luch t1l11St"(llIt'ntly n ....,..ive- an illl'n·'N ...1 fraction of an i.v. holli S dose-, par-
tkHlady ill th(' ('arlit'r monu-nr s. Fur (' ." lIlmll)' ilt1illJ!; alltl t·iln lioa(1i\·t' il~t·lIls . tilt" rate Ilf
atllllinistmiioll of a IXllus dust· 10 patients with dn:lllatol) ' d l'pn'ssiull mu st 1)(' 1t'1Il!)(·n...l if
till' rtsk o f loxidl)' is to Ill" n ...luced. In tlWst' t1t·pn·sSl...1 d rt'ulaltll)' stall's, eartliat' Olltp UI
CHAPTER 10

tl K. 16-3. i\ ,In'''R1'''''1;.... n 'JTt"Loli.." Mi,"

1"1\00,,,,,, till' dl~""r"'ll't· ..{ hd"nu 'll" and i."Io:..
co 20 •.,.",,,illl" K" "' '' i" p.alio"T,h "'i ll""'1 (.1 ""'MI "'ill>

~ • l"llh mikl (o) ...od ............ (. l " "' K'OS!iW .-..nlia·

{;til" re-, It"n'''' Zil" . R.:\. ;UM! 1«';,1. P.R : l .iclo:..
:5S 15 • • (;l.i'M' ki lM-til:s pn..1il1...I I~' ;IMI.M-,.,,"i "" W"..."
cl..ara,,("f' , H.-pri"I...I. h~' prrm i..i"" or 11,,·
~ •• ~ ...... .:,,10:1 ••,,1 J,,,,n....J "I" M...Ii..;", ·, ,29'j :l lfil~
u 10 • •
• ••
~ 1111.1, 197'1:.)
~
~
~ •
zs 5
~
.? o 0
• 00
~

.~
• 0

~ 0
::J
0 5 10 15 20
lndocyanine Green Clearance
(mUminlkg)

alltl thr-refon- Itc'Il<ltil' hlood IInw and , to a mlll,h It'ssN extent . n -nal blood How an ' ,llso
n-duc....1. T hu s, a dl'{·n·,to;c.' in d" "tnuu..· of hi~lJ ly ,,·xtra(1....1 dn l~s is (·xl')(...1t..l. E\ id"'nl"l'
s ll ppo rt i n~ thi s lu nn 'pt is il1 ustrah..1 ill Fi~. 16-.1 by a st nm~ positive ....Im·lalio n be-tween
tilt' d t'ar 'llll't·s of Iidol".l.illl· am i iudoc:yilllim'l!:n"t'n in patients hot t. wuhout and with \-a l)in~
t11 ·~n."t'S of l'CJIl!-:"'slin- ca rdiac· Iaihm-. I~ I( IJ imlc)(:.')'an itlt' h"Tt"t·Il. IISt"t1 as a d~llall1il' te st of
Ilt'palit- [unc tion. allil lido..... illl· an' lJil-:h h"'!);ltic ..-xtraction mtio d rugs whoSl' d ..amno-s
should rlu-n-fon- n -llr...·t a d iminish.....l lu-patlc blood How. Sohc't' in r'i ~, 16-3 the almmt
I6-fold variutiou ill dc·anll1et· of hoth lidomi lw and illllo(.')'auim' ~n>t 'n . This nll1~t' is almost
n:rtainly ~n·a l r-r than till' nUl ~"· of lu-patk- hlood flows in ,",,"S(' pat it·ub. TIll' hel );ltit' tlow,
usllally ahou t I~ llll JlI1i n/l;~, is unlikely In fall to a vahn- ll-~ lo\\' a.s 2 m l /ll1i n/l. ~ h.......IlISl·
....-vr-n- anoxia Is "'\I')('{1t>tlln result at ..-cr-n lrigherIlow rates. 11t·1);11t1(.''l.·Il11lar ell7.)ll1..· al1hit)'
is llllist p n illailly al.... 1 depn'sSl'l1wlll"lIlli·rfusicm is Sl"\·,,·n·ly ..Iimillisht>tl: thi s \'o'tlllld furt he r
dt·pn·ss till' (·II'anlll('C·s of both lidl)(".tilll· and indol_').lUin..· ~n,,· n . As Iidnc:ailw 11;1-'0 a narrow
therapeutic s\i mlow (S1'l' Tab l... l.'i -2), dOSiI~t· sllould Ix' reduced ill patients wi tl l l'C m~t'st iw
('anlial' failun' if 1111" risk of tmi dty is to 1)(· k"'pt low .

RENAL DYSFUNCTION
In pat it'lIls with l'C lmp ro1l1io;c."Il n-ual function, urin al) ' "'\{'n1ioll of t1 m~ is dumuislu-d. TIll'
dq~f(",' IIf reduct ion in n 'lml d imillat ioll depends on till' n -duct ion in n' lIi11 fuuetion, ,LS
sllU\\ll in Fi ~. 1fi-....4 for l'l·fl,pin...., a filurt h-l-:t'lll'mtion l't'plullosporin illltihiotit'.
\\'ln-n tht, usual i.lII. n "j.,rinwll of amikadn is ad millislt'f('{1to a pati e nt with n-uul fun ction
that is only J7ll- of normal. till' d OlI-: accumulates eu't·ssi\'t"ly. a.s sllll'\ll In en ....'t· B o( Fi~.
16-S . Tlu- fj~lIn' u1....1 n 'm imls us Ihat tilt" ..-xtent of 'll.'t 11111ulatiu ll delli' lllls on bllih Ire-
(I'WlIl'Y of administratiull allll lJalf-li(e. and that the time n-quin-dto appnl;ll'h plateau is a
function of half,lilt' unly (C hap. 7). lI a\i u ~ a mul'l l louJ.:t·r ha lf-Iif..• than llsual. till' tilll!" to
n'aeh sli·ady st" Ii' is mud, Icml-:t'r in II,is p;.ltil"nl than in a p<d it'nt \'o itll nOTmal n 'nal flllll1ion ,
Ohs iously, 10 a\uid I'\l't'ssis"{' al'('um ulaliun, dUSiI~t· lIlust 1)(· n'( llll't'{1 ill tht" l);Ilien t \'o it!.
n 'lIal dysfunl1ion.
Th e din i{'i,1Il lll"t"lis information on whit'h tIm h'S i\('('ulil ulat..• "'xt't'ssi\"d\" in rt'uallh -s-
fundioll alll i. ilion ' impo rtantly, Imw to adjllst d Ol/!; <ltlmiui.stroltioll tn al'h i;"\'t· ,Ill op th;lal
t1wrapt·utk rl·spoll....•. Tilt· h;l-sic primipl.."S that I')('nnit this mklllatinn follll'\'. T lwy an'
d' '\ 'I'!opI'(1 \\ilh till' \it'\\' that d m~ t·lTl'l1 alltl tlwn,fon' dmg {'C m{'t'nln l!ion nc>t'(! 101M'
Il1aintail1l" l.
'54 CHAPTER 10

. '111:' 16-4. n ... I1 M'a ll .......' m,. {'>l'- Creatmine

{'t' n lr"ti"'H i lll" rn,lil. ~ lO r .,.f,-p;"....
100 1 Clearance
a ...-pI...Jc.. I.'"" antil,;nh, ', an- ,Iiff" r- (mUmin)
0,., 1 ill 1""'it-uh "" lh "ill); n~ llo:1-tn't"S
<of n -" .. I ("'diu" ;oft", l.v. in("\i,,n "f
a I I " I-",~ ,.. ..... ' ...-r 3(). ",I,,_ n M' 10
" -"
-....... ........ <10
,
. 11- 30
'"
\" " jo" 1< "',_n' Ii:n"'I"'t1 ;l<'O Jf'< 1i1l1l: ,..
II,..;, n..•... " n ..1t-r\-. tlinint' d.·..r........ " '
•0lI,.... /i " ", ( /ru i,, ). (A....pl ... 1 fn>'"
Har hhllip . , " .11 .. Knup p . C .., .. <.
F"'Xl"', ST.. ~ l af7.l.r. G.R.. <: 1I~ . 1 • 31-60
D .H.I'.• ;I'MI Piu", .." , F..-\.: 11...n "..· 61-90
('(.kilwt i"!i u f (,(·{(,fIi mt· i n suh, ,'(-h
",i ll, n·,...1 i"."tlK...·'K':\·. e li" . 1'1,;<,. >90
lIlan ~ . n "'r" Pl:2&l-2'fi. 1991),) 0.1 +--~-~-~- ~
o 6 12 16 24
Hours

1'111:. 16-5. SLti •.ft " f ,h., .." ...."'1 o f arni!<.l.

rill . " If....· in tI.., I..~· "ith Ih' M' f"IIoM'inR"
r.-s;n,,-n " f .';IM' "'II: '''\T'~ ' I i I,r in .. I"" M-nl
"'1....... n ',,.J (11 "<1i,," is nllfT".. I. •" ...... '" ;UK (
in a fUliI·"t ~ ...... ~. ;",, 1 " .-iI:!'1 ;on' II..·
...." ..· 1..,1 ... t · rt'l' llJ f"'''1M'' ' i-~ I ':'~ uf 1M... •
m;ol. l~ oIun~1 (~ ".~ ... S , Inl•• " "M"1< 1M.!'" ;od.
mini.f ratioM ' i•• i "lllLot,~1. l1" ' lIun " lti h f·!if..
i. .... ."',M..l to I... 2: lor. TIM' .1.. ".... 11" an'
,1M' ;l",r.K1-' 1)/;0"';0" \......"S,

o 12 24 36 48 60 72
Hours

Deaeas. in Clearance
111t' r-k-ments of the problem of renal dysf""l1ioll an.' S1l0\\1 1 ill Fip;. 1f)....U. Ct·rt;17jdilllt·
clearance , 11111,0,,11(1 clea rance here hr."l.'<Uls(· till' d nl~ is nor ho und 10 plasma proteins. is
tow wln-n rena l [unction, measured I~' c n -athunc ch-arance. is Inw and ill(;n ';l\l 's lillt'arly
wilh renal function. !'\uh' thai souw elearauce re-mai ns (y. inte rt'l·pt) even wln-u then- is 110
n-nal funct ion. 111is rt' p rt'St'llts clea rance by nOJl(t·nall><tlhways . T I,t' lI m~lI i l ll tle of d lall~t'
in unbound dt';Ullll('\' dPI)('uds o n Ill(' renal [unct ion (('mai n ill ~ a lld 11ll' fmd inn t'!I(t'rt'!( '(1
unchan ged.
In what follows . em phasis is placed Oil unbound rather t han total ch-amnc..-. This is not
onl), because the all-im po rtant unbound roncent rut km is n-lated 10 unbound ck-arance bill
also be cauw . for man y d n lj:!;5, fi' varies in n-nal dist'a.'it·. mak inp; interpretation !><l'it'(! 011
total plasma concentmtkm uncertain . TIlt' j:!;Ui.lI is 10 t1(,\;se a rt'latiun ship that allows es u-
mation of the maintenance reg imen ill a p atient with rt·IW.1 dy..[unction. TIlt' finl step is to
relate llllhollmi renal clearance in tilt' pat ient with renul dysflllK1ion(d ) impairment .
C I"u H(d J. 10 un!Ju u"d (('!1<1I c learan ce in Ihe typk,lI(t ) 55-yt' ar -old . 70 -kV; patu-ut, CI A1II(I) ,

CluM) • RF · Clu.~
CH.6 PTE ~ 16 m

T Ilt' nihil of tilt' Iwo is IIII' n-ual function Off') in tln- pa tie'nt rdalin ' to Ihat in the Iypiml
pat ient. l u tln- typical p atient. Cl"'n(t ) is a fr.1l1ion,fe(t), of unbound (n-nal + nonn-nal)
ch-arance-, CI",(I) .

Uy t'l: lI l1 hi l1i n~ Eels. I end 2. till' nubouud n-nal ck-arunce ill tilt" path-nt can bc' n-lated to
CI"' (I/ . hy

T Ilt' 1lt'\1 Sh' p is 10 ('(Illsidc'r tlu- unbounc] clcanmce II)' nOlln'n ;d rou tes . Cl"' ,\H' In tilt'
I~Vit'al palit 'lIt , it is

O n Iht, ass u mption tlnu CI" ' ," I is 1101 dlangl'1l in renal d iM';l<;.t ', its value ca n ht, c'stimalt'(l
for lilt, pal it'llt by laldu g into account his or her agc' and u 't'i)!hl.
(1 -10 - A ge ) ' Id (r/) o ;
Using lilt' app m\illlation 1fi60 for tilt' factor II)' which nonn-nal cleur-
m i t'(' t1t'\;ah's [mill Ihat ill tilt' t~l)it'al p.uicnt (C hap. IS), its value ill tilt' lndlvi dual pat it'nl
I M'('( IIllI ' S

H it. 16-6. 11M' h~OII ("1c·......,K... ,,1" IIIt'I'l:1,1",1c"'1'1)-

150 ri o . ("c.' f1....id im.. . ",rit" hno'OIrh ' with n .... l in ill .·
• d" "r."K~· ill OIlo:"'''P IIf 11l1'"'''''1'h ",lh '~;nlo: .Ic··
2 lo:rt.... 01" n;-rual fUlK1io". :"ott· 1....1 ""11t· d....""'M~·

~ "·"lai,,. lJl·h'!t' rt'l:1>lj"'h....l 11..·1l' l~ 111) rt'lW I""' K~

hnn . t D r_ Tl I"nlll1 tI....L.I" nf,.." 1>..1.'". R.• \ ·n ....
§. 100 T it , Roan. A.M., 01110.1 Tt'T1",,,,.J. E.: D'_ J:r ;Itt·
•
i •
f........flv.io.lilll. · ill p;atin'h with im(lOli .....1
jU'>!I1I.. nl
...·n..J fundi-",. 1':11..." , J e lin. 1 1'OIn";It~>I .. .)'''.5!l; -

~
filr.i. IWi.l

E 50

J •
••

o +--------~
o 50 100 150
Creatinine Clearance
lm Um in)
'56 ( HAilEI1 10

Fur a ~\'t' ll <l~l' amI w(·i~hl. C l..U\ 'II(t!) is c qx-ctcd to 1)(· constant . independent of n-uul
function. whill' CI ." R(tl ) is (·.'(p('<.1('(1IEq. -I ) to (:Imll~l' in direct pr oportiou to n-uul function
(RP). Thus. thl' 1111110 1111(1 ch-arano- i ll thl' patient, CI..u(d ). illl,.'rt'a.ws lillt·arly wit h Hf'. Th t·
ex ten t of till' Increase depends on f j.(t ). til..• l 'u n trih u l illll (If tilt' n-nal I'Ullk In all mull's IIf
d imi nution in til(' l~]l i<.~.ll palit·nl. l1li_~ rt' laliomhip is shmm ill Fi ~. 16--. for a t1m ~ \\il h
an fi·(t ) of ll.s.
On sll hs lit ll t i n ~ Ells. I to 5 into Ell' 6, the rollO\,i ll ~ usefu l rd atinm hip is t1t'riwd for
R,I. lilt' 1111110 1111<1 dt'ura u{'(' ratjo, C l..f,(d )/C I .u(t ).

11 '40 - Agel ' wIId)O')

7
1660

Tln- fi rst tN IJI . RF .J(o(O, does not Incorporate il~(' und wl·iJ.:llt t1in'(:t1y. 1 )( '<.~lllW HI" is
("Slimalt't l From crr-at iuine clearance ill tilt' dpfull(.1 ional palit'llt rt'l alin ' to tllal o f tilt'
t)'p it'al patit·1l1. A~t' and \\l'i~ht , of course, play a m it, in de!t'nllilliJlI?: tln- \1.1111'.
Fig. I fi--S:\. illllsl...a tes tlu- n -Iations hip ht'twt't'n l~d ami n -nul fw lt'liou for vahn-s of j d O
in ;15.'>-yt·ar-tlld . jO- k~ pa tit·lIl. It is appan'lIt that [(.I d lilll~t· S the most wit h n-nul fllll(1iol\
wl u-u fi ·(t ) = I am i is unchanged wllt' li F (t) = O. The- vahu- o f j e( t) is, liy dt·fillilio ll,

when- CI .R(t ) and CI .(I ) an- ti lt' n-ual and total ck-umnces Hf tilt' d nt~ ill tln- t~'P i('al(l<lti (,1I1
for whom t!ll' usual rt'W ll w lI is Inte-nded. EXIX'rill1l'utaIlY·,fi '(t) is tln- fr.lt:tiull of au int ra-
H ' Il0W; 0 ,\ '.) tloS(' rt'(,)n · rt'(l lI lId mll~t, 1 ill uri ne in a lyp iea l ll<ltit·lll.

I\('('all that t 'IJ = 0.693 \ '/lIC I../I . T ill' half-lift· in a patient wi th n-ua1 t1ySfllJld.iulI,
t " I(d ). ('tllll(l<lrt't i tu Ihal in a pa lit'lIl wit h fully fUllt1innillJ.: kk lru-ys , , 1/,It ), is tlu-u

. ' IR' 16-7. 11"0.01. n"I\ « ·n,,1. am i 1.5

' nlal ""1• • ,,..1dt·..r..... ~.... t.. pn ......~1
n-L.oti\~· I" tl..· t"l al "nl• • " .. 1 d ,·ar·
..,....." f Ii ~pi<,.] r-o-«." 'n,,, « 'n;</
li" ..1io", (R F) fu.. a .lnll( "ilh anjt1t l
,·..1" .. "f o ,~ , U" tHlll ," 1 0 00 . .. 0 .. 1
dc·.. n n ·maio . n .,,"a,,1 alKl in·
, ..". 1... "1 of rr nal f" "t1i" " . I" (u ,·
tn..., t. lIul. ..md n·na1 d.·..,...." ... ln-
tn '"",,,, in ,lin ..1 p"'p",t wm 10 n -nal
f" " (1i"lI. TI,.. rt-.lIlti ll!it (I"t..\) ",,-
bonnd d ,·arlllll... ( ~,J "r ...1 da"h..<1
h,l<' )i'" ·........ in I'ar,ultol " i llo n-nal
do·anuK fn' ''' II \>11".· "f 0.2. n,..
......·,," ..1by ...",.......1 ('1o''''''''''~'. I" a
,..1,1<' of 1,0. "~"'1' tI..· n·na!fur..i'"''
i5 th..1 of Ih.· t:.pil.. u pali' '1II, In , hi"
itl" \tr.. lw,,,. ...,oa\ rlJl"iwm ,......... i" ..
~"'P of 55-~"'df""'1. 71 l-k!it palw·n . o ¥---~---~--~
S,..,n',oal d. ·..nt...... ii, "f (~", ,- o 0.5 1 1.5
pN·" -ti tu d , llIlK" witl, .. jot" am i
,,"';1(111 (<:1"",. 15 ).
Renal Function (RF)
 CHAPTE R 10 DOS' AS! 2"
A B
fell)
1.0 felt) 1.0
~
0 5
~

~
~
0
~= 4 0.75
~ ~ 0.75
~
~ ~
-
025 ~
-'"
<;: "
~ 0 ~
~
~
3
::::I ;;:; 0.5 0.5 ~
0 0
D~ ~
2 0.5

,.
~ ~ ~
",1;;
- ~
o~ 0 25 0.75
•-r-• 0.25
g 1 0
~
« "
0;
0
1.0 0.75 05 0.25 0
1.0 ,. 0 1.0
«
2
0.75 05 0.25 0
Renal Function Renal Function
H I(. l fi.-..'I . 11,,· .·,"·"I..f ,I........"... ill"" 1"",,,.1.·1.·....-........-. (.-\). ..".1.um" I'" ".L"lt i ' K'Tl~"'''' in l"o.If·l;f.·. (Ill.,.. "" ..1
I,;,' ...·".,1tl"f'" wh"" "I.., .1.1,..,,,1,>I, II,,· f"",1Mo1' IIfhio""';ojl,,hl.· ,1....1: ~llK'IIn:.. ,·",n1,..1i" "n,..· "'K~""'I:< .. l.ji1n
~,~ , . 111,,1 1:,·",·n,,11,\' ,Ie....• ", IJ'" I"",nl " ,,,,I.I , ,, ~ I...· ,..,,,.ic"·.. ..1 ""I.... II.., ""t.... ,T\<I c.J.·ann"..· in II..• palic 'n l f,·11
1..·1"•• ';'( ~ "f II,,· . "1,,,· till .. '~l'W"l l'"li' ·"I . 11..,1i•. 1>••1.".. tI..· I.."..;""..,laI "'~ I, ..l li,..·. 11,,· (·ak-ub l;""'. h.",' I....·"
IIM'I.· fur a ,;,u. ~( p"h" ,,1 "f ",mpa hl,· ..(•. '" a ~-pkal patio·lIl. 11M' " "I MIIIIMI \~ >Il1 n ll' (If disln ]II,I;"", "f tI,,· <1m\(
i. ~'1>t " ", . 1."" . 11..· ..· ·, 1 · 1" ". ,\ , I..· ,."" I'i".oll< "ffi -il ) ..".1 n·,...1 f"' ,,1i"" flor whk'," " i"
ro.,,·..f ",1" " ni,I...,I1<'" 1 .,,, , I,,·r"l..·" lil...IIYI' n ..1.1'1.

wln-n- " 11(11 ) a nd ' '1I(t) an' tilt' lI11bu!llld \lll ll Il W~ (If t1i ~ l ri hll t i un ill tln- patu-nt wit h n 'na ]
di !>t'a~, ' am i ill 111I' t~V i('''] pa til' llt. n'~p('('l i\l' ly,
AI"" . n-e-al] that \ 'u 1t,IItIs tn ' , II')' ill t1i n "t1 prop ortion tn 1....ly \\l.'i~l l t . If n 'lIil] Iuncnon
dnl"~ not afT,"t1 "u,tlu-u

10

F i~ll rt' I(~n Illust run-s III<' t1"I)I'lId" I1('" of half-lift, o n 1..,l h n-nul funt1inn am ] Iractlou
t' \(Tt"t('t l lll l(' l l a n~ ... 1. :\'otict' t ha t fo r a dn l ~ e xt'rt"tt'(l t'ntirt'ly Iln dmn ~t,(1. half-life dl ,ltl~t'S
tilt' 1ll0~t wln-n n-ual [uuct ion app m",,·ll('s zem.
An addi tioll,,1 poi nt I u-t"tl.s In lit, mad" wit h fI-sp' '('1 tn data ''''<Illin ''tl ill till' di!Tl'fI 'nt
im li\idllals in Fi j!1In' I fl-il. 111t, r-axis . cn-atmiue clearance. is a function o f ;l~t" , weight .
allt l n-nal d isl';l'it" O llt' miglll "\1)1'('1 th at nonn-nal d ,'a r.lIlt't' may alsn II<' n 'la lt"t! to a~t'
und \\'I'igllt. I l i ~] l(' r "alm' s of nonn-nal d .'ar.U1''t' occur in )l lllllv;er lind larger pat i t'IlI~, ",lUI
han' lti~llt'r t'fI'a tinill,' d' ·ar.u l('t·~. and s maller mlllt,~ ar e ('xp<"t1t'() in o]d,' r <I1ll1 smalle-r
pat ie-nts. This pos itin ' corn -latiou tlf 1I01lTt'lm] dl'a rlillct' wuh c rea tinin e clr-uranee Illay
dis tort t h" r,'~n's~ io fl ~tl t ha t tlu- y-illh'Tt't'pt is lowe r a nd till' ~Iop(' is ~rt'ah'r th all l'xl)t"t1("t1.
hh-allv. n 'llal eh-ur.nn.., shollid I.., ('lIm'laft"tl \\i th creatinine ck -ar auce, a nd lilt' uonrt-nal
d ,'a r;;H('t' ~I lt lllid 1,,' ('\alllint'(l !>t'pa ratt'ly for its d t'lw ml t'II,'t, O il a~t'. wt'iV;ht. allll l)t' rl.a ps
n -nul t1iw 'lS" ,
Estimation of Renal funrtion
COllluum[y I'rnp loyt..1 IIW; lS ll n'~ nf n ' na l fun ct ion a n' h...S1"t1 011 cn-arirum- II ~ Il s('fu l m '~~
IiI'S in its d, 'a r.lltt't' \ '<l l')i fl ~ ill dire-ct pm po rtioll to tilt' n-nal d t'a r.lIlt't' IIf mallY t1n1/-."S (t'.V;.,
F i.~ . 13--- 11).
III l'Iillit·al l' rad i,'t·. cn-af imr n- d .'a r.m,'t· is lI~\l a! [y t'~l i lllalt"t ) Irom !>t'nl llI ,'n'atinim' a1o nt,
ruther than [rum 1ll,';lSlln'IIl,'lIls in 1" ,tl. ptlsma '11111 urine. :\ p,;\11 From tilt' t'\l m analysi ~
 CHAPTER 16

involved. incomplet e urine nJ llt'<.1ioll is a major p robh-m n -su l t i n ~ ill lilt' underr-stimation
of crcannlm- ch-urancc. Senun <:n ',I!in iTw aloll!' can 1M" used h' "i.'OIIISol' its daily production
is ma tdu't l hy its elimination under nonnal drt11Illstan('('s. (AlIISol'l"llIl'ully. Sol'n un ('n'a tilliIW
is rdah"tl lu (·n'a!illint· ck-aran ce hy

Rote of creatinine production

Serum creatinine - 11
Creatin ine clecreece

Tahl, ' 1fi- 2 '1l1111llari/"'" sonu- o f tilt' n-huionslnps ('urn'nt l~' found to appm-ximah' en-
utuum- (·II·a(;lIl('t' fro m \I' n UIl r-n-at inim-. l1]('S(' n-larionships Include com-cticn s o f en-at-
[niur- p rodrn-tiou lilr a~" . \\l'i ~ht. and gender. It should hI.' e mph'L,iZl.'t1 thai tlley a rt' mos t
al'('II(;I\I' for illllh-idual, \\i lll all a\ c 'ra~, · muscle- mass [sou rce of l·ft'al illim') for tlw ir a~t'.
wd~h t. .urd Ilt'i ~ht . For "lIl ilc'ialt'c!. h h:h l~ IIlm(·ular. or oht'S(' ad ult p atients , POOT r-stimutes
art' " h lailll'l i. For Iii" ,, · pal it'll h a u, 'alillillt · dt',lf<uwt' meas un-ment lIlay 1M' mo n - a ppnl-
p ria lt ' than all (" limait' of ih \-atm' [nun serum cre-atinine- uloue. Filially, o n tliL,sin~, it
, lrtJuld 1M" 1I111t-1I IIMI ra In tl f IWllh producriou and d l',m lll(1' (If t:n 'atinillt, n-ud to dt 'l 'lillt'
in paraH,"1 \\i lh at:t'. CIlII" 'q ll" lllly, serum creatiuuu- n-uuuns n ·latin·ly constant (about I
IlIWtlL) front a~," 20 yt'ar~ tJlIwa rcl for p atients with normal n -ual funcuon for th eir a~e ,
Ik ll;11funct ion ill lilt " illtli\i tlll;ll )lalit'lIl n-mams h i 1M' ('ak lllah 'd . Th is vultu- is W\l'1I by

RF - C0dl/C0~ 12

wln-n- C l .,.,.(t! l ;lml C I ." lt ) an' tIlt' creattnnu- dc'ar.U1(1·s in this palil'lI l am I in IIu· t ~llie.l.l
pal u-nt , n " Ill 'l·th 1·I,\".

Adjustment of Dosage Regimens

T Ill' ;11h-m"thn II,r udju-tuu-nt of maintenance am l lo;ltlill~ doses in pa tu-nts \\ i lh n-nal
fllndioll imp,lim ll'lIl app ly, ;11 prilldplt·. 10 all dist',L'it' cnmlitinns in whieh d mK r-liminuriou
is all,' n·,!. For 110 ull ll'r r-oudittou. hm\l'\l "r, is t!l(, adj 1lSllIwnt n-qum-d iL' n 'mlily p n-dicted
and <I\ \, ,\\( ,tI .
\I i1inl t' llilll ('(' Hah'. '1'1 11' simpl('sl \\~.ty (If l"l )lI('t.' i\i ll~ lilt' adjusl llit'lit of a lII<1in tell,Ul(,('
ftogilll"11 lilt a p.un-nt wil l, n-ual illS ll ffil'it' lI('~" is 10 mai nt ain tilt, s< UI1 P an"r.l!{t ' unbound
(~ ,ll(1' lI l raIi01l al ~ lt 'atl~ vlatt-. ell......:

,.bl. 16-2. IJtlm.tlon of Cr• • tl nln. CI• • ra nc. l. A...lh- .... Chll.. ,..·

Ad -" :20- (f ,ow'''' ; :Y.:l"'

1 23 x p AD - Agel x
""~ 11 .:0 - Ar1 " V\ e y h' W~ghl
12 X Se<lIm "~ ',n,ne $e<um Cf@(]l,oir;e
11 40 - Arl x 'Ne'g",1 104 x 11 40 - Agel x We,ghr
Se-um «ecnoee
., . I i ,"":J" J 'J ~
85 x Se-tum C'M"O,""
. 0 AS X He 'g~' )( ( \\'e 'JI-,l) 42 5 x Heighr x (We>9h1)"
Se<ut"l cecnrwe 70 $e<um creol,n,ne 70
... lYO>l'-.1 ...... ,C~'JOO'J
.v, l~_ .. '" ,.." .... "'''''''8
j,o- " , • • . _."._.~
_r ,...""..
""''''-...,,.J ..
.". ?o
"'"
,"" "'"
"'dapotd """' ... _
r " 1 4~1 ~, r9 7 8
boo too ~ S .,..j-.-
'~h"""" ... ~ ..,.,
j'>3" ....".-J .. ". t ' <J ~ cJ- -"9 , """_ c~ . .. " " _
....., '"'_ P>..". ]7 CJ'. ?~
...,. ..,..,., b ,'• ......",. '9
~"'''' t.-A,_-<1' ' 1 r.... """"""""'\I'_boo ... ~to.o>_n'<ld;... ., <Jd""'b b<>1>-""O:X.O''''' • ""'dcJrord -g-ob
f....' ". ......
CHAPTH 16

13

Halt' o f udmiuistratiou ill n-uul insu llid t-I\l:', (lJ.\tlt)(d) , compan-d to the us ual ratt' (If
ad ministration to till' t~11kal patiellt, (I)u!t )(t ), is then

ID"'/'lidl C"MI 14
IDMl<II~ = CLvI~ .

when- FIlI i am i F(t) art- til(' bilJ.t\'ai l.ahilitit~ of t1nJg in tilt" path-ut wit h r enal im lillid l'nl''Y
t ~]lil..,l palit 'lIl. rt'spt'{·tiwly. \\llt'li hioil\';,ibhility tlOI 'S not d llUlJ::t', tlu- required
and in tilt'
ran- of administratioll ill a patu-nt with n-nal d~sfll lld i oll is

15

Till' n 't!lldillll in dosi llJ:: r ute- is rln-refon- SI't'U to dl' pt'ml only 011 the mt io o f unbound
d t'aralll'I's H,I' Asso(-iah-t1 with tht, n-ductkm ill n-nal fnlld ion is a p ml f)ll~at ion in half-lift"
Wllid l IIIt',lItS that till' tinu- to al'hit,\'l' 11ll' dcstnd plateau is I Ol1~l"r the mon- seven- the
dysfulJ(,tilln (Ell' lu}, Thi s tl,t featun- is Illustra ted in F i~, 16-9 for constan t- rat e ad nnn-
tstnmon. III prad iet', admiuistrut ion is hy (Iis(;n-!t' d(lS(-"s and ",Ijus tlilt'lit of a maintenance
reginu-u llIay II(' ITl<ldt' b~' dt'{·r't-;I-s illg: till' fn"lllll'nl""of ad millh tratioTl, dt'{"rt'a,ing: tilt' main-
It'IHIII( '( ' tloS('. or a o uubiuatiou of both. Ti lt' outcomes of tht'S(, appmal'!lt's an' diffe ren t.
T o ap prt 1.·ialt' till' difTl'n' nt'('s nlllsidN tilt' udjus tnu-nt of thl' usual n1'i nlt"ll o f amikaci u
sulfah ' i ,5 1IIWJ.;g: illjt't'h '(l intramuscularly t'n 'l)' 12 h r to a 2.'l-)l'a r-oltl. &i-kg: patient with
all I'stimatetl l'n' alillint' dea r.IIlI'(' of 13 m lJmin.
As tht· t" I)('{'h 'll cn-annnn- dear'alll'(' ill a l)pie.l.15S-YI'ar-old, i O k~ patient is ii ml/min
(C hap, 1.5 ), the value of Hi" ill tilt' 23-~'I'ar-()td patiellt is U, I i . U sill~ Eq. 15 , it is app,trt'lll
tllat tilt' mainteuamx- do sing: r.tlt' llf amikacm sulfa te should he dt '{"rt';l'>t'tl hy a faetc r o f 6.
TI lliS. tlu- lIlainh-nlUll'- rt-hrimt'lI Ill i~ht he OIl('of the fol1u"i n~: ( I) dush l~ interval increased
si\fnld , rt '~i nlt' n : .'iUII 1I1~ (7.05 TIIwKg: X 6Ii k ~) 1'\ '('1)' i2 h r. (2) Ti lt' maintenance tloS(' ma)'

RF
1.0
;;- 0.5
~~
0.8
0.2
u
~
~

U5 0.6 0.1

" 0.4
C

.~
0
E
5"
e
0.05

.~
0
E
0.2

0
0 5 W m W ~
Time/(Typical Half-life)
 2. . CHAPTER 16

he- n 'tlul'('t! hy a fact or nf 6 , n-w ult'u: S.1 lUI: t'w l)' 12 hr. (3) Hoth , ltlSi ll~ mn-rval alill
main te nan ce.' t1n<;t' Illay he:' adjusted to n '(llIl't·tlll· a\ 'I · ra~t· dusill ~ rate sh.fold . " 1.';lIlt'lI: ('. ~ .•
167 1Il~ ("'"('1)' 2-t hr.
TIl(' typical half-life of amikacin is 2: hr. so fur tln- pa l it'll l under l't lllsitlt' ra tio ll the-half-
life is prulnn~('(1 shfnld to 12 lrr (Eq. 10). Fi~. 16-IOA is a , kd d l of t i ll ' amount in tlu-
hCKI)' \\; 111 linK' fo r the tllR,(' lIlilinlt'lI aun> rP)..';IIlt'1IS con sidered. ~\"t'll Ilml 'lhso rp tion from
til(' t.m. silt· is ('t)lIlpldt' ;Uld Instantan eous. A lth ()lI~h hnlh t i ll lt' to n -ach plalt·.m an d av-
era~(' amo unt i ll hody plate-au an' the sauu- for atl tlm-e n..·W"wm. tlu- p il1 un' is \"(' 1)'
; 11

t1i lTt'rl'n l fll r 1'<1(:11 0I1t'. Clearly. dlan¢ ll ~ tilt" interval to th ree <lap «h sllt'd (·urYt·) results
in Ihe ~ rt'a tt'st Hnctuatton. with mallY hours al ho th h i ~h an d lllw ll"'t'!s. C hallj.,ri ll ~ IIII'
mai ntenance dnst" (colored curve ) reduces 1Il1l1ua!io n h ut SII!Tl'O [rom t he int111ln 'nit 'ul,('
of Irequeut i.lII. injt '(1iull s. Finally. dlan ~lI ~ bot l. ma ill!t·JIiUll't· dn~' a m i dosill~ tnterval
h lnUet! t ' I I'\"t' ) n-duo -s hott. Hucmat ion am! tncouv enleuce tn Iht· patielll alii! ,{<; Sill''' lIIay
IN.' Jlwfl'm't! fur this d m g illl d fur many urln-rs.
In this example \\i lll amikacin, admi uistration of tht, USll i11 I ll lSil~t' re~ lilt 'II to IIIl' llilt i('111
with n-nal dysfll lll1ion rt'Sults in a f\\1lfold illl·rt"L\l· in till' max iumm umouut in II." body
and a sixfold lucrease in tln- an' rage amonut a l pl.tl e a ll (F ig. lfi....,'»). It is illlporta nI. 110W(...vr.
to ('ullsitll' r wllt'tl.t' r Iht' maximum amount (o r l111l{'t'nlmlion l o r Iht, an'mgt' a lllount is
mon- d osdy n-lan-d to (' ffil'lll',," alll! lo\idty of till' d m g. O uly a Iwn fole! n-ducttou in tln-
m ai n!t' llilll('t' (LIS(' \\nuld hi' n -qui red (C hap . ' ) if tht· fo run-r wt-rt- t rue.
LO.llding Do se. Pa rt k1,la rly lafJ'1' difh-n -uces in 11 ll' ;111\011\11 of amikacin in 111I' bIK !~'
extst f,,!IIMing thl' nol dow of tbl' Ihn"(' n'~ llIt ' ns just constden-d ( F ig. l fi..-Illa ). \\'ilh lilt'
n.-WIII('n of 500 rng ~\'('n t",'('ry.2 hr 10 a patient \\i lh n-nal d~'Sfllnl1 iI)1I . us wi th 111I' n ,;mt'lI
of 500 1Il ~ j.,ri\l·u eH'T)' 12 h r In a t}Viml lliltil'llt , then- is Iitt lt, ;t('(·lltllllb tion Ill'(·allst· Il.e·
l!osin~ int e rval is much !ongt'r than Ihe llitlf·lift'. A('('()nl ill~ly, d Tedin' It'\ t'1s a rt' n 'adl(1:1
a ftt'!' I hl' Hrst dn.\(' . In ("0111I'lL\1. a p p n'liahlt, accumulation (N.'(·Urs wi t II Iltt· rt 'lati \('!y frt'(jllI'llt
wW llI(' n.~ of ()lll,(' ('\ '('T)' 12 or 24 hr ill patients with 0 '11011 dysflllll'tioll . 1111' initial dose' is
IIU", much Il'ss t ha n th e a\'t'm~(' umouut in tilt' hody at plan-au. Under li lt'S\' l'in:·lllll \tallt.'t·s.
a case Illay lit' made' for a Io;\(lill~ dust,. (; i\ill ~ a usu al do<;(' of soo Ill!!: can It-iul 10 h i~1.
level s ill till' hellly for all ('x!t'm l(1:l lx' riod :Ifk r i ll i lial i n~ Illempy ( Fi ~. I f~B ) . ", Ilid l may
inl·f{·<l.\(' lllt' d mu l't· (If :U1 "d", ·f'S!· (·!T('l1 . A sllla llt'r l l liid i ll ~ diN ' Ill i ~h t Ill' p n lllt'lIl. In tilt'

500 ,, , A 500 , B
,,
,, "",, ,"'
00 400
.s ,, , ,,
0
.s
400 ,,,"',,
,, ,, ,, ,,
~ 300 ,, ,, ~ 300 ,, ,,
,
.'"e" 200 , ,, ,, '" ,, ,, ,,
"
~
0

"
« 100
,, .. ,,, e 200
~
0
E
« 100
,,
,,
,,
,,
,,
.N\
,.

,'
.
'.
,

'.
,
'

0 --- 0 -- ~~ - , '
0 24 48 72 96 0 24 48 72 96
Hours Hours
I'le. 16-1 0. Sh 1d , nf tI... '''''1111'''' "l "",i b •.;" . " If" l.. ...I"i .·..lt·1l1 \ ill 1111·111111).' .. ill, h nM' ill " 1>;11 ;"''' 1 " III · n 'na!
r'"I11;I" i. 1 1>.~q. ,If 1111' 1~1>it...1,-..I,...., silt"'" lin " n 1.";"" ·'I.' ..;111111'1 ttl I ",III w;II' IH) .. .5l . " "'1: 1< .....10,,1:,t. n ..·
"~lIh-'''''l(~ 1't')(i1l" '1I.' om'; ( )-.5( J) "'I: (.... .~' 72 lor; I"ol"rt..l li,...) - ,lj.l mit (..... ~. 12 J.r ; (· ··)-. 11>7 "'I: ~. 24
I,r. S 'Il" ; i.\'. 111 >11.. ... lmi" ht r"t i<"lb . iIllUL." ..I,
CMAJ'l£ 11 10 26'

pa rticular ( ",1St ' IIf am ikalin, ha M'(1Oil ('Xpt.' rit'I1("t', lilt' manufacturer recomuu-nds III It chang-
iuj.( lilt, uSllal h .l(linj.( dllst,.

General Guide&nes and Umitatiolls

Eu"t'p t for d m gs \\; 111 \'1'1"). Inw Ilu'ralx'ulil' Indkes, a reduction of les s than 3f)l;f in till'
d osing rail -. Il<l\l 'l1 0 11 a d l'llIj.(t' ill n-nal fun ct ion alolil' , is pmbahl~' un wa rran hx ] for iudi-
\;dual.s ill Iht, usual pal il'nt populatiou. For a \"aril'l~· of reasons ,-an'lbility ill absorpnou.
divtribunon, une] cxtran-nal d iUlinalillll is Ilsnally 011 least of this llIa~ui l llt lt" an d till' the-r-
"lwllli(' r.tIIj.(I' i" olil'u s,,!lid l' lllly IaIW' til lI1akt, atlj nsllllt' nt lu-n- 11ll1lt '{'t'!>~II")'. ConM'-
lllll' ntly, ,lS 101lj.( us lilt' fraction t,\('ft,!t'(1 t1 lll'hall~t'( l in t'Vil'al l'li.llil' llts.ji'(t ), is O.3fl or less
and ti lt' ll11'tahlllilt 's an' illat'l iH', 110 d JaIl~l' ill II ft1.'illWIl is l'u llt'(l for. lI,l\l '(1 0 11 n-nal
fUlll'lio n. rt'~art ll(' ss nf IIU' funct ion. Simi larl)", rt~artllt'Ss of tilt' ('()fltrilmfion IIf ti lt' n-nal
mull ', if n-nal flllll'lio ll is (1.70 o f tilt" I, Viml \1II1It', Ull dJan~t' is 1\('('(lt'(l (St'( , Eq . I ,'; ), 111t'S(>
rt't'(lllllllt'lldatillus an ' sUlllumri/..t't1 ill Fi ~ll n' If).....I;A .
As n-nal Funcnon a ppnMdll's r:..t·rtl. tln- importance o f nonn-nal dl'am nn ' increav-s.
J I OW( ' \ N , lIo lln 'nal d t'ar.iIl("(' lIslIall" vari es w; <!d,·wi thin tilt' po pulation , making pn 'tlil1io ll
of till' optimal dn'i;l~t' d ilTit111t for all individual wnh margtual renal funct ion. \ \ l lt' n ji'(t)
a pprt l<l('!lI'S(JIll' and 111-' approacln-s ..a-r c. tolal clearance is small, and tilt" t1osi ll ~ rate must
1M' d r.l\ t i ('"I1~ · n 'llllt'('(1. l1 m"C' J"l<lrtil11Jitrly di ffil11h probh-ms an' r-ncounn-redlu-n-. OUI' is
a rdaliH' ly Iargl' d lilllj.(I' ill rlu- chronic reqnt n-nn-nt s for a d r ug with only a small d l;UI~t'
ill n-nal function. t·.j.(., a dlallKt' faun 0.20 to D.O.'; ill fl'lIal fllllt.1 ioll reduces tilt' rt'lillirl 'ti
ralt' ofadm inistratillll fourfo ld . 1111' M't'(md pro blem is ll'>.su d at('ll w;lh accu racvof measure-
IIlt'lIt (If rt'na l funct ion. TI lt' thin l relates to IIn- stahilitv o f renal funct ion with tillll' . 111t'
flllld iull lIIay 1)(' illlpnl\; n j.( d uri ng convalescence or dt 'k riomtin j.(. All thn-e- p robh-m s ere-
au- 11IIl't ·rtaillty in prt 'l lit1 i ll ~ t hl'i;t~t, n 'fl" in 'lIlt'llt s.
A Fu rther t'l'lIIplit·;ttioll ill pat k-uts w;lh M'\"('n' n-ual <liM'll';t' is lilt' concurrent and rt"~II ]ar
UM' of a ,lia l,~ i s It"l·llIIifllll' to n 'lIllJ\'t' unwanted ("1Il11~t'llou.s lin k stlbst' l!Il't'S, which would
othl 'I'\\;M' al'('u lllllb lt, am i t"IlIM' prtlhlt' lIIs. Unfo rtllnatd y, dialysis Sflllll'tiTllt'!l al'ill lueteus
t'li minal ioll of t1 m j.(s. t"omplit1tling t1mg tllt'r.tpy in these- patients, a topic l'own'tl in C hap-
ter 2-1 ( D ialysis).
TI lt' forl'gninj.( n-comnu-mk-d adj llstllll'lIls an' h<ls('li 011 a num be-r o f assum ptions . 111t,
mdhot! faltt,J""i if hi o'l\"ailahi l it~· l·h ;lII j.(t'S in n-nal d~"SfIl1l(1 ioll, ,d Jidl is n-lutivd y uncommon:
t'lllllp mmiM'l1 n ·n.11 fun ct ion uln-rs lilt' ah ility to nwt aholi 7..t' <lnlg, which (1l'l1IfS wlw n tilt'
kidnl ~· is all ofl.tan of IIldaho lislII as w"('11 as t'x('n 'tioll , or IIwt aholism o r n'n.J.! t'u 'n'lion
1'\llihits t'llllt'l' 1I1mtioll-tlq)("IIlIt'llt "i nd ies , ilS tht, relal ionship hd '\"('l'n Intal d e.mUlt'(' and
n 'na l flllwtioll Illt'lI IM'{'llllw S ext rell w!y ('llln plt,.x. A prtlb] l'lII also ('xists if n 'na l fUIl(1ion
\11rit'S \\; 111 li ml' or n 'n al d t"lf;lIll'l' is not di n '{1ly p mporti oual to tilt' IIlt"lsun ' o f n 'nal
rlllldillll.
A llIpl i ~\; II j.( nil till' h ,1 flualifk alioll, n1::ard lt'ss uf wllt'tlll' r tilt, d nJ~ is t'\('n 'It"{1 by ~Iu­
Illt'nl lar fi1tralioll ur a('lin' st'{'rt'liuII, ft'll.11d t"lr.lJll,(' is aSSIIlIlt'tl lll dt't'n'aw in d in 'l1 p m-
po rt ion to l'r!'ali llillt' dt'a riUl('t'. 111is 'LssUl uplion appear,; !o lx' ' -alid ;lSa 6r,;1 appmxi lllalion
in t'!ln lllit- n 'nal t1ist',L\I', I'am-amilloh ipp uric add . pnx,;tinltmidt " (';lrIM'nit-illin , itlld lM'ni-
lilliu <ll't ' all t'''lmpll's of a(1 i\"t'I~· M't'n '!t'tl (,(IIll[XlIlII<ls \\; th n 'n;t] d t'a r.U1t'l's di rt't1ly pm -
po rtinll«11l1 t'IltII)~~t 'nlU l s l'rl' atinillt, dt'a mn('t', fi nally, intt'IJlalit'lit di !Tt' n 'n('t's in ahM).,)-
tioll . t1istlilllltillll, alltl IIlt·tahlllislll . til(' n "'jl" llst' 10 a ~\'t' n plil,ma ('lllil'l'nlm!io ll, alld
t,( lIlt'um'lIl tliM'ils(' slalt'!> ha\"(' lint !M"{'n l'llilsidt' f('ll,
Ht' ual fund ioll is tlllly lint' lIf M'\'I'r.11 MlUrt't'S o f \1tri;tbilily . :\ dj nsl lllt'nl o f t1 n l~ «d m in·
i\ tmtioll I"Lst'tl lJll n 'lla] fllllt1ion alllllt' lIlustlM' put into IM'J""ipt'l1l\'('.
262 C HAFTH 16

Furtfter Considerations
Heual d is.<'a.<;t· nflt'li alTt't.'ts ilion' t han jml n-ual ch-arancc. Furthermore, {1 J1l{'U ITI' n l di s-
t'lL'it'S may alte-r d()sa~t· requin -nwnts. Di~()llill binds lIIuI-II less to lis.slIl's ill un-mia. rc-
sll it i ll~ in a smaller volunn- of dlstributtou iUld it shorter- half· lift· than that p n '(l il"ft '(l From
loss of n-uul function. This dec reascd nssue hilldiu!?: reduces ,h(' hllliu!?: doS(' n-qum-d hut
11a_s little o r 110 dT('t:! Oil tilt' mai lllen,lll('(' dose I lowt...v r. th t· pn'st 'ul"t' of St'\l.'n' t1 l11gt'St in'
ca rdlac failuft·, a l'tltlt lititm fur which the dmg is IISt-I' !. is 'Lss.od a!t't! \\;111 decn-ascd uu-ta-
boltc clearance and \\; 111 a daily maintenance dU<;;I~C n-qum-uu-nt rt'tllll't'{1 he:- ~ md tim!
t'llpt,<-1t"'ll for n-ual flllll1:iull impai rnu-ut ulonc-Tlu- dJ<tll~t·s iu d iJ'oll:in dt'a nu ll"t' a nd voluuu-
uf d ist ribut ion \\i th "m al function a nd l"tlllgl'Sti\l' cardiac Iailure. o htai llt't l fnllll pllJlula tion
phanuaco k tm-nc studies, an' summarized ill Tnhh- 16-."3.
P11t' 1I~1 0i n a nd 1ll ,1Il~' ot her acidic d rugs an' two 10 th n-etnm-s It' ss well-bound to plaxma
proteins in un-mtc t ha n in normal sllbit-'t.1:s (F ig. 12-10), Part o f t his ('ha ll~l' is dllt· 10 11 e11'-
cn-ascd omrcutrattou o f plasma allnuniu. 111t· 1II1't.' h;lIIislII al't.'ollilting for IIII' rest of till"
(:hallJ'e is uncertniu . alt l ll m~h d hplm.'t·lllt·nt hy <Il l ('mloj:!;('n oll s l"tJrnpOIlIllI(s) Ilial ;!t't.'UIIlU·
lates ill n-ual impai rment h,l'i ht 't'n s ll~eslt'tl. Even so. the unbound vulues llflxlt h clearuucc
allli volume of distri bu tion u f tlw~' pri ncipallymetabolized d mgs rem ain eSSf.·lltially uuclnm-
gt'( l, ami 110 dm ll~l' ill dosage nW"lt'n is a ntid pa lt'l l in n-ual fu nl1:ioll impairment . 111l' total
plasma clearance. ho\\ ·l...'er. Increases two- to rhn-efold. ~\i llg riseto a ('o m 's pomling d m p in
Ihl' sleady-slatt' pla.'ima concentration. This d mllgt' lIlusllM' can-fullyconskh-n-d wlll' ll inter-
p n 'ti ug plasma ccucentra nons uf du·st., dm~ ill patien ts with n-nu l di ~'a......-.
Allot hl'r uurom mon hilt potentiulcomphcat iou to adj usting IImg ad minislmtil l1l in n-nal
di st'llS(' is metabolism in tilt' kidlU~·. An example- is that of Inupeuem. an antihiotic that
llndt' rgtJl's h)ll ml ysi s dll ri ll~ (',en 'lion byu renal bmsll bonlt'T dt'h~-d mpt'Jllid,L"l" Paueuts
\\i lh renal d i ~'a.....·lm\"{· a decn-ascd ahilitv to Ilw lal xlli7.t· a\ well ,L'i n-nallv t'.\t·f{,tt· tln- dmg.
111(' changes in hoth total a nd n-nul d ('a'Tlllll't'S an- slul\.\1l in Fi~. 16-1 flIT adult patients
i
\\;111 \",u')i n~ dt~n't"'" o f n-nul function. 111(" t"IJl'l1:aliun, ,l'i IInll'tl ill Fi ~. 16--; . is th ai lo lal
plas ma cleanuux- and renal clearance increase ill p arallel when non n-nal ch-nrance n-mulus
constan t. I nste;ld . it is ap lla.n 'nl 11.011 Ihe d ilTeTt'lI{"(' hd wt"('11 them Ix-conn-s s malle T in
patien ts with 111\\"('r renal fllul'tiull. Here, 1I ("tJmIJllllt'lIt uf till' SU-{M.l.IlI'(! nu lIn'lIal dt'amllt'('
IllX'UfS ill t ht, kid lll')' ("'"{'n thou~h it iIl\1Ikt.·s llIt'l aho lis lTl . Furtllt'nllllTe, Ihe in h 'f{'t'pl valul"
p n .slIlIIahly wht'n' no kid nt'Y funl1:inll is p n·~'l\t . shll\.\'11 t ha i 1I11lln'lIal llIt'lotho lislll IIlIlSI
tllX'\lT ll\ \\"{,II.
P{'Tlmps, tilt, m(l.~t (,(lllllll{llll)' invalid a.\Slllllplioll is tha i mt"talxJIiIt,s a n ' pl mTl n;ll."tll l ~ ­
ca ll)' a nd to\ i{,,(llo¢ {'a1ly inadi n-. For ('Xilmple. tilt' lIIt'tal xlli!t· of 1II00vhiue " lIloTphilll' -6-
KllIl'IITOnide, is also adin-" Pn '(Iic..1 ioll of IIII' lo lal at1:hit)' o f thl' d m~ lind of ti ll' dnsa~l'
adj ust mt'nl Jl("('(lt'(l in n'mll failu re (~n hl:' lllueh mUTt' {"tllnplt·lI:. :\"ulIl'l ht,ll'ss, th t'n' an'
W,,)'1I u f t n'ali n~ suc h sit ualio ns , a.\ ¢n' u in C bap. 2 1. ~ I t'l;tl x ll i l e Kind il's .
In th is c hapiN , <Ipp madlt's han · IJl'(·1I pTt-S<'nlt'tl fn Tp n't li{1:i ll~ l'h;Ulj:!;t'S in ti lt' d l ;lT:IIII"t°
o

of d m g.s in \~rioIlS diSt·a......• sta!t·s, Rules for l;"sti lll at i ll~ n 'nal d eaTlllll't' of a dm~ fmlll

,.It~ 1...:l. ......... . .. CI"_RC V.I DI.Ift t DI••• I.

I ....... .,. WIth MlitII • • tII h • • _ c. Ca I_ f.II •

M id
5eve<e
Ct t> + 0 Q.4 8<
OQ': CI". + 0 02
" .
1'C)U",·,'i Of (llSTW$,ITlQN

JB + 52 Cl",
3 B + 52 CI".
·~"""':S;- .18 ~ B. - o - , vv f_,j~"""""""",,,,,,,,jP"o-x"'_~'I..,.._
cWocaldalo J ~_ ~ ,' «~ -4lJ'Q 1971
"Cl,. • e - doooota .. Vlw/l.g
' ~...-. ,j ~l<nod>okl~
CHAf'TH 10 ~"ASE

400 . -il(. 16-11. Tntal pla." "a ~ ~~ ,I"r )

aud Il"na! i hla<.-k ) d .......a'l('M "f tI..•
• In("l~·a ...•
• anlibinlk imi1"·,,.. m "'ilh

E ••• tI..· n·..al c" ·ar..,.. ~· ' ,f ·' ,Cr.... hl·I,.....••

M Total diam l"'1rl ruo.'f'1 i,: add ( '''Kll~ i7.t't1
300
"-
~

~
~
t Il 1.73 m ,,( "n,~' ~" rf...T' .....a ). a
l

nmrk"r uf ~1l1"'",lar Filt ralinn rate .

Snrp risinj.,'ly. tlo.· l\Oo~1 dl'anll"~" d"
c •
• n"t I" lTl·.....· in l'",raIk-l ...< ....I"'l1 ,..1
E •
::J 200 • ( Slot" H I:. lfi-71. i" dil.. ti UIit that tlo.·
- no" r('I,;. I" d ..ar .." .... "f tl,.. ,In ll:
S must il.. o,,'l"n·lL,I,,!i.' "'ith d....,...a.....1
~
u
c 1 • n-na l function . TIll' .·'pl..nati nn I.
\
~ Ihal tho· tlmll: i. " .... a1"~rn ..ll o:-· n·"..1
~ 100 •
~

13 ." Renal • hm<h hnn ...·r llo 'h~dn'P''f>lic4... ..,,,I

.1.•.
..J lhal Ihi. ;KiM!) ' ,......"..... ., "'i l l.

0
0
••
..1l!!:....
'. •
•

50
- •
• • • • • •' -
100 150
m 'lLl illl/: n ·na! f" 'lcticll1_ Th' i""' r'
....pl ;mli.,.. t ... ,10..1 m m.· n"" ....n",l
",.,t ..h" li,," 10"" I... "c~' '' rri nll:
(Adap'" '' Irom \''''1''''Il,·n. G.A..
\'.'rhi..I . I•. fh mt ,," . "~ Po Enl\Ooi "k'.
51Cr-EDTA Clearance 1. A. J.M
...,. K_II . "'rKl n,·lIn... :o.U:.;
(mUmin per 1.73 m2) TI,,' ph.." ......'JId"'..iu ,,{ im lp" "" m
(lhic·nanwri,,·fun nllmichtM') al..1 till'
n·na! o,,'I;~,jn ,p.'-pt iola.... inl.ihilo r d -
\a..tatin ",.Jium in ", mna! subjt..1S
ar K! p;rtic·" ts ...i lb n-nal fail" .... Hr . l-
Clfn . rl,ar m;l.('ol .• J!j ; 11i3-193 .
19'>-l.l

creatinine clearance or wrutn creatinine havt' be en giVt' li. This kind of infonnalion is use-ful
fnr initi alin g d m~ thempy in an indhit hml patjent, hul til t' \1Iriah ilit)' n-mainiug is often
su ffid t'ntly la~.· thai monitori ng of plasma conceutratmn, ti l t' topic of Chap . IS. lIIay lx'
prudent fur a t1m~ "ith a ua rrow th" rJ.jX'utic windo w .
STUDY PROBlEMS
{Answers 10 Study Problems ore in Appendix 11.1
Li ~t ami hri plly disr-m~ ~ i 1( .I i <;f 'ast·~ in ,,1Ii('h th t' pIJann,u'oki ,wt i."'i of dn lgs is known
to ht' alte red.
2. a. Hank tlu- situatiu ns in Table 16-4 , fmm most impo rtant tn least important, for
('(msitll'ring a dmllgl' in a do sagt, regimen of th e cephalospc rins listed ill adu lt 1);1-
ti.'nts \\i lh \1tl) i ng dt~n't's o f n-ual function. Given th ai all tll.,S(, drugs have com-
parable therapeutic indkx-s. II...• anticipated change in clearance as tilt' hasis uf you r
ra nking.
h . :'\al111' th t' situat ion s in Tahlt, 16-4 for whidl you would rec om mend th at consld-
eratiou 1)(' ~\"l 'n to a change in the usual dosage rcgtmen.

..
T. ltl. 1 6-4.
F't J!CE NT o 00Sl' t</i!-MlJV
ElC tfT£O ~O
,
A CeIt,zo~,me 2B 10
B Cefon"od QB 5
C Celo"'Ondole Q6 40
o Celoranide BO 20
E B4
Cef!az'd me
'"
2. . CHAPIH 16

3 . Tahh- 10-.') ..llIl1ll1otri/l.·" phamMI"lI\..i lll' lk uhst' rYatioll s tlf I",,. {lifT., Tt'n l Clp in id alla l~t" •
..il.,.. ill pa t it'll h ....u h ,11111 .... nhout Iwpatic d r rho<;is.

r."1e 16-5 .-

'A_ _ d_'-""loaIIA
~_ t __
Oro! BoolNo,oool,lyb
Blood c'ec-coce- n;"ull!

e-~ nQo>- lo} IQl'.l

1..-_<1 _ _ ...... """' • • 06
1""",0.:- -4..(;."'_ . •
0 18
1 15
"""""'J e,..",g",..,' 6
.... 06 ... _OC<tlOoClO'O
<low
<I"d~ II
0 08
0 08
t ~.. ~"B:It " __
0_ '
0 00
0 87
0 57
t~d""""","",'"

a . K I " ,"i li~ tlMI ,)t>llt;v.lldut· iUKI ITIl'pt'ridint> an' (·liminalt-c.1 prilllari l~' Il)' I K 'ratK: me-
lothol i\ lIl. "lI~("!it a 1llC"(-hanism to t'xp lain till' a1tt'n'tl \..im 1 i{~ in Iwp.dic ci rrhosis.
h . E\.p l.Jill ....11Y tltt' oral hif)a\'ai Llhil i ~' of pen tazoci ne- is afT('(1('lllll ud. ilion' tha n Iha l
l)f 1lIl'Ill'rilfillt-.
-I 111 T alllt· 16-6. '-aricm" dat a UII fl Mlr p atients wi th \-af)in~ tkWt"'-"'S uf n-nal fUlIl :tiull an"
li'Ott'tl. X Ullt ' of tllt' lII ts U1l(k'rgoill~ a dialys is proc ed ure.

,.We 16-6.
,.uiNl
'"M " •• "M
""""'"
Age 1)«1" ) 25 82
eo
F
3
F
15
:::J,hl rig1
5efum
I (em]
C'eot,....r>e Img/dU
"
18'10 I t<)
25
15
06
I 6
08
160
30

;I .Estimah' tilt' l'n'a lini lit' d c-arall(.'t" in (·'K- h of lI WSt· illdi\;cluak

h . C " I('lllah' 1111' n-ual fu ndiun i ll each of tilt'S(' pa tien ts. Express n-nal function ,l'i a
r;tli u of ('n 'a l inillt' d c-amll('l.' ill tln- palit' lll In til(" va lu l' {':\lx"(1c'(l in II t~ llk·.J 5.'i-) (·a r.
Hili. 7U- k~ 1);,l l il' lI1-
5 . \'am 'ulIl) "('in j<; dU )'\('1I for IIII' t he rapy o f a 17. kJ{. -t-year-old. IUIS-(:Ill lall IMI)' \\ilh
\ Iapllylul'ul'{'al p lll'ulIlOl lia, wllil'h is n ·frad0l")"to ot ln-r antibioncs . Til l' cluld h,l" mod-
t'fald y hupai n-d n ·nal fUliC.1 ill ll ,1.\ indicated hy a serum l'n 'ati n im' of 2.• IIIWdL. All-
p rU\ imOltl'ly tj.,)Cl llf a df)~' o f vancomycin is normally {'x(:rt"ll"~J IlIl(:h all~c '( l . Its IlIllf-lift"
and voluun- of t1 ist rilmlioll an- fj hr a nd 0.-1 I J1~. n>'I )('(:ti\'t'ly, ill a I)Vk aI 5S -)"t'a r-ol ti
pa til 'nl .
<I. Est im a lt' till' maximum and uununum stt·il(ly-slalt. eonce-ut ration s ll'iSCIl;ah 'C l t th
IIlt'm py in a I) Vieal 5.'i -yt'a r-old palit'lll who n-ce-ives a )()( )O- IJl ~ i.v. IXIIIIS tillS(' ( 't.!') ,
12 h r.
b . ()I'h' rlllillt' ;1 dnsil~t ' " 'WIIlI'1I fu r the 4-) l 'ar -oltl to a tt ai n a nd uraintain tI... .unouut
(o r C1 l1u'('nl m tilln ) .... -ithin t ht' limi ts ) UU dt' r1w"t1 in "a" al xnl ' 10 m inimi 7j ' the Iikt'-
lihol xl of tl u- d lild d("" t·lopi n~ utol:o\ idly a m i a Iurt her de-crr-ase- ill n 'na l Iu ncnou.
IXIIt. h J\it· m,lII ift '~ lalioll s of ('.\!'t'Ssist'ly h i~h tU lIt't'u l:r,d iu m of \"llllt' llll), ; n .
e. P n 'pilll ' sk('l l'Iws o f l ilt" an tidpalt"tl amou nt o f S"llIlt't II1l), ; n ill t1w ho(~' ....i tl. time-
ha d tl... IIsualllloUnlt-na lK'I:' d o.....· bt"t'll ad jll s!t"tl for:
I. TIlt' l'Il iltl... a~t· a nd .... 't·i~h l ullly ( 110 atljllstllwlIl fur n'lIill d i~ ·aS(· ).
:2. TIlt' l'Ili ltl's a!{t-, w('i!{ht, aud n' nal runt1iull.
:\"(1 luatl ill~ ( "N ' is ~\l' n in t<il!J('r sit uation .
CHAPT E ~ 16 , .
6 . T Ill' kiudit's (If IX'lJloxifyllim'. U 1 lt' lIIorrl.t'()I (,!~il' u!{l'nl p n -scn b -d fo r Ihc' trea tnu-ut o f
p -riplu-ral arterial disl':L"l' and i utennit te nt claudicat lou. is affected by cirrhosis. T ahlt·
Ifl-, s!lows tln- d l ;\l1~t 'S in half-lift, aud ,\ UC follo\\i ll~ t.v. ami o ral (s ustained- release
la hlt't ) admlui stranons. Le ss t ha n 1% is l'xl' rel l"d 1 1Il(-,hall~t'll in til(' uri ne. For till'
jl ll 'l)t IS!.' of t h is probk-m. 11M' Ullly nu-un val ues.

,.ltl. 16-7. M.H·Uh ..... AU~" P....:d fylU. . I. H_hhy hltiMb .... CI",",tlc
htl....-
'"'f ..... THYSlIltKTS ce-orc PATIENTS

Inlrovenou~dose
(l 00 mgl 0 8 ~ 0 .3 0 4 1 :!: 0 .0 8 21 :!: 1.2 14 :!: 0 5 1
0'01 dose (400 mgl
(w~i nech eloo!le Iobletl 0 52 + 017 330:!: 170
~AWI<xtod~ ~O"I8> '" Po-<....,J -MI<I:.o.t, f !Io'o<b<I",,~ l«o:;q,B Gorv-!O """"""' R , C ~ G a<dJaolc>-.p~"""""
01 ~, ""'<l,)"" ,- I<->""' ''''''' -' ''''''--' '''''<l .. ''''''''''''' ~ 0.. ~ Thoo 47 J S4 · J ~8 . I QQO

u. Dl'I N lIlillt' d ifft' rt'lIt1.'S in Ix' nhnifyllilll' kim-t iepar aun-ter valm-s ht'h\1."l'1\ Iwalt hy
suhj('('ts and (:irrlloliL' IMlit,uts wi th n 's(M"l1 10 III<" foll{)\\i n~;
I . AhsOIv t ilJll
2. D istril uuion
3. E lilll ina lilll\
h . Brit'lly d is('lIsS how Ilt'p al il' cirrhosis is likd y to produce ti lt' dl;tllf:c ~ ('al('lIlah'l l for
tlu- abso rp tion. di sl ribution , and elimination parameters of this d nl~.
7, T Ilt' plm rm;\('okinC't K'S of loraz epatu . a !x'II:f,odi;u.l,'pillt' \\i lll tlelllo nstrattod t'llk ac.·.y ,L~
an a llXio!yt i<-', aut kxmvulsant . antiemetic, and sC-''tLa ti\'l ' hypTlot k . was studled in patients
with spinal cord injury . Ti lt' d Ol~ (2- mg: t11)s(' ) \ \01." ¢ \"l' n ,L~ a sing:lt' I- In 2-min Lv.
Infusion. TIlt' res ult.. of Ilu- st udy ill I t't mplt~l'S , par aplegics . and controls art' S U IIl -
ma riTA'l1 ill Tahl t, 16-K 1111' dOl ~ is bo und 10 albu min O.()9). </" ""
,.ltl. ,...... Lor.••ptI. . Ph.....c.kl....c h_....... I_ ......... wi'" 1p1_1 CenI
1_lury .... I. C..... I.·
c ,
SU5,K 1S 1"..;.....; .. 1) "I
Tt.>lrOpleg >c (n - 91 20 ~ 0 ""
1,6:!: 0 4 31 :!: 13
Pcropeqc (n - 0) 37 ~ 11 10:!: 0 .5 25 :!: 9
Conl'ob (n _ 91 4 2 + 19 15 :!: 05 20:!: 12
'-tIaooftop. Soogn JI ~ S ' Ell:>«>, 1M ""'<lV.,lpo M Doc~...-dooo<o<aol~ .. ~.....,'I""'<JI<<nl ...,.. !
On P>o- ~ J I6 ~ I -M¢ l QQI

a . \\11c'lI ~ \"t ' li or. tll) , tln- bil o;l\'aibhilily o f lorazepam is gUll , UShlf: tilt' ktm-uc d al a ill
Tab lc' 16--."; and ;L\slITlling instantan eous abso rption. calculate lilt, mean pe ak aud
tmuf:h concentrattous t'xpt"{1t'tl O il oral ly ad llli n istl' rill~ 2 1llJ;:: "~it1.·llti ly (t"\l-' ry 12
lrr). a typic,,1 rq~i nl('11 for t reauucut of anxiety, in ti lt' tet raph-gic an d abk-bodu-d
spinal injury) patients. U M' an average weig ht of 7U..kg am i F "" 0.9 for all
(1I1l
sl,hj('('Is.
IJ. Loraz epam is pri marily l'I iminalecl by ln-pat ic g;11I('lIn midation, Discu ss each of tln-
follll\\illg mechuntsms a.. a possih lt, expla nation for tilt" dt"{'n 'll.'il'll clearance of lor -
,uA'Il;11Il ill patir-nts with spinal co rd inju ry,
J, 1)('tTI ';I.'il ·d hepatic hlood Ho w.
:2. f)c't'n 'aSl.'tl lw palo(1.,lIular Illt' laholic ad h ity ,
266
"w'" CHAPTH 16

3. Entt'mlll'pafie l'),:lill g of tlmg l hmll ~h its g h ll'Urllnid t· ....illll('·" Ims of drug or

meta bolite in f('(:~..s.
4. Inc reased biudi ng to plaMI'" pmtl'ins.
S. TIl(> c!t.'a rnllll," and h.alf·life "allies for IIl '(.":li nidt" an untldvsrhvtlnuic a~l· ll t . o!lM'rY('(1
in six patit'nls wi th !It'I);llic c irrhosis and six Ill"altlJ~' SUhjl't1S . ll·rt·listl"l:! in T nhle 16-9.
Tln- IW:llthy sulljed >; .... vre-, 0 11 an'l'dgt' , matched in u-nns fir agl' and wl'i~l l t \\i lh tilt'
cirrhotic group. The dmg (2 mglkg) "~d." ~ \1.·n 11)' i.v. infusion over I.') min.

r.It•• 16-9. 1...1,,14_1 V.I_... CI_NM_ H.lf-lif.l.. ,I. P.....h With

H~c CI",,_.I••IHIII. II. "_Ithy Celttrel liMtII·

Clecrcoce ImVmm/lgl 1.1,16. 4 2. 4 6. 57,5 at> 6 2, 8 2, 8 3. Q 5, 96. 11.7

Holf.lole [1111 18,28,37, 43,78.107 Q 1.92,9 4.95,95 , 10.0
0Adopood ..... ~, _ I . ~ Ckrog, ~F Com>d GJ ~ ,-. oI ~ ",~ ....<.....,.,. oI "''''''' 0...
~ n. . .u s«>-sn . 1088
"'..... _ ~ ... ..........-.gad.

Do tllt·St, ohservations support tlw notion tha t variah iliry· in ch-arunoi is ~n'ah 'r in till'
hepatic ci rrhosis than in its ahst'n('('? B ril · ll~· stat!' the 1Ja.\is fO I" ) U IlI" con-
pTl'St'IIt1· of
du_\illus.
 INTERACTI NG DRUGS

OBJECTIVES
The reader will be able to:
1 Discu!>S the graded nature ofdrug inlet'ochoO$.
2. kcettaj" whethet phorrnoc mencs 01 phormocodynomics of0 drug. or bo!h. iscbeed by
uocther drug, giveo unbound pIo.vno dfl.'9 concentrolioMime dolo.
3. AnhCijXlle the likely chonge~ in plasma and unbound coocenb'olions with time when Ihe
phormacc*inelicS of 0 d,ug i$ cberedby concurrent drug odminiWOtiOn.
4 Showgraphically thecceseqceoce of 0 phormocobnetic drug inletOClion when the mech-
anism and the circumsceces 01 itsoccurrence ore given.

)lal it'liis ( ''UTll III O ll ly rt 'l"t'iw ' two or ilio n " dm~s concurrently. imlt"t'11, inpatients Oil an' r.lJ.:t>
",("t, j\(' fin · d m !-:s d u rin!: a huspitali;,.atioll. 111l" reusons for Illultiplt' ( I m~ Ilwrapy ;lrt' many _
Our- n';l'iOIl is IlIa! dOl I?: com bfnanons han ' 1)1"1'11 found to 1)1' 1)I·m·Rei..:1 in till' treat ment
of SOlllt' ('ond itiolls, i lld lltli ll~ a \1Ult' ly uf cardtovascnlar t1 i!\t·lt<,(·s, lnfectious, a nd cance r.
Anotl u'r n ';(\l1I1 is tha i 1);ltil'n ls fn '(1Ilt'n ll)' sulTt' r from seve ral concurrent diSt'il<;('S ur (1)11-
d iliollS, ami p<lt'h ma)' n- qui re lilt' 11<;(' of Ullt' or mort' dnlJCi. Furthermore. tlmJCi an'
p rt'M'riht11 h)' tlilTt' n' nl clinicians. and I'<lt:h clinician ilia)' ht' unawa n - of tl lC' ot hers' thor -
apeuticuuuu-uve-rs.
\ Iultipl(' dnl~ Ih('rap)' t'an ~h't' riSt· 10 a tim/!. i'llt'mc1itJII, i\ ,Im~ interucnon Ilt'(1lrs
when c'illlt' r pllanmllll"i nt'lit,; o r phannacodynauucs uf e rie t1m~ is ,lltt'n11 b)' another.
D Ol ~ jnn-racttons an ' of ('UII(,\'01 "t1:,IIISt' , ec ca sfonal ly, tilt' outconu- of c..1J1lc..1Im·1I1 d Ol~
ad minislratioll is d iminisl ll't1 tll('rap(:ulk t'ffic..-llt.,., or illcn ,.l'>t11Ioxidty o f Ollt· or 1II0rt' o f
tilt' admtntsn-n-d dm ~s . A t1wrtll1f'utic tim /!. i'ltl'mrlum has then oceurn-d.Tlu- IIndl'sirabl"
t'l Ill~'I I IJ( 'I1('1 'S of a d Ol ~ inll'ra{'tinn lIlay arise Irorn a 1.11,k of IIll(lt·r.ilall(lin~ of, o r a faitlln '
10 recall, th e mcKie' of action and til(' pharmacokineti cs of each t1m~; Illan~' undesimbh-
int eract ions <In' therefon- poll'lIliall,. a\ui tbhle .
The IMlssihilHit-s fo r illlt' rat'tilJlIs ;U llnll~ d OlV;S \\11"111 tilt' IXM.I, · an' almllst huurlcs s. Yl"I
ft'\\"of Iht,!>t, Interactions an' o f a !)1)(' or of a suffil'it'1l1 mav;niltltlt' to he chnicra II,. im portant .
'toUl" illlt'r.lli iu llS 11t'IWt'('1I t1m~s wtthm Iht, hod, - ta ke place wtthout alTt'(iillV; ettlu-r tilt'
II1llXlIIIld dOl/!, l'\)Ill't 'nlraliun or till' t1lt'rapt"lIlic alii\1!)' of 11ll' (ImJCi ill\u l\'('(I. .\Iso , lilt'
dnsa~c' of lIIa" y d nl~s nc'('(lt11I u demonstrate a d ill i (~dlly si~n inCl.ln l d n l!?: int e ract ion cau
t" (,(111111t' medinu lethal dose. Furthermore. man" alTt'(.ie-d pmc..'(·sSl-s and pathways of
tim/!, r-luninanon art' " XI minor ttl ht, (If ('I1I11'('nl.
Implid l in lilt, defin ilion u f d m /!, interact ion is lilt' c..,mc..'(·llt 111Ol1, like' t'sSt'llt iilU" all
n 'SIJlJIlM'S of tilt' IMxl)", Ihey an' ~mdt1 1. The tlt"grt't, of in!enlt1ioll t!t'pt'll(ls o n tilt' 1'1 11I('('11-
trutton of lI.t' illtl·r.It1in/!, -"1)('(;I's and hence on dose and lim e, That a ~\"('Il tim /!, combt-
nation tlOl'S 1101 t'nSIITt' 111I'occurn-nce o f a clinically SiW lifil~,U1t illft'T;ltiiUIt is Illust rated hy

"7
,. CHAPTEl/ 11

17-' . Pre.-..
'."'e ,....-eII•• lhtlly ef 237 W.....rI ••YreeIellI .........._ DetectI• •
.t All htw W.....rI....... CIII_I Ny••••-
All po!1eIll$ who receoed chbol hydto!e dvllng worfu"l1 Therapy 237
Those ~I!> who recewed c"b al ~'0IEt Ioi olleo~ 3 coeseccnee ~ 6Q
Impou, bIe10 e-.Jluole ,nterOCloon ld,"ocolfy umIObie CIt mv/l,pIed,"'9 chor.ge~l 28
P()6e<lllohon 01 hypoprOlhrombonemiC ocree 01 worfa" n 2]
No deomonlhoble ,nle<oc hon 19
· ""-xtod """' o:.xh-w .... J ~~ ......d-ug_"""' '''K(l~...-'''''_ C... ~d , .... 141 )9-1 .16
l Q1)

tln- dat a ill Tahk- 17-1. Cilluml hy,Jmh·. a S("tlatin' hypnotk . is l llllll~ht til poh'lIliah ' tran -
sic'IIt1)' ti lt' ilulkua.L':ulaul (·lTed s of warfa rin. Yt'l in olily 2:2 of 2.17 pa lit'lIls. who wert- sl lld it'(l
pms pt'(1in ·ly and who n't't·j\'t'·d chloral h)llmh' d llrill~ warfarin Ilwrap)'. was pote-ntiation
o f warfa rin's (·fTt'(1 1II1all1hi~ IOIlS I)' demonstrated. 111t· rt';NlIlS fo r tht'st, d iffe n olll'(" in
n 'sl'Il lll_'il' an' "'<Ill)', Illd lldt'(l art' im li\;dllal differences ill II\(' dU!,;I~t' n'¢IlU'1l uud duration
of ad mi nistrati o n of l'al'h t l n l~. in tilt' .\('f!llI·llt"l· o f drug adminis trat ion. a nd ill paueut
l'l lmpl imll'l·. I'l m nlliu.ud~lla lll il' and p ha rlll ;K'llkint'lil' d ilTt' n'lIt"l's ehn- to ~t'lJ('t il.". . to eon-
l'lIm '1I1 di St·,I....• states . ami 10 m,III\' utl lt'r fati o ",," a l<;(l t Ullt rihlllt·. T Illis. tilt' lin1UlIslallt"l"S
'l.s "od alt'1l \Sith a d inimlly si~nifk-~nt intcructiuu in a n inclivalual shollitl always ht' l~Irl'fllll~'
dooum-nted.
A fillill ~t' l\t' ral connncnt no-ds 10 1)(' lIIadt· n:'~anlin ~ tilt' 'it'fillt' nt't ' u f dm ~ aduunlstra-
l inn Ix·fon· l'llllsidt'rin~ sl)("li Jie mechamsms u f t l m~ inft 'rati io ns , .-\ d m~ inlt'ral'tillll is likt'l y
ttl I. · d t'h"l1t'1l ouly when tilt' illtt'ral'till~ dnl~ is initia!t'1I 11r wit hdrawn. For cxamph-. ~H'II
th t' uSlIal largt· dt~n:"l' u f \'ariahilit~, ill patit'llh' n ·j,lltlll ...-s to d m ,.,rs, it is unlikdy t hai a dm~
ill!t'mtiion \SHuld Ix· dt'tt'f:1t'f:l if tilt, dmg:is ad minislt'n'1110 a palient sla hili7.t "ll o n tilt' d m g
l~ltIsi ll ~ tilt" tnn-racnou. Ct ·rtainly. tilt' t hlS:I~t' rt""lt'n of ti lt" a ITt'f:it"ll drug woukllx- mon-
daTt'n'nt ill tlwt pane-ut than would orlu-rwtselx- tilt" l·,l...-, hut ti lt' rtoslilt i n~ n~i lllt 'lI llIay
still Ix' wi ljuu ti lt' lIo rlllal mll~t· . III this loLs(', unly if tln- o lTl'JI( li n~ t1 m ~ is \\ithtl r.n\ll first.
wln-n tilt' Ililtit'lIt is stilbili1.C.'11 on tilt' dm~ combination, m il l ht, inlt'md inn 1)(, M'1·II. 111l'
iuteracrion would alStI han' IX"l'1I ck-n-cn-d if t ht' i nlt ' r.K1i n~ t l m~ had 1" '1'11 adminish 'n'tl
10 lilt' patieut aln'atly slahili7.l."l1on tilt' ori ginal d rug.

CLASSIFICATION
Om' s~~ lt'JTl nf d 'l..si f); n~ t1 "'~ iut emetions is 10 1I0lt' wheth e-r dmg rt'S[M IIIS(' is inl"n';L'it"l1
or decreased. \\l lilc' [•- rha ps d inimlly lISt·fll l, this d 'lssifl..alinn tltM... Uflt Ilt'lp tn tlt·Jim' lilt"
nu-chauism of tln- inlt·r.l<1i oll . In t his book . int eractions an' d ;Lssifil'1l on tilt' basls o f
wllt't1lt'r pha n nill't.lkillt'tit"S or phann'll't.. I~llalllil.". is aln-n-d. tX"lolsillllally. lxltl l a rt' dlilll ~t"li.
Dist illti in ul..-twecu rlu- two is madt' hf rt'lalill~ rt.·SptlllS(· 10 till' IInlxlIIlIll pla.sm a t'lllll'l'U'
tmholl o f tilt' pl.ilrll1al'lll llWl~dlly atii\'(' SI)("l:it·s. Xu dl 'lIl ~t· ill 1111' unI XlIlIltl l'lIIWt 'n lmlioll -
rt·slltlllst· t'll'\·t· illlplit·s it ph,tml'K'llkilwtic t1m~ iuft'fiI li io n, wh id l l<1Il a riModiller t1mlll~h
a phrsk~l l illtl'r.Kiioll , slId l ;l" l'OIllI)('lilinll for prolein hi lltlin~ siltos, or t1 lrtlll~h a!te rt"ll
physinll)"~Y, .sue h 1l" ,tlk rt..1 hlontl flu\,,' al ,ill ahsUllllio n silt·. TIlt' n ·sult is a dlan ~t' ill OIl('
o r 1Il0n ' of till' primary pharm 'K'llkilwtil' p.;mllllt'!t·rs, kil , F. \ ', Ct.#{, C I. II , whid l ill tllm
alt t'",," till' St"l'lJllda.f)' p!la rm 'lld d nt'tit· paramt'tt'rs , slld l ;l.. half·lift, a nd Ji'.
I~·fon· pnx"t"t"tl in ~. a di Sl-1lSsioli of wlllli is IIlt'alll hy Ih t' uun l i ll t..,-m1;fm is \m rt J.wh ilt·.
S t rit.i l~· s pt'aki n ~. Ihis \\l m l implit·s ,t III"t""l tffi'f1. Tl w ill!t·r.u1 inll ht·twt't ·1I " m t1n1 ~s . A
a nti H. llIi ~ll l thllS 1)(· i1t'noted by A H B. An ('Xo'lmple is tilt' t'lIIllPI.'lil ion IX'''''''('1I two
t1 n l~s for a l'lIIllTllflll hilldill ~ silt· 011 albu min: {)I\e tl nI~ dispI.K't·S hUI is alStI tlisp l'U:"l't1 by
t11(' utlll'r. (;('Iwmlly. lIu..", ...'t' r. tilt' It'nn illtt 'mdl,," is inh 'q l n ·!t'1ll1lon.· hn:);l(lIy 10 iutl il'lllt'
an y .~ ih l illi()11 ill wh idl Ullt· dnl ~ alT('<.1 _~ .Ultltll('r. Fur t·:>;a mple. pllt'lluha rb ital ap llt' ars tu
rt't hll'l' tilt' " bsurp tio n of th e tliun ·Iil'. fu rtl'>t·mid... hil t th e n 'nlll d eOlrdllt't· llf pln'lIllhn rhilal
CHAPTER 17 INTE I!ACTING DPUGS '69
is i1 K' rt';L~( 't1 hy tilt' d iu rt'sis pr odue-d hy fuwS('midt·. l l1is llIi ~IJI lit, regarded a-s a hic!;n'C-
HO/wl illtam1ioll alld lllay be denoted by A ~ B, Clearly, ill tht' case of mutual and
h idirt't'ficmal tnn-racttous. tilt' measured resptlllSl-' of O lll' d ru~ caunot lx- cousfde n -d \\i tlum t
also dt·fjnin!!: tilt' It·\"(·1 of tilt' ot her.
\\1lt'1l ~\"t' n in sulTk it'nl q llanlities, tv.' l d m ~s almost ah\"d~"; affect t-;teh other. this may
not lit· lilt' case. hOwl·'v r-r. at roucentratious achieved ill the rapy, For example, tilt' antihiotil'
euocu-in inh ih its tln- nll' taholislll of th('tlphyllim', hilt t1lt'o phyllitlt', at duS('s nonll al l~' gin'n ,
d(I('s 1101 alTt'd tilt' rt' SptlllSt' OT tilt' pba nnaco ktncucs u f enoxacin. This Intcract lon is f/lli -
tl in'c1iOfwl am l mnv ll(· dt' lluh 'tl bv A -+ B. In a IInidirt't.'fiOlIllI interact ion . tln- un alTt'<.'ft't1
DOl!,": A. ('.~. , t·l1ll~ll'in. (".111 1M' n :nsidert'tl indt'Jll·mlt'n tly, h ut till' chengc in rl'sp(lIls(' of
tilt' uffecn-d () m~ H. (' . ~. , tlwop hyllille. 1';.111110t II(' adt't luatt'!y dt'fillt.,,1\\i lhollt also constd-
Nill ~ tlu- {1m{'l,'lltmtiou· rt·spmlSt· {'UT\"(' uf tilt' t'fT('{'f of D m g :\ Oil Dm ~ B. Esamplcs of
d m~ inh-ract iouv are listecl in Tab le li- 2.
'111t' material in Chaps. ~ to 12 form s tilt' basts fur <li S<.'tI.~s i ll~ many ;l~I)t'{ts of phurma-
('ukinl'l i{' d m~ mtr-racttons. FOT cnuvenience , in this cha p ter. tilt' effect of one dm~ 0 11
anotlu-r is r-cunmed under the S(· I><tTiltt· lJt'ad in~ of altert'tl absorpti on . a1lt'rt'tl distrihutton,
and altt ,rt'tl dt'aran l,(', Howe ver, it shoul d ht· borne in mind tllat S(,\,('ntl pba r macoki m-tic
panul1t'tt'rs rnn ht' alh'rt'tl sil!tultallt'tlUsly.

AlTERED ABSORPTION
It was stated in C haps , .,\ anti i that tln- mort' rap id the absorption p n x, 'ss the h i~l lt' r and
r-arln-r is Iht' peak plustua ceun x-ntration am i th at nei ther total ..\ lie aftt'r a siJ l~l t' dust' nor
Ace within a dtlSitl~ interval at plan-au afu-r chrome do stng dla ll~t'S unless tht' hin,wail,
ahility of tilt' drug is altered . Therupeutk-{'Ons("'!llt'nl1'S of a dmJl~e in t'itllt'r rate or extent
of d m~ absorption wen- dist.·llsS('t1in Chap. i .
Cousidcn-d 1I0W an.' situations in wh ich hio;mtil ah ility is alte-red. wit h eJll r h,l~is Oil
l-!J; tI1 ~('S in a\·t'm~(· ptL~ lItli concentranon \\i tll tiutl': an alte n-d rate of ubsorpnou l'ha ll~es
only the t1t·~n.'t' of f1ul1 uatioll around the a\l.'rd~e value. TIlt'S(, situations art' common in
chronic dnt~ tln-rapy. T Ilt' t·\"(· uls an - iII ust mlt 'tl in Fig. Ii-I.
Fi~u Tt' 17- 1:\ t1t'pit'fs tln- situation in which a patient sta bilil.t'l.1on Dr ug A. ItOW rece-ives
() m~ B, which reduce-s tilt' hi();1\1Iilahilit)" of D m g A. It is apparent Ihal if no sle ps art·
taken to change till' t1osi n ~ raft' of D mg A, its concentration falls 10 a lowt'r plateuu. tht·
ti mt· I M'i n~ dcternum-d by t!lt' ehmlnatton half-life of thi s d rug. Suppost.· that it is tlu-u
Ilot it'(·t! thai tht' pat ien t is Ill) l un~er 1 'It 'i ll~ tTt';att'tl t·fft'<.ti\'t·ly \\i tlt D mg A. illtd Ihat, hil\i ll ~
rt'l.'("til.t'l.1 tIlt' pmhl" m, tilt' nlT" Il( lill~ d m~ is u;thd m \ \ 1 1. 111t' t'()ft{'t'ntratioll of Dm~ A
mJll ld t!lt'n f(·tuO\ ttl Ihe pn,\; olls plateau \'alue in 3 .3 e liminatioll half-Ih "t·s, l1ll'rdl)t'u ti{'
{'(mtm! m lllld a~a i ll 1M' Tt·sloTt'l.I. Ah emat i\l.'I~·, on anol ltt'T(Il"l'llsion , in alllilil><ltion of ti lt'
prohlt'ltl h ilt dt'si ri ll ~ tn ~\'(. the two d m ~ t<~t·t1lt' r, till' dosing rat{· of D n l ~ A i.~ i n(' n':L~'t1
appmpriatdyal tilt" liull' thai D m~ n is inloMlu{'('t1. As 101l ~ ,LS Do tg H t.'(mlinllt·s 10 II('
adm inist(·n.'tl. t!Jt' Tapt'n tk {,(lIltml is satisfal'tOt')". A pm hlcm ariS('S, howt,\"(.·r, if [)m~ B is
sllh"t't!IIt'ntly \\;thti Tau lt , hul tlw dosin~ mtt· of D m~ A is not {um'SI'ltmtlingly rt't lll{,('l.I.
T lwll. in 3.,'3 d imination half. li\l's, till' {'()It{'('ntration (If Dmp; :\ f(·adlt·s a Ili~l lt' r p lat eau
wht'f(' toxki t)" is Iikdy.
Anotllt'Tpossihlt· situation is O llt' in whkh D m~ A is adtlt'tl ln tlw n ogllttt'n of a patit'lll
stahilil t'tl U ll D f(l~ U (F ig. 1i - I B). Ht' rt', Ol\ llt'foTe , op tima l t1lt' TaP~' \\i th D nLJ!: :\ in Ihl'
prt'S('lll,(' o f J)f(l ~ B is adli('\"t'l.1 o nly if tilt' usual d()si Jl~ mt{· of J)rtIV; A is appmprialdy
in{'Tt·;l'>(",1. II n\\"'\"('r, tilt' dall~t'r o f tit(-' t.,(lIl('t'lllration o f [) rtI~ A ri si n~ t('It) hi ~l , if tilt'
t!osinp; ratt' of D nL ~ A is not f('a djus!t"(1wllt'll D nl~ B is \\; thd ra\\11, mu st always lx' kepi
in mimI.
270 INTEiACTING NUGS CHAPiH 17

. ' ....w', '\fU.l'<)f\;<,

""""" " .....'"

r By Inh'b11flg mono"'ine o.odo~.
Itony\cyplom"'-.e potenhOIeS!he
sympothom"nellc oc;llQI'l d
phenylpropanolomlne
Mutual -*:Il~ eIIecr...
ChlorpromClZl1le rh '~ uplake of
guot'lelhid,ne or pc»lgOngloonoe:
OO<etlE'fgoc neuron,
Eocb Io-w<s the effec;:tlver>e$$ 01

....-".' ..... . ".,. ... '~ ""'n,:"'lI',<,

me """
p.u.wta; I1SPONSl
r "'''''' j .... ... ' . '

f>/elocbpromode "'a,lto n, gwric

, emptying
Epineph"ne decreoses blood
Ibw 10 ,nrecl,on s,le oS
lidocaine
r CIITlelidne ..... NoeloproIoI ('meI!d,ne mllibon meIOp(oIoI me-

,
IOboli~ , e..pr~ as d,m,n-
ir.hed l,'*PO» efled
Calcium ..... Tetnx)d1/'l8 Calcium Iorms 0" mldoubko com-
plex ....,;t!l lI!lroc:yd ne
r ~ ..... Volprooc odd VolprOIC cod d,~e5 pherrvtom
, Ouiotdine ..... Dtgo>o;,n
hom album,,' ,
Ouintd">e d ,~ d'gox,n Irom
It_ blnd,ng \.lies
r
, IMompofl ..... WtJrtonn
El)'Ihromyc:,n ..... TheopI¥lone
~Ilampll'l indocM
'Y"""
micrmomal en-

Erytllfornycin inn,bors Iheophy4Ilne

rneIoboli$ffi
r CilosIOl" -0 Im,penem C;1o~hn ,,,h,bor.. rhe 'enoleeecb-
oIiWl of imipene<n . In this COloO.
organ clearance is ollected.
IlOl l!lt(;f elo<y ceoc-ce. me
meaning 01 -eecl cec-cece by
delouh
Chlororhiaz.de d,miniY-.es
!l6CrellQfl 01 hlhium
~ 0 .....,.j_>o'\(JI ... 0'1CM _ to.,Jlo,:tod d>\O)
~o~ ._

TIl(' ~ i hJ:lt if)m; j ust constden-d t· lI1 p lJa.~i7'(· th t • d t'p('nd e ll('(' o f tune scale o f events Oil the
half-lift, uf the a fT("('h'1l dmg, Thus. fo r afT("('kti dmg.s "id l \'( '1) ' long ha lf-Ii, "\'s, such as
p llt"llllharhitill (' 112 (If -4 d'l~'!i ) , change s ill n 'sp0I1S<' MI.' Insidious. and til(" C li ll i d il ll lll a~' !lot
a\sociah ' lilt' interact ion wi th the causative dmg, which was e ithe r iniliiltN I o r stopped
sOllwlimt' pn"\ifl usl)'.
AlTERED DISTRIBUTION
TIlt" most common explanation for aln-n-d dt stnbunon ill a dmg Interact ion is displace me nt.
Di splal '\'ll1l' nl is lilt' n-ductkm in the binding of a dmg to a macromolecule. usu ally a
pron-tu. (Hotll s('l i hy compeuuon of another d rug . til(" di...placer, for l'OllllllOIl bind ing site(s ),
TI I(' result is a n w ill the fract ion of tlm g un bound in p lasma o r tissue , or bOlh. Somettmes.
himlillg is dnuinished Ihn ltlgh an allosh'ri c effect . TIle second d rug. hi nding 011 anot her
si tc-, Indu ces a confc rmanoual dlOlnge in the protein , then-by ({'(luling the affinity of the
first dnlg for tilt' protem. Occasionally, all allost e ric ('ifNi causes an enhanced affin ity
ht,twt'('11 dmg and p rotein; dmg bind ing is then Increased.
CHAPTER 17 INTERACTIJ'"G DRuGS 271

Conditions Favoring Displac:ement

Two u md ilions must l)t· met l)t'fnrt· sub sta ntial di splace ment ()C(111'li. Fil'li!, in Ilre- abM·Ill't·
of a d ispla(·N. Ilw d OlI-: mu st l)t· hound IIlllstl~· to 11 p rotein. th ai is. its III mu st 1)(' Illw.
Oh \ioll sly. if a dOl ~ is 1101 hllund. it cannot 1)(· displaced. Second. the dtsplacer mus t IIC(:IIPY
tlu- majuritr (lf thr- hi ndin ~ sin-s. tllt'R 'by suhs ta ntially l{Jw{'rill ~ the' number of sin -s ami lilhlt'
to hind Iln - d Ol ~ , This S('('! III t! ('Ilnd ilinll is likl'lr to 1)(· IIl<'t wht' ll thl' displace-r ( ){"t1 1pi t· s
most (If the h i lldin~ sites.
Tal ll(· I, ~1 lis t s " ,u g;n Jllps of dOl~s thai biud 10 ullnuulu. a protein thai ('-usb ahu llllantly
ill ph sllla ( 1-10 W3 L: OJ, III ~ I) and in tilt' int t' rstitial fluids (2 10 ~ ) . x ot all d nl ~5 h ind

4
A

" 4 • " Potential

ToxiCity
C o 3 ---------- 3 -------- ------_ .
D
, -O
i5£:1 2 H
0_
2
Oplimal
ThelaP)'
eO
,,8
• 0 --- ------ U ------_ .
Ineffective
, , ,
-2 2 4 6
• 10 12
TimelHalf-ll1eof DrugA
0 2 46 8 1012

Dosing
Druo 8 Dosingl Drug B I
~:e ~ 1--=='=-=-=-=-=-=-=-=-=-=-=-=-=-:;5 ~ :'
Drug A 0 L
O~eA rI - -- ---- -- n --- -}~: :1

. ·i!l:. 17-1 . Ah.·" ,,1 ah"''1lti.." A_ " " 'l{;o.> Do ,lt R i. ;oo; 'mini_I.·......1. tI..· hi"....-aiW>il ily ,,( Drult" i> " " I'K'O " I I".-
... ..·-half Fur 'i'''ph<ity. D o ' l-: ,It j, a..urr..,,110 I.., ~wn al a ("..,sla nt rate. n ... Illt'roll",," 'tK' (111K..'nlrati" l1 r,ulltl'
"r U nl lt ..\ lit... 111''''"'' '11 L5 aJ .. l .l lllli'V1~
.". I'atit·" t ,t"hillA" I .", Unlit .'t, n..· pl;o., nl;l (111 K..-olr.ti<II1 "f D nl lt 1\ f;dl. I~',,,,, ··ll;<]r(r-ol\(' I). un....... II..•
' ~ .. i ll~ r.'''· b , ~ " ,',I."I <r-ol\(' II. n ''',r ). ""~"'fl D m l!. H is (""K'\t rn'fll~' ...Imllli~.·.....t . .\ p""''' '1lI p:lt''''Ii"I~' "ri"..
if ;M lrnilli, l ralw", ..f U m ( .\ is "<>' n "I' K~,,1 to ils p","istlllieroll.....1..'n I) n 'l: R l. ... n.....,,1 (Ol-... II. ("...,,-).
R. l'al it'1l1 >1.d>iliJ>,,1"" Dm l/: K, !\ n ;M""jU" I'· l"" ""- lllr.ati"" .. f D m lt.A i. ,.. II ..d lin.,,1i.".... lt u"h . tI... USII;<]
..... in~ r" I.· .. r tI,l>.Iml!.I. ... >t,I..." I I,....... ' II . (".Ie...). " 1M'n Dnll!: H il will..ll1n\l " tI,,·", i' ll l"II,·nlw l,,,.I,I.·m ii llliLor
I" 1 1~'1 n m,i.I.·" ,,1 ill ..\

T.I.•• 1 7-3. .1 .... 1..... hl.ctMI D....... AI....I"

O'VGS n-v.T sec ro »o CoYI£ll ~ oe o rwc SITES, OESIGNolTEO I ~ I

"'" ''''''"
""
ClliorOlhiozlOe 8enzodoOzepo ~
F",owm,oo ac..ocillil'l

-'"
lodomeohac,r{ DidoxociMIII
Nopro~eof G1,bencIomode
lbupr<::krl
Svliod'melho ~'ne l~,n
Salqk: acid Napro-@Il
ToIbvlOmrde' Oxocillin
volpoc ocid Peobeoecd
Worlorin Tolbutomde

'- -
O
""d>et_ -0",
"..",.,."''-9' b«l to _ .-..
272 INT(iACTlNG OIIUGS ( HAPTH 17

In and 1ll'lln ' ("fllll l)(·!t· !i:lr lilt' suuu- pri m" r)' hi ml ill ~ si te 011 albumin. Alhunuu ami sOllie
o l llt"r prote-ins han ' "i('\t'ml h illt li ll~ sites, ('<1(:11 ('xh ihili ll~ SO Ill I' dl"~n"t:' u f Spt·(:ifid t)': pos -
Sl,'ssill j,t all ad d k function is lint a su ffide lll (-m erton (or pn'(li<:t ill~ tln- ;ahilit)' o f (lilt ' ad die
t1m14 10 dispLu.'t· ;\ 110 111('1". ~ I ()rt,( l\ l·r. ('\l'1I t !lO Il!-t1J alnlC)!;1 ;111 t hoS(~ d m!-:s that t ll lll pt 'll' fur
the- ....IIIU· silt - haw a hi!-:h affinity for allumun, o u l)' a fl 'w art' !-t('lwrallr lislt't! as t lisp lal't·rs .
s!I<:1i us sa li<: Iil' add, \"a lp m i(' add, and p llt' II)'lhulazollt·. l11is list is lilllift'(IIM."{'a u"t' tilt'
ptlsmil eence-n tratiou ad lit'H'd dll ri ll ~ t1 lt' mp~' IIIm t app mad l or ('M'('t "(! 0.6 III ~ I, till' llIo lar
("f lll('(' ul ral io ll o f p!,lSlIl,1 a lh u m in . F o r a su!lsla m "!' \\;111 a 11101"<:111<11' \\1..j?:" , or 2.''jO, Ihis
l~lI ll't'lltmli(lII l~lm'sp(lmls 10 ISO II\WI~ T h is ccncentranuu is appruaehl'll durill~ salicyla te
uud \"a lp m il' ad d tlu-rapy, ht "(,.UlM' t ll(' M' dnl ~s an.' l~ llllllltlllly J.,';\'l' n in doM.'s ilppnlill:bill~
I ~ a nd 1)("('.lIlM' tlu 'y I)(ISWSS n:lath't'ly s mall 'Ulll lllt'S of distribution. III 10 15 I.. " 'jlh
pllt 'u ylh lll;u.ullt· Iht' ptL'IlHI conceut runon ael.it,\'t'l l with lilt' usual d OM', HilI III~ ( \ ' = 10
I ,), is only 1lI1rlWL h ili I)("(, m st' its d t'antnl,,' is low a nd ha lf-li ft, is I nn~ (3 d ays ), t ht ' plateau
comvntratton ult illl at t'ly adlit'\ '('ll is hi~" when till.' usual mniutcuance n '¢ lIlt'n of 1lI0 ttl
3(11 1 1Il ~ daily is atlmill ish'rt'l l.
I>ispl a('t·rs sha n ' a ll t'Xpt'l'!t't l l"tllllTllIIIl pmpt'rty; i.e., tl w ir fil vahu-s d mn~(' wit h pl:LSlTlll
concentration. \ \ 'i1h 1110 .. 1 sift' s t)("t.'u p i('l l hy tilt' cbsplacer. tilt, Fraction 11II()('t'lI pi ('l1 is <;('11-
siti \"t, III a d"lll ~t· ill IIII' concent rat ion nf di sptl<.'t'r. Tln-n-fon -. dtsplacers IIlllsl s hllw l1 J11-
n 'lIl ra tion-dt'llt.'IlIIt' 1I1 d isposit io n kinctn-s (C ha p . 22, DoM.' and Tum- Dt'IX'lI(lt'lll1('s ),
SU f ar. t1i, tim1inll h'l' IIt'l'1I lHad(' IM'''' 't'l'1I displacers a lit! d b plal't'll dm~, h UI il sh llu M
1)(' a ppan.'nt thai thi s d :LSsifil'al ioll is urbitrary. Plu-uylbutazmu- is said to di splan ' warfarin
fmm ulhuuuu, hUI n llly J,t'l.' UlM' tln- p l'LSlIlil (1)IJ('t' Utr'dIi01l o f pllt' uyl hu tiVm lt' ( HilI mwL:
n.3 1ll~ 1 ) appn li,dlt's th.. molar (1111(1'n t ra lilll l of ,(Ihumin (0.6 Ill ~ l ) , wllt' rt·.l.' t hat of wa r-
fa ri n (I til .. mwL; 1l.On.110 lUll 1lI ~ 1) d,)("'i not . Bot l. dm~s IIiM ' similar alIilli!iI's for tilt"
SiIIUt' silt' 011 alluuuin. ;tm l if tilt, l1111('t'n t l'llt i(lIIS wt-rt- n-vr-rsed. warfarin \\ Ullld IM' l , tllt'll
11lt' t!isp la("t'r.
T Ilt' (,"tlud usinll s dl'll\\ ll Imru li lt' iu h-ractions Ix'lw('l' n acidic d m J.,TS and alhumin a rt'
~t ,IIt'l'llll)' applit'.lhlt· 10 a ll dmg-protetn mteraetious, I)('ari ll ~ in m imi t ht' \-\idt' l)" t1 ifT('ri ll ~
molar l1J1l('t' ulmtitJIIS of rln- vari ous hind ill~ pr oteins in p l'LSIll<l (C hap , 10. p . 143 ). For
examph-, tilt' mola r ennc-entrution of u l-.td d ~1)"{"t lp mlt' i Jl , wllkli a\idly' hinds ITlmlY baslc
t1nlJ.,TS. is low ( ~Z.1 JJ ~ I) , ami t ilt,rt,fon. ' t lisptw(,Illl'llt in tN ' l<.1 iu llS can occur a l plasma
1"t",n' n l m t illllS 1I111t'l. loWN than t ll(IS(' n-qut n-d fu r d isplan 'lIIt'lI t of acidic dn lJ.,'" from
a lhumiu (fiI l1l JJ ~ I t1"'('t' li l ra t io ll ).

Therapevtk ImprKatlon,
D isplaeenu-ut inl('r.1(1iolls ill p l.LslIlil ha n ' ht'l"n st ll(lil"tl p rima rily 1/1 dt m . TIlt' pon-uual
tlispb' ''t'r is <tdtlt"tllo a sample- of pl ,mlla {1 1l1tai n i ll ~ l ilt' dm~. alltl dl<lll~t'S in its h indi n ~
a rt' IIIt';LslIrt"tl. Su hst;lIIt i.11 d isplal't'lIIt' nl is frt 'l IIlt'lIlly dt'lI\ollS lr.lt('llln firm ; )'t'C t" is may
1M' o f littlt' t llt'mlM'll tk L"tIllS("{ llIt' nec' . ~ l lleh <It'I)('lI(ls on wllt't llt'f Ih t' ('n'll h <lrl' <ll111(" Of
11( "{ 'ur a t plalt'a u durin~ dmm k Illt'rapy.

Acu le En'n b , T\-\u s it uat io llS (<tn h(' (' n\i S;l~t"tl. Dill' in\uh"t's tilt' mlmin istmtio ll o f a
Ini(d i ll~ tI(IS(' of d m~ to .( !);(tit'lIl .u n.'ad )· sla bili:l.("tl 011 a di sp!;I("' r. TI ll' o tllt' r iu\"olws lilt'
admin islration o f a d oS(' of di splan ' r 10 a patit'llt a ln 'm ly st ahili n 'll o n a d m~. In IMltll silll -
;d io lls , l Ilt' t jllt'st io ll uf al lt-ri n~ till" usu al tl uS(' {If d n l~ ari,St'S ouly if Ih(' Im lMIIII1I1 ( I n . ~ ("(III-
1"t'lIlmtion ill('rt',N 'S ,," m ·t' tht, Iht ' r.lIX'lItk r.lII~t ' , in t ht· p n.'St'm't' n f tilt' t lisp la(,,' r. Sloth'll
tlifTt 'rt 'T1t ly', is lilt' unhmllld \lllulllt' of <list rihutiou (" II) d('(.'n.'llSt"{1 si~lI ified nl l)"? S ud . II
t1t"('n.·aM' il\ \ '1/ t l("('lIrs only if, ill li lt' a IN'Il('t' o f Ih t' t1ispb n : r, ti lt' dnl~ is subsl;llIlia lly IMmll(1
in t ilt" lu ly illUl ll lt' di splil("{'r (,111M'S si ~ l i fi l'an l d ispla("('1Tlt'nl of t1m~ fmlll Ih t' major h int! ·
i ll~ sift's . FlIr (',am plt" lI lt' IIllhll ll lltl t1 l11n ' u tmlio ll riS('s if d isplan'lIIt'lI t 1l("l1Irs fn llll ,~ i l ('s
ti ll a p!oL<;ma pmtdn fur a dnl ~ \\ilh a s lllall \11111111(' of t1islrihlll itln, a n lllm i In Ij'j'o k~,
CHAPTH 11 INl tRACTING DRUGS

ur if displ.ex-mcut IltX'UTh fr om tisSllI" btndmg su es fo r a t1 nl~ wi th a large volume o f di s-

trilmtiun. ; \ 11 e-cunph- of tlu- Fonner situation is rlu- displacement of warfarin from alhumi n
h i nd in~ sitt'S by llapm"I'II. Au exampk- of the latn-r sit uation is tlu- displucenu-nt of d i~tlXill
Iromttsxtn- hillt li ll~ siks h~ ' quiniduu-. TIleS(;' situa tions arc rl'1atiwly unco mmon. howewr.
\ lon ' rmumon is displace-uu-nt . From p tlsllla hilJ(lill).': sill'S, of a dmg: wi th a lergc \u lull1l'
of t1islri lllltinll, 11 11"11, 11I"l' tu st, so Iittlt' d m~ resides ill plasma o nly a millimal ehang:1' ill tilt'
unbound t1 mg: l,(lIll't'nlralio ll Ilt"l1ITli even when all lilt" d m g: CJIl tilt' p r oteins is t1i.spJal't'(1.
as d is('us'wcl ill C ha p. W, D istriliutiou. Fur exampk-, if ti lt· volunu- o f d istrihntion is 100 L
am! ~1.}q: of tln- d m g: ill pla.sl1la is hOlilld (f ll = n.ol) . then ollly 3% (l IX) X (I -
fill ' (p t lSlI1a \Ullllllt· )!\" of Illal ill tln- htMly res ides bound in pla.s ma. Ewn if compk-tely
t1isplae,'t1. ti ll' small .unoun t aITel"t('t1 \\tlllid ft'tlist rihu'" Ihmug:llolit tilt' res t of tilt' IMIt!y
am! stJ \\ll uld only Itlal},rinally inl'n'ltst' th t· unbound Iltltly !'It'ltll and IWlll'(' unbound lUU-
reutratimrs in phsma ami tissut·, Conceivably. if tl1l' displao -r were Injected mp id ly t,!ltlllg:h ,
tlu- UlIlIIlI lIld d m g: concoutnuton in pLl\ lIlil wo uld rise appn"<.'iahly, but only mOlllt·lIta rily.
1'It '('all\t· di spla{'('tl d m g: wOlIl<l lllOW' rapidly dow1l tilt' nl'w ly I'TNlt'tl unbonndconceurra-
non ~rrad it 'll l iuto tilt' liI~t, tissru- water spal,(', In pract ice, thts last situation is unlikely to
arist, III'('a llst· of adwrw n-act ions ofteu expe rienced WIW ll dm~s art· injecte d too ntp idly,
nt't llmill ~ 1o th t· Iw o t·,.,am plt·s al'ltl\'t': \ \ 'ith di ~uxi n , qUinid illt· causes a suffk it"lltly Ia ~l'
t1('('rt·;lst· in \ '" tn W<ITr.Ult l'llIlSidl' ring: a n-dncnon iu tilt' lomling: dost' o f d ig:oxin in tln-
p ft'St'nt'(· of quintduu-. \\'il h warfa rin , I'It"<.' lIISl· tilt' dinim ll't"SpoIlM' (p rut llm lllhill ti uu-] is
stl t1t'!ay('t! end iuwnsitive 10 acute l'hall~I'S in warfarin I'(JllI't'IlIr.tlioll (Fi~. 5-7, C hap. 5 ),
110 adjllStllll' lIt ill dosag:l' o f this oral antit'f);IWllanl wu uld ht, coun-mplated in tilt' event of
at'uh' t1ispb t'l·lIlt·nl. :\ mon- important consi deration for 1111111 uf tlll'st· <Im!-"S and most
utllt'TS is lilt· I'ITt"l'! (If d ispJaI't'lIlt," t on events at plateau. as most drugs. ind llt lill~ displaccrs.
<ITt· ~ \l'n chr ouk-allv.
E\ t'lib 11.1 1)llI.h.:lIu, Tltl' iulhu-nce o f di splal'('lIll'lIt on tilt· unbound couccntranou 111
steady stalt' ( C II .. ) d ept'lIds 0 11 ext rac tion rati o am i route o f adnumst ranon of ti lt' aITt"!.'!(,,1
c1mg.
Conskk- r a d nl ~ \\'111. a lou' j'rtmc1ill/l m tio . Hecall tllat d t'llT;Ult't' dl'pl·m ls un fll . h ut
11Ilhllllm ! d('aTillll'l' ((,' 1..,, ) dIM'S !lOt. Also recalltln- ('tpm.lilil's (Etl. ZS. C hap . II )

Rate of elimination ... Clu ' Cu - Cl , C

\\'1It'1I t1m ~ is infuSt'l1 OIl a constan t mit', It", ;1m! sleady slalt· is adlit·\'I'(1.

Ro '" CLu ' Cu... ... Cl ' C... 2

11fl\\,t·\·('f . Sillt'(· u nhlllllill t'!('a nUIl'l', (' .~" Ihat of a ~mlll ·m la rl,· filtt'n '(! d m ~, is IIl1aITI"<.'!('(!
by di spla('1 'IIlI'nl, tilt' s.;1I1l(' is Iml' of till' \-011111' of Cu.. . TIlli S, alt llou!?:11 t!i.splal't·lIlt'lll hy
i lll' Tt·'l\ i u ~fil inl'n·llst·\ ( 11'<lTiIlI('1' (and IWIl('(' I.'i1Ust'S tilt' tnlal ptl\m <l I'tllll't' lIlmlioll 10 fall)..
110 d l;lII!!:" in n 'sl'ltIIlSl' <llId IlwTt,foTt· in dosing mit' is lIntidpah'( ! al slt'ady slah ·. ~ ei tllC'r
is any d lang:l' llillid palt'ti in (,'''..-", , IlI'ltJll t'h runil' oml t!osing,
:'\o\\" ('1ll1sidt'r a d m g \\i tll a lii!!." ('r t rn ct if", m t lo, IM"C<\IIS(' dearalll't' is unaITt"!.'!t'(l hy
d isp la('('IIl(·nt. tilt' sh·;\t I~·-s t ;\1t' hlolltl 1'tllll'('lItTiition is also uliaITl"I.'!t"(l foIJO\\ing:a ('onst anl-
....It· iIlITiI\'('IlOlIS 0 ,\ ',) illfusillll, II n" t'\'('r, ;t\ hi lldi n~ is dim inished, Cu.. alll! tllt' n 'fon '
n'sl'ltJIISt:· 10 11lC' d m g: IIlIlSI he iUl' ft·;l\('t1. 111t' mainl ellmll.'(· dosing mt t· of tht' tlmg 1Il<l~'
1It"l'(l lu Ill' Tt'tIIl('1't I.
('n 'tlid ioll of till' OUtl'(IIllI' whell a t1mg \\itl l a high t'xtml'! ioll mtio is gi\"t'lI tm illy alltl
wl lt'u elim ina tioTl 1)('1'Urs p n 't lom inant ly ill till' li\l'r is dill k nlt, In IIII' pn 'St:'nl'(" o f Iltl'
d isp la('1 'r, l'ltllh IInl'ltlll lll! d m g: d l'aT;U1('t' and oml hiullVai lahilit)"dt"<.,rt',t'if' (M'(' Cha p , 12);
111I'I,ITt"!.'t of Ilisp!aI't'IIII'r11u n tht· UlihOIlUd Ilm g l'lllll'l'nt miioll at p lalt'au is IIll'ft ·foTt· likt'1y
2 74 CHAPTIIl 17

to l ~· n ·lillin4y small. I m 'spl 't1in ' of all~' d TI't1 of displaconwnt. ht An'H ' f . tilt' unbouud
coucen t rarion al plateau is IUW(' f t han that <!t·h it"\"l"(! f()lI()wi ll~ an ('qlli\ 'alt'nl i.v. infus ion,
nil' events pn-dicn-d at plateau befon- and an N di spl al't'menl for d m ",rs o f low alJ( l lJ i~h
extraction an' Sh(,"11ill Fi~. 17- 2. Slim'l l in Fi ~. 17......1 ,m' th,' tota l and Illlholilid plah',1lI
pl;lSlIIlI couceutranons of t ilt" lllltit'p ilt'ptic drug P"("1I~1 oill ill paueuts befon- ami aftN
rt"{'('i\'ing calproic ;lli d, anothe r .mtiepilt·plk <Img, which di...plaex-s ph('1I~1 oill from allmm iu
hill(ling silt-so As pn-dicn-d for a dmg of tow e-xtraction, tilt' unbound couce-ntratiou is
unahr-n-d, whil(' the tola l plasma couceutration is ( It·Ut'alit 'l l. A('(:unlinp;ly, ba.'i("(1 Oil tln-se-
obscrvunou s. th e n ' is Ill) need to uln-r the dosillp; r ate of pl. t'lI)1oill in patien ts n'<.'t.'hi llp;
valprotc add.
Kinetic Features. Boll. acute events and t '\"(' lI tS al plnt eau Im\"(' 1)("('1\ d i.o;(·lI~st'( l . Itt · ·
llluillinp; to 1)(· discussed an- tilt' kinetic ('o ll<;t"fltleIlCt 'S of di splao-nw-nt 0 11 appmadl 10
plateauunder the usual co nd ition in whi(..h ho th d rug and dtspiacer art' p;in'n d m mil';ll1)·.
To do so . constder tilt' expected changes in di spositio ll kinetics of a d m p; UpOIl displaeenwut .

low Extraction High Extraction

n l(. 17-2. C I... n ~. ;41 p1;4I,'an . i" tl... 1"lal rgl ......1
UlIIM Mll...1 11 1",nn·" lnal:io MlS ( J) - <Ihpt......t C - Intravenous
<,,,, ,In >! ) ,Io.l"'ml 'M' tI...· ....l r.....t io'" r;4l1" " f II..• , lm~
;4,..1 n Md., of ,Iru~ . lmini . lr;41io:",. For ;4 "nlll: uf .."".
""l r....1io.., r;4lin. tliminid....1 hi,.. linl( If.. f ) ....I,....."S
II... llJt;d.IM'l lllJt tI... U"IMMU"1. ' ..........Ill natio ..' n~l .
J....... " f ll... ",uf" ,/ . hnilli-tr"" IIl. fo'nl"II ,Inll( " f hild> Oral
1"1""lk .-:\l r....1iom r..lio•. c!'·aI"41Il.... a, 1 "'. I,ot;d n m·
,,,'nlr..lio:,u, i.. ,., rr...1,..I I · oIl1" ini'I 1l>i,..I"'I("I..•u
II...• ,In'l( iJ ~ n inlr..' ; ,.J,'. 11..· tl"I M.." ...1 n "'·
C"l'T ,Ir;41io:",. 1 ...,. iJ •• -..10..:1, Bo'<-..ll...· ,1i",in i".....:1
hit..linl( ,..'(.Tt· "S u...J 1o;''''''1liL.hih ~' " f II..• Ioi,;l' I,'
d,·;m.,) "mil:. tI · likt·I,' ,...,In,,,...· of .h. pL.c...." ..·ltl ;d.
n-r or;d . h" i"i olr..l io:.n io lit , lo'(.Tt ,......• in lh., lutal ,.
('f'Tltr..lio: 'n ;0,,,1 I,u l.· ,... ,..., '''';0''1:'' in tI...· u"I " 1
"""".. "lrllti n" . T h.. <1,,1,,111 " ha nl(" d "p"",h " "
" -t ·r II rr."<1 on " n.IIIit""'-aiWJi!ityor .
J'"":k>l"i""I'"I C 0 C o C o

"" 1(. 17-3. n ..· ' '''pn>it· "",*I--I'I"''''~1''in 1""·......1 ...,,, 18 N- 25

i''''.....'" .1i.pt.....·" ......1.." Iy. AltI"",,;I, I,la." ml l'" ot.·in
IJi",II"1(of pI"''''~1ui'' lo ''' C'R'll...,,1wl....n ....liu", _>d .
~ Total

pT'' '"Io' io ...1",;nl-kn..:1 d'I'I"'io:.." II, tu a ~ "'P of i"" S 16

~
tif'nh ~lilt.ili7....1'''' p1"'·fl}1uin. "'111. ;0 " "Sult;o"1 f;oll in 0
till' ' 1o·;oJ~·.OI ;4'(' p l...."';o plll'll~1 "l n ...",.,,'n lrilli.m. .~ w-n
ti,.."" "'.... 110 \l, I..I;o"ti;o1 d lillll(" ill tI... n " I...",,,,1 14 Total
pI"'n~1'Ji ', ,,,,,,,,,,·nl natio .., ("olt...). n ....., ' >!"'·n -..J io:..." "
~

0
0
~
;on ' ."""i" ..,,1 wil h II ,li 'p l""'' ''II''' ''1 i" l.. rlK-ti"" of 0
pI"'''~1' Ji'' I." _-alpl'loK' "",;d . s .ot" thaI I...• '"'W''''' " f
p1"'"~1' Jin "i,pL..~n",·n' ,1o.1",,,,I. '1Il II... .10.... flf .. ..
'-' 12
~
"0
N
,,,"-'
or
,Ii"", ,-alpn ""I"'. II..., 2S l"'hr "l.ool;dJilin .,) .1<.1 pI"'"o s:.
~
10 =v='
~
~t'Ji n . I I ""..-it..,,1 \JIIIO mil: ....It"m _"'p"~lh' 1"" 1' .... ~.: ~
9 " '('(-it...,) II 13.'it).. ml( .L.i~. .......; ",tot! oon... .. " ..'i\~..:1 0-
I...Jth 11'1(1"" '''0 (I mWl·
- -Ill ",Ml. IT;o~.'Tl [rnsn
0
~
2
Unbound Unbound Unbound

~1 ..lhfln . lUI., C r..,.,..r . J.A.. \\l l1ioa"'''' IIl. P,D., S'" ''
..l/y. K,A.; \'alpruk' ..* 1in rpiJ.,..y Chll k-..l" ,...1pl...r.
tIl"",~"'>w<-..I ..rr,,,-to. An". S .."n>!.• 3 21)..25. I Y';'~.l
~
0 D D D0 900 1350
CHAPTfR 17

Di"IHJllil io n lUnd i n, 111l" subv-qu e-nt poi nt s SUIll Ill'II;7.t' those.' made in C hap te rs 10
to 12. Ht '(.'U u ~, dt'am m.'(' of a lln lg with a high extraction rdtiu is IInafTl"(:h"(l by di.~plan_' ­
ment , til(' hal f-lift" (:hangl"S with volunu- of d isl ribution . I II contrast . for a d n l,!!; of low 1" -
t ract jou, b("('au st" uubouud clenrancc-, CI ." . dIM.... 1101 dmll!J;c·, hillf-life either n-mainv 1"(11I -
staut [wlu-n \'" does not d l'lII ~t' ) o r sho rte lls (if \ '" tlt'l:n 'll.SI'S) wi th di sp lill'('JTlt'UI From
pta~lIl a prote-ins,
pla1Cma COllct' lIl ra l io ll- Tim e Profile , Altho\l ~h then- an' many l'M ,ssihl e ("(,mh iualions
o f r-vents, only nne rouunon situut um is ("(msidt·f("(I. 111 this (';l.S(' (F ig . li-l ) tilt' di sp la('('r,
wh ich I..l.~ a 111ll ~N '1IIl thau thut of till' t1m~, is mlllt'tllc i till' f(W lnt 'n of <I pauent stal,ili"J."(1
Oil a low ex trac tion ratio dmg. T o s i lll pl i ~v mat te rs. IMJth dmg am] dt splacer ure mlm inis-
ten- d hy constant- run- infuskm and both an - ussuuu-d to aIW"d)-S 1 1t~ at dist rilm lion t't illilih -
riUIII. \ \11i1e th t'S{' o uxh tions an' somewhat n -stru-tive. IIIl' situalion d lOS{'1I dllt'S itlllSlrah'
till' i mportance o f both k i l1t'ti(~ allllth(· mumu-r of d m g ad ministrati on on till' Ii kt 'l~' rln-r-
apc'lItic outconu-.
:\otit"(, in Fi g. I"i'-I th at slnw al'('u lllulatio ll alJ(ll"( ,rn-S!'M mtlingl, · slow t,liminalio li t,f tilt'
dt splacer results in ill si~lifil.".llIl chengcs in till' 1I111Mmmi d nl~ ('tllll'(' nimtioll and then-fen-
rt'SIX)lJ<;{'. l 11is is a l"(llloS('q llt'Il{'(' o f till.' ki m-tics u f tht, d isp tw('r I x"in~ slower than Ihal o f
til(' d m~. 111t' ooncentratkm o f tln - di spl an 'r is d l'lII~ ng ~ ) sluwly relative to that of tilt'
dmg thai at all times tilt' dmg is OIl ;I virtual slt-ltdy stutc-, \\i lh rate u f l'limi natic m
(CI.II . e ll ..) matdlin g Ihe ran- o f ad m in ist ratio n. 11m! is, ahholl ~h there is a k ndc'nl'y fo r
lilt' unbound dmg conce-ntrutlon Itl ri ~ ' aIMI\'p IIII' (UIII"("Jlt r.atin li .tt slt'ady stall' d ll rill ~
accunmlat lon o f tht ' displacx-r. then- is an 0PI'MlS ill~ h'n d,' nt)· fo r tilt, un bound conceut ranon
to fall be cause the rate of eltnuuution (e l." . Gu ) would tlu-n t'x("('('t.1 111t' rutc of atl min is-
trutton (CI.II . ell..I. 1111' n -verw h 'ntl l'lld e s 11('(.1 1r fin stopptug th e displao -r. hul tlllt'('
a~ai n Ihey lJablll't, 1"Il'1l otl u-r out . A{'(."(mli ngly, ahhou ~h thl' unbound co nceut runou rc-
mains cs sennully unaltered . the total p l.LsllIil drug concentration changes ill wrwly wi th that
o f till' dis plao-r, rt'f1("{1ing tln- d l:t!l¢ ng d l'grt"(, of d isp lat:t' mt'n l. ,\ transient dlan ,l::c' ill

Displacer Drug
Total Oruo
~_ _ -
100 1.0
~ 50 0.5
§. ,
c ,,,
~ 20 0.2
,,
,
"c
~
u
10 0.1
,,,
0
u
~
5 0.05 ,
E
~
2 0.02
"
c,
1 0.01
" 0 1234567
Time (halt-livesof drsptacen
5 Drug '7
Displacer

. -i.lt. 17--1. \\l ,,·"'~ "'-tanl l~'

inf"... ~ 1. 11.,· .."1••,,..1<..t .. ~'''tr.o'.", (" .I",) nf .. ,In'lit ,,;11. a 10- t-,;IT;oo.1M", rollin
... ",ai n '! \trt"" llr ",tI, .. 10-" '1{ half_lif" . n·I.1t,,,, In 110.· dn ,lt. ;~ rili...r l"f,
", ...-hanl:<..1if It ,Io'l'Lot..-. 1or .. ;1", 1 r-~1l .
n ... (-ha"I{<' in I'Jl..II>la' llla ,Inl): (,o1I.., · " ' .... h.1I, n·H,..1~ tlw ,10' 1,1.1""""'1 '1,
 ". INTE ~CTlNG ~S CHAPTER 17

IlliboUlld ('1 J1l('('nl r.ttio ll ll1i~"t ocvur if th e kim-t ics of 11ll' d m~. rather than that of tilt'
t1isp lal'(·r . luul lx-eu th t· slowc'r. 110\\,("'1'(' ( , thi s situation is I'd.din-I)' 11Il( ·OIll IllIll I .
In till' (',l-W just diSl-11.\S('t1. 110 dmll ~l' ill l'lTt"(1 a ndIn-no - In tlu- d OSll.l:l· rt'¢lnt'n of l ilt'
t1m ~ is ;lnti dp;llt'tl e-va-n I l.oll ~h d ispl;ll'l'llwnl 11,,,-\ oc ou rn -d. Indt'('tl . if only « 'S p U Il s(' wen-
uuuutorex], displaceuu-nt \\1I111d Ilo t !MH' !lt'('1l slIspt '<.1c'tl.

DIMINISHID UNBOUND CIIARANCI

1\ n -dncnou ill lillhllllmi ck-umnce is 1"01('1111;\11)' tln- mo st dal\~t'rt m s 1~1)( ' lIf dm~ interne-
uou. T Ilt' unbound dm~ conce-ut ra nou <';t11 111('11 n sc 10 a toxicle-ve], unless a ll at ljusluwlIl
ill d OS<.Ij.tI· isnuuh-. <:OIl'\('( jll(·lItly. it is (·~trt·"l('lr impo rtant to he aliI,· to i<!t·utify. charac-
It'ri u.'. a llli \\1\('n ' pll.... ih lt·. a\llid IlJh 1)1)(' (If Interaction. I nlnbitfon IIf d m ~ metabolism i..
li lt' nmjor ('auS(' o f n-dnc cdunbound ch-arunce.

A (ase Study
Sllll\t· patient s n '('( 'i\il\~ t1lt·nplayllint· dt ,\·(·lnp mUIS('a wln-n euocn-in, a n a l1!i·inft'<.'fh·(' qum-
(Jlim·. is "ddt'l l 10 li lt' Iht'(lp lJyllim' r t'WllIt·n . TI I(' mlllst' a is a\s(K:ia h"tl with uu t'! t"'111t'(!
('Ull('(' IlIr; I!it lll tlf Illt,(lp l'yllim ' (·il.lIS('(l lly euoxaci n illhi hit ill~ tilt' nu-tal jolisru of t1l1,(lphy'l-
[i 11(' .

'2 Enoxacin
Slopped

~ -
,,~
Started ,
• •••••
>'E
~ -
0
~
~~

-0
-
8
,• • •
•
Theophylline
Stopped

,
~
~ '"
ro- •
E :0 •
~u
ro
-
~
0 4 ••
~ '-'
••• • ••
•
0 •
60 ' 20 ' 80 240 300 360
Hours
FIll;. 1i-.5. E""'.... 111 i" I'il' ih t1 1< ~, >I I\II; 'I< ' 1·limin.,I1<n S"I';''''1' n ...... ;\t~ I I.'stl "'It 111<~ " h~ l1 il1<' lin II "I<' I",I"~ I-
n ·"·.....· ,Io:...,~ . f" n n ) " ...J l~ ..... .r:'" 1;21,. r..,. 12 , I.o~ .. (2"'''' hr ). H~' 72 h r. .... ''''P''''1'~1. ti l<' In, uj(h 1 .I ...,.dM~I ..
pl.,Io'''u ,,,II, "" a"'r;l~' t~,,,n·" lr.<l i,,n ",Ihi" " .".. ;nl: in" ·I'\.,J uf 4." "' WI . (,I< " ..11<"" ' 1. .:.........;n ' ~.·u . .... 1
n , ~ ur..l1~ ,..... r:" I ~ I.. fur 4 <LI~"' . •lal1ltl\( IJ6 I.T ito' " II,,· ' '',.." hyl1 ,n,' n "Kin"·,, . ( h i ...lo:li' " I<' " f r n s n. 11... ""'alr
I ","~" t1 1<~'l"~·t1 "M' (~ II I<~· .., ....II" " n · I.. .. '1<....' "to,l l,il:""r 1'1'11""" (II'~'''''I:' ' inl.·n" · (~ 'nn·nl n.r.li.. " ,,(U "'WI..
'1<11 , I"", ,, ), 11..· I,n..· ,'I<,rv ' " f II..· n · "'It.' ' '' 1.·nn iJ II':',11M' 1,..lf·li(,· .. f t11<..'f'II~i l; · in th.· pl1... ·,,,,.·,,r,·,.. n ad n
122 1,0 . ,·\lI I I< " , ~II. u" will..I......·..J "f ,·,,,n .•du . II..· 1'1 "'.. 11" ~ or',~Il" ..•t"'M:1·nlr..h" ll f,·1I1' '''OlTd tI... p n ·..·' I< .....,,;u
\·"1,,,· l ~"·r"I0:' · i" .. ·n"....· ,,"I<.·"I ....li,," "f 4 .,,"'"' ~ "u' , 11<"'11). II..· " "I<~·"I ....l;'>I' "f •.,1< .....";,, """t 1"1'01' 11<~'n
. " Ili<;'·"1 In ",,,rnl ,,;" "1'1' ·d ,,I.II· int.il,;I" m f"r .....", . li",.. . 0111<·...1,,·. II..· n1"", "r 111<.. opI ,~· lIi .,, · In II..· I,n "
,·""..." 1" """.·"Ir;ll(.", ", ,Io llu-.. · In'n ,," ,,·h . 11< "to-r. 1"'; 111( " " l<-nn;''''II I,:,' ti l<' ' I< ,n nal " alf·lif,· IIf 1 1 "'I 'I>I,~ lI"M"
" .. h, (l 1 "~'I>I ,~ l h, ..·; I "'WI. - ."i.~ ~ \ I ) " \I , ..lifi..l l'n H" R,'IO:t·. \I e .. So""'''I<''' . \\"It " So..I",..... .'I.,J . \\".·l h ,,~
1' ( ;.. K,.. ,I" J R . ."..1 \\".'Io:,,,·r. r G.: 11... t11<"'f>l~lIir"'''''I<>:\ati'' i"" ·..",1;',,,, 11 e h.. n~ .. ill II..· ,1i'1".;I"'" "r
11..~ , >I,~ III1" · ..,,,I,h " ...Iall< >l i" ... . Iuri,,~ i" "'n " il"''' l ...h" i";.I....I" 'n or •.,1<...." ;,,, e lm. 11", n ",... >I. l1M·T.. ~Ii A ~()-­
I ~"'. I~!l l
CHAP1H 17 lN1[RACTING DRtX:>S 217

1111' d ra m,ltie riw ill t ilt' trull ~h plasma concentration of 1!l('oph,.lIill(' wll('l1 ('110'1(,'1111 is
ad d('{1to li lt' rt'J!illlell a nd t ill' n-tum 10 tilt' pre-euoxaci n vaha- ",,11t'1I t'lI l1 xactn is \\11Iulra\ \l1
a rt' iIIustrah'{l in F i!!:. Ii ...'). :\oti('( ' that it takes appm ximal(·I)· 4 AI) '!' o f enoxacin admtn -
istrutiou for 111(,('p hy llillt· concentration to rise to the new pla teau and a similar till\{' for it
10 return to t ilt' pl"(·-(·lJoxaciu vahu- a fkr r-noxacin is ....-ithdru....lI.
:\ uum- quant itative pictun- of tilt' events Illay lx- ~ai ll('{ 1 Frorn twu equations. 0 111'.
prt'\111Ilsl) ' t'\;\millf,1( E ll' S. C ha p . i J, defill("!i Ih t, a\'l'rd!!:t· concentration of dOl!!: at plateau

F - Dose
c .<~
• cr . t 3

TIll' u tl ll' r c'flua tio ll d d il1f's IIIl' III " \" (a llll lo IlW' r) hal f·lif(' of th t'f'p h )'Uillt· ( ' Ir.i!~n"iI",.. t) in
n-lation I" tln- no rmal !Ialf-lif(' (' II2.•~ ...... .J)'

wlll' rt' CI.....","" aud Cl' lnl"J.".., an- the clearance s o f th ('{)phyllill(, in the al)S('!ll"l' and p n 's,
n f tl u- inh ih itor. rt·"llt'l.·!i\'d)·, Equation 4 foll ows From t he equation k "" Cl./\' and
( '11(,( '

fr om till ' know!e dgt, that r-noxacin does no t alTl'("t tilt' \"(,11I1I1t' of d istrihutinll of t ll(>(lphyl-
line , a dmg only w('ilkly hOllnd ill plasma and tissue.
1111' hal f-lifl' o f t1wophyllillt , ill th e ahst 'II{'(' o f ('110\;\<111 is SB IJr . ('st illlah'ti from t!l(·
d('d i ll i ll~ couce-utrution wlu-n th ('flpl. yllin{·mlminislmtion is stop !lt't l (d ay 13). As expected,
\\1111 \111'1 1 a sho rt h.tIf.lifl', thl· plate-au coucentrution (C ........ I, <lppnJ\i lllatt'I~' -1 IIIWI.. is
rl' ae h t'tl \\it llin about 2 d;l,.... o f s t;\ rti ll~ IIIl' t hl>(Thyllillt' 1"('J!illw n .
Euoxacin is mpidly ab..orbed and illllll('{liah·ly lnhll uts Iht >(lp lJyllilll' lll(·ta lll ilislll wln-n
admiutsten-d u n lilt' fifth day into Ihl' t h(>(lphyllirlt' n-giml'I\, \ Vil h conttnual administmtiu u
o f tlu- sa llll' t1ns a!!:I' n.~llIt'n o f tllc'tlph yllil\{·. its plasma conce nt ration rises to a new platr-au.
a ppm\i lllat t'!~· H IllWL. t1t' te n n ill{'t1 h)' t ilt' I W\\'. am] lower, clea rance \1.1\1(' (CI'.nl,J..,..t ).
A{'l'(mlillgly. by n ·f(·f('Ill't· 10 Ell. 3.

C...aY• . -moI
5
C"'aY.;"lIob;~
and on s n hst i t u ti n~ 4 lIIWI. a mi ~J lllWL for C...",..... ..-.I and C ..... , .I..I,II>it. .' , O il(' ohtams
Cl ', ~j,Jn'<T/ "" H,4·1 Cl..........J. 111011 is. enoxacin reduces tilt' ck-anmee o f t11l>(lpla)·ltillt' h)' 56%.
Thi s calculation is h;l"t'tl 011 rhe a ssumption that th e bioavailability of theophyllmc. whicb
is usuallv well «I."o rl)('(t is IllI.tlT{"{·!t"(! bv cnoxacin.
1111' ;It·W half-li ft· o f tht'flphyllint ' in tl l(' prcst'n{"(' o f till' inhib ito r can now lx- {'akulat('{1
hy apprnpriatl'ly s ll hs lit ll l i n~ tutu El l' -1; it is 22 hr (8.1; L X 1111,44 ). 111is lm l ~{' r h;tIf· lif(·
('spl a ins w hy it lakt,s 4 day~ . rutlu-r than t lu- usual 2. 10 reach the I \l'W plateau. It is also
W llsistt-n l wi t h tilt' o h"t'I"\'alion t ha i 1111' plas lIla coueeutm tum o f l llt'tip hyllill{' (6.5 mgtL )
mid w;!y llf'twc't'1l ti ll' p revious and Ill"" plateeus occurs I da y afiN atl min ish' rinl:( (·llfl:l:ad n.
11\1' slow return of the ph~lIla thoophyillnc ('fJll('('n tmt io n to tln- pn--e-noxacin value U ti

wi t hdrawal o f enox.u-iu re ma ins til Ill' exphuned. A h hull~1a withdrawn. tln- conce-nt ration
uf ('IlO\;Il'ill ill ph'illla !It·rsi.s h al <I sllffit'ie n l l)' hi~h \'allll' to ('tJll O ItI l(' to inh ih it tla(.' lIlt't<ll>-
O!i Slil u f lllt>(lplly llilll' fllr a {1111sit!e mh lt' pt'ri()(1o fti llit' . As sll{k til t' ha lf-lift' of t h(>(lp hyllill(·.
w hid l ('fmt m ls t ill' rdum o f th(,{lp hyllilJl' to ils pn'-(' Iloxad n {"llll('('nlr.llion. rt' lltai llS t'1(O _
\':111"11 fo r Sll lll(' t illlt'. H ad illhi bitiull ('(·..."t"ll illlltlt'{liatt'!y Ullt lll \\;t1l{lnl\\;lI ~ (·llO\adn. t ilt'
half-lift' o f Ihl 'f'phyllillt. wo uld ha\'t' f('\'l'rt('l1 had; til its l'(mlrol \'a lut'. k.S hr. :lIld th{' rt't um
of Ilu>( Jp hyllim ' {1l!J{'('nlraliolJ til tl lf.' prt'-('uoxadll \'lIh lt' \\"fluld ha\''l' Ill't' ll mudl q uit l t' r.
 lNlERACTING DruGS Cl1AMf l! 17

AGradedlHeet
Til l' ];L~ I stat euu-nt ru-eds St JIIl l ' amplification. TIll' illh ihil ioll o f Ilwophyllim' hy enoxacin is
1I0t all <l1I -ur-noll!' n: spoIlSt·, hul rather a ~radl'(l 0 111'. The dl'}~Tt'l.' o f inhih itio n varie s wi th
the- ptL~ nJ;l l,(llIl't·nlratiulI. and IWIll't· <Ius..-. o f cuoxaci u, 'L~ Illustran-d in Fig. 17--6. ShO\ \1 \
,111' hoth tI n- plasma conccut rutton-nuu- pmfil...s and AL'C u f tl1I.'o phyllim· follc J\\ill~ a si ll~I ..·
duSt· ..,f rh...oph~ lI i m· takeu alOl1l.' and al sll' ad)' state d unll ~ n 'Wm... us o f 2.'i. 100. alll.l-4110
Ill~ clf "'IlOXill'i ll ~H ' 1l I'\ "" f)' 12 h r. As (·xlx ·l.-It'l l for a d nl g of low clearance, INIIII AUC am i
Ilalf·l if... of Ih"'Clphyllim· illl·n ·w.... with inlnbi rion. :-';011<.... thai inhibition is (...i d( ·ut (...·..·11 i lh
tln- 2.'i-lIlg r-uoxaein n 'WIIlt'1l .md 1111.'11 illl·rt'll'....s , h 'mling to "pp ma<:I1 all IlPI)('r Iimil i th
tln- .Jln-lIl ~ Tt.'WIll(·I1 . Rr-sl'II('C I, ('\'l'1I Ihough the- plasma ,,' 1I0XiI<111 ('{)lI('t'llt ratioll falls afh-r
a -4UO-lIIg ..10<;('. inhihihon I)(~ rsists , 10 \'ill)ing dl'}~n'l.· 5 . for some tillw then-eft..-r. Ck-arly.
tilt' lo n~..-r tln- Imlf-life of all Inhibitor. th e mo re persistent is Inhrlnt ion 011 \\i lh d m\\ing it.
T o appn-eiate- ilion ' fully 111(' ~md('C 1 nalun' of illilibitioll o f me tabohstn, consider till'
fulltl\\ i ll,g. Hccall (C hap. I I) Ihal for ..' a(.. h Illt'tahulit' Il<'thway

Vm
Rate of metaboli te formation - _ · Cu 6
Km

,,1."'11 the- unbound d m~ conceutranon , CIl , is \\"1·11 "dow till' \l idl;l...Jis-!\!t'1lft'1I 1'{ llIstanl,
Kill . O r. ('\ pn'sSt'C 1 ill I...rllls of IIl1l NJIlml clearuucc associated \\i th m(·taho litt· formation ,
C l.llf ·

Role o f metcbcbte formotion = CLu/ ' Cu = fm · CLu . Cu 7

,,111.'0' 1m is till' Irucnou of thr- doS(' uf ( ! nI ~ th<lt is ('(lIl\'('rft-ti to till.' lIU't alxllih'. lu htl ution
<I''l'O',L<;('S C l.ll of a lIll.'tahu lift' . A ('(111I11I1111 IIIlx!,,1 til t1,·sc n lll.· thi s d T.. '<-1 is
f

A B
4 150
.......,..•..~
-, ? loo
~

\"4 0.
§.
i
i
•••••lI.
'-'
~ 50

o o
o 12 24 36 48 o 100 200 300 400
Hours Dose (mg)
!'·l l( . 17-6. n ..• i" l,ih;ti.." ,of t l " ~ 'I"'l\lI i' ..· ..linm li"" loy "Ill_ i n lO!fr t. ~I . ..., ......t.·lln~ 1 ,~' tl..· p n>ltl lll(;olIM'" i"
l..,If.lill· " f . t.~·li, ..· ..f pI..., ,,... tl.. ~opI,~-tlill.·,...K ntr...t it"' (Al ..., ..1 il .......· in ,.\ t 'C: lll) ", I,,·n ... 2t.I. ," ll..t.....• .. r
tI..~ 'I'I,~ lJ i ' ..· j, ...llI1 i" j, lt·.. ~ 1 ale" ..• {_I ;,,, ..I .I" " " !f j .. Lo~ "" ""'no "f 25' 1I11f (0). H.1.1l1!i: 1"'1. .uKI 4t.I.",ll. (lI.l
.·,..,......i " !Q" '" '''' '1)' 12 I" . 1>,,1... ....... II..· " ..·... n. "f .. 0" I 'jo~1 ' (I "'WI. - .'L5 1ol .\ I ). ( I)",... fn >nl R,"I«'·. M.e ..
S" I0 ", ..", . W.R " ~Ima" ..' .J .. W.·llm\f. 1',1:., T""th..k,·r. !i l).. ...nd \\·~" ·r. J C:.: n ..· 1I..~ 'I>h~'1Ii1"· .. ·1.. .......,1l
i" k r... tioM" I. EfT t " f .·,..,uti" , I.",. 0;7<'..Tl II.... 'I,h~·lIi'"· ,Ii' p"'i lio ,n , eli n . 1'I,an n'It..I. n "'r" ..l :.s7U--.Yt'i . 11M.)
O W'TH 17 INTf iACTIN G DlIUGS 27.

Clllf ' ClI

Role of metabol ite Iormetion = 8
1 + ClI/K,

when- e u, Is till' u nho llnd conee ntrution of lilt' inhi bitor lind h, is till' inhibit ion e usstau t .
/Q\'t'n h)' the unbound couceut rattou of inhih ilo r that dl'('n 'a.<;t's CLuJ by tw"fold. C ll'arly,
Iht" !owt'r the h " th e mo re POk llt is an Inhtl nto r.
T wu main conclusions ma~' 1M' d r awn fmlll Ell . S. Fi rst , thr- dcgn-e of inhihition of a
part icular p<llh\\ "d)' dt'IX'lll l~ on tlu- unbound concentration u f fill' inhibitor rt'1al in ' to its
h " Man )' compounds have been ShO\\11 10 inhih it dm~ met ubohsm /'1 ('Uro but fail 10 d o
so JFI t: jtJ() , ht'l"lUlw the uul xuuul concentrutions iL\'illliah"tl \\it" f!JC'flIpt'lIlic rt'/QlIlt'IIS o f
th« inhibilion lIrt' wd l lll·low the h , \'alill' .
Second. tilt' impad of inh ih ition 01 1 d na ~ elinunanon dt ,!'It'mls on f m, Inhihi lion IliL\ rlu-
mos t p rofou nd d T('{1 whe n till' alTt'l1 I"tI Il;ltl t\\"lty is f)hli~ator)' for tilt' eltnunutiou of til('
d r ug. Ihat is when fill ... I. O ffl>n then- art' mult lph- pathwa j-s. E\,{'II al the hi~ht's l dost·,
t' no~ldll is o llly ah le 10 reduce lilt' (tulal) dt'a m nl1' of t1lt'o pltyllillt' hy app m\imat d y "m-
fold \\i d l U t"(IrT\'slx mdi ng dOllhl i ll~ of d ll"()pllylliltt' half-lift'. l1woph)'lIint' is t,lilllillalt'll hy
dt·lIIetll )'I;ltioll. ri ll~ oxidation. and n-nal cxcret tou. E\idt'nlly. eunxaci n inh ihils u nly 'ilIIllI'
n f tllt'st· p athways. Tilt' antidepres san t d t'sip r.Ullillt' , Ilw ta1lo1i;r.('(1 h)' the <')1OC'h nnJl(' 1'~ .5()
t' nz:"'Jl(', C YI"'2 D6 (st·t· Chap. 13 . ( rl,'uetil"S ) 10 form :2. hytl mxytiesiprd lllille , is anothe-r ex-
amp le , Qutnldrne. a IXI!t'1l1 Inhtlutor o f C YP'2D6, t·ITel 1iwly co ne...-rt s exte nsive nn-tabol -
tzers of d eaipra tniue, in whom this path way is a major nne, 10 IXIIX metabohzers. with a
pmnouneed reduct ion in d eanUl{1' of appmxillmlt'ly fOllrfoltl ant i {,( IrT\'lip0lJ{ li n ~ prolon-
~a ticm ill llalf·lift ,. In such caws. the clmk-al conseq uonces of an interact ion dC'l'It'nds o n
tln- n ·lali\,e {'tm trilm tions o f d nt~ an d 1llC'laholitt· to efli t';ll")' alit! toxicity. \\'ilh desi p rumim-,
til t' dOM' ill exte nsive lIlt' taho li/.l.'r.; sho uld ht, red uced to avold toxicity. if quinidun- is ('t)-
lldminislt,rt'tl. As Ill i ~ht Ill' cqx-ct cd. llu iniclim' h iL~ liUIt' t'lTc't1 nn tln- pha n na{,(lkillt'lks o f
desipranun « in th e alrea dy poor C Yl"'2 D6 nu-tabolizer pht'llot )llt" bt'l"lUlSf' the alTc'(.'lt'll
p<ltll\\"ll)' is uo w u minor om-.

AMultifoceted Interaction
Although lilt' antt-iutlu mmatory dmg p l\('nyllmt;wmc' is 110 longC'f wich-ly used . its inter-
action with warfari n is \\'t,II-du(·UllWlllt"(1. 111l' int e-raction has {"lIU!\('11 st'rin us hlc"t'l ling 1'1'-
i!\()(!t-'s. Warfarin is laiglaly IXlIInd in plasma 10 albumin. PIlC'nylh util1'JlIlt-'. c!t'\ u id o f inlat'n'n l
anticoa gulant act ivity, di sp lac'('s warfa rin . CIIll!\('(IIIt·nlly. <Iisp la{'('llIt'nl has 1It'('n adH)(';(k c:l
as tilt' pri mary mt'l·ha nism fo r tlais tnteracnon.
Ftgurc 17-7 shows the temporal elTt'l1s of plwnylhllllvJlllt' admlnistru tion u n till' p],lsllla
am i unbound concentmttons o f warfarin ill a suhjt'l'l who illgt'sh'l l 10 m ~ wa rfari n daily,
Tilt' laalf-lifc' uf warfcrtn is 'lpp ro\ imalt'ly :2 days , am i the-refon- ;L\ anticip ated. a ~h 'ad~
stalt' for this d nt ~ is n -aclu-d wi thin the first 12 d ays . wlu-n \\"llrfOlriU,,1mit' is atl llliniskrt'( l.
AI this tinl(' lilt· \\1lrfarin p\;LSIllOl {'UIl(,\'nlmfi nll i.~ appm\i ma h' ly -I m w L and o nly IJ.SOl
(11.tr2 IllWl..) is lllllxlIlnd , i.t·.. fu :: (). I M ~'i Warfarin is l'tJlIlp lt'td)" Olh'ilJrht'll, alJ(1 tlll'ft'fo ft·
ils d t'ardll{,\' , t"Stimalt"tl hy tl i\id i ll~ tbt· dilily dns iug mit' hy ti ll' sh ';uly-st;l!t' ptLSIII;l {'( Ill -
{'\'utm lion, is 11.1 lAir, T itus, \m rfarin is .1 highly IMmlJ(! d nt~ \\i th a Itl\\' ('xlnU:1ic lll m lio.
P!wn ylhu t;v.ont· is al'il) IXMJrly t'\ tmdt'll, is high ly IXllIllt1 (f" :: O.OIl4 10 O.OIOl, uncl ll<t\
a h;llf·lift· (app ru ximalt'ly 3 days) t'\ '('11 In ll~e r than Ihat flf \\"drfa rin . l\ l't.'tJn l i n ~ly. w llt'll 01 1
d ay 13 Ih{' !iuhjl'l1 {"IJl11 1llt'll('('S tlit, llSllOllly n 'l'tlllllllt'mll'll c!OS;lgt' rt'jQmt'n n f pht'II)'lhnla-
;rJllll', WlI mg Ihn't· ti ml's a day. fh l' pl.l\ llla ('tlllt'('nimlinll o f tbis t1nt~ rist·s am i t·\l·ntually
n.'adlt·s ;l p latt·'1lI o f app rm illla td y 11M) IlIWL. aftN ;lpp ro\iTll;lIt'ly 10 d Ol)";. D ll rill ~ thi s
pt'ril)(l, Ihe p];L\lIIa \\1Irfari n falls slt'ad ily in half. lu :2 lllWI.. ;Ind lIlt" ' Will' offll fur wOlrfari n
rist'S appm \ im att'ly th rt"t·fold .
 ,to O W l H 17

AI Clli<. point. Ih t' ("'I'nb ill p l<l..\1I101 appl'ar n' lI larka"I~' \imilur 10 th o"4' dt1lid'''l1 in Fi g.
17-4 fora pun' t1ispl.u'l·tnt·1I1 in h ·r.k1iIl1l. 1I0w('",r, tht'n' is run- Important tlifT."n'I K'l'. nit"
uuboaud wa n .ui n concent r anon rise-s and rt'maim l'11"\"aktl dllrill~ pl lt'lI)-lhul aJ'..lIIlt·llllmill-
i"l r..tiOlI. H ( '(·.III....• tilt' t'fTI"C.1 of warfarin i... R,lalt.. 1 tu ib unbound (1)m 't'lIlmliclII. this \ 11..•
l;unt .. 1 d t'\ ,ttklll i!i in at'{'(ml with til(' o h<;(·I1.1.'(1 sustaim"(1 <l u': " lt' lIla lio ll of til«" d T('(1 a.. k)fl ~
a.. IIlll 'lI ) lImt.uw \I· i" 1"l);lIl m in i"h'rt"C,l. Examina tion of f AJ. 2 i IK lil.."lt·~ th.d III at'l'Ollll t for
til(' d l'\'i1!t'l1 \..IUI", IIf IlIIhl"lII11 ll m~. t' itl w.' r 11." ra.tt- o f t"IlIf)' of dm j?; iulo 11M" hotl)' i..
iIK'n'a.",...l or III(' va lue of C l"l' is decreased . 1\... l ilt' (it _ J;::t' nw nwII (If w.ufarin is IIl1ah.'R'(1
ami w:.uf a rill it; fully hill;I\-ailahlt·. C l .ll must ha"l ' (k"lTt·iL"t.'l1.
W a rfa rin i\ alllKJ"lt t·WIIL\i\l·I, · IIlt"tah uluJ'l! in dK" liw r In t'ifh t'r "1 ~a k1, · itC:'( i\,' o r inalti\,·
llM·f;lhulih.... 11111\. a !tM" r \..ullt" for C I...fl illll)I M~ a dt '(Tt'a...• in tiM' a hi lit,· o f Iht· liw r to
IIIt·tdhufi7~ · wa rfa riu . ;\ n'I~ ... i'i nf "' ''\'t"r.tl n""tal lll ll i h~ o f warfilrin in llllllh pk\lI ld a lKlurilM'"
\IIIN "IIUt'IlII, (''fInfin llt'l l d ldt. illtlt"t'l l. pI M'n,1IMlhlJlllll' inhibi ts warfarin dimin.ahnn. a ud it
i\ th i' inhihi tHIIl au(l llut (li\plal"f"lrwnt fh.d sccoents for 11K" d illie'.tl p Kt ll A.·.
11 "," illftoraltiull ht 'h\' 'l'1I pIK'II,fhulaznn e and warfari n is ("\''11 IIJUA.· (l.llll p!t"ll. than pur-
Ira' l 'll ah u\(·. GIIlIIIM- rdal warfarin b it racemate. d ldt h . a 50:5() mixtu re of R( + )- ami
S( - )-"-drfa';ll.• mtl tilt· S( - ) Isome r is fiw lillK~ murt" al ti", t han fltt' R( + H ~ 'IIII·r. N tt'n -
, lh llla7u llC' p rimarily inhihi ts tIM'" fo n liOltiulI of 7. (S )-h, u ml;) warfari n. tl tt· ll101jor IItt1al 1llllih'
uf Il.t· lIIu tt · 'K'fi\l · i-.c 'IIM·r. 11 M' les ...nll is d t'a t': () m~ inh'ral'f HMllO call ht · l''Ump Jt.,; ca r eful
IIIN ·n ' ltiulI\ an' n"lillin'li to lIurJ.\,·IIIK" (ali s.

e
tlC· 17- 7. \ \ ';&r{M1n--phrft, D"II...... .. ;nlrn.1,nn ·C 0.04
.......
0

••••
\ ...1"..1 " ..~ ... I lll '''l .... uf.."n onTh. ........ cla:-'
.. ,,1 11M) ml 1"...." 11,,,1,.."",... .h...... Innn it '~' un
.L",.. 11III 2.2..\ ' .1..• r1. ..~ n" 'I"""""·"'''''PT1u~u..n
'"~ 0.03 000

~
e 0.02 • •
0
0 0
" ...... 1.""..I "lI.rf~ nn .....' t1,-rt- ~ .. I. ......1 tlwo rL<-"'" ~
0

'IO';arl.."n '~" " ...n. r.ot" ", f..lI, n.·.....;&1......1..1."• • '" 0

~ 0.01 0
e
In , I... " " I. "" .. I "·~rl..",, ,1,," ,,1tr1" "'~ D"'I............ 1. =>
0

"'''''''rod"", 1,,,1'10....."1"1".,,,,, III .. ~f..n" .·hlni"..· 0

tIl '"~ ( I'I,, · ,,~ II" 'I"" " "·, 1 ,, ~1 . • .1.2 .. \1 ; .. '. uf<ln n. ~
I "'WI. - .1 .1 ",\1) . ( \1,. 111" ..1 rn,m ~;":I~ . W I •. E. 0
o •••••
1 <I~i •. H j., ..,..Itt< ....t .,..I. \ 1.: \\ ·;&r{..n " .pI.·~U", .
0
e 4
.""' "... 1" " ·, ...1.. ,,, 'n"'..,,;" \"")( Wn n ",,,Ilipl.--
0

~ e
0
•
0
••o • •
,....... '-,,,\:0. II .·•. ( ~ ..,," " '" eI"·,,,. I'...,.. ~ _ I'II<lr. ·C

" 3:
0 0

~
o~ 0
" ..... ~ . //) f;.1."l---n ':" 2. l Y';"~.l ~
u
e ~ 2
0 0
'-' 0
~
E
~ 0
~ ~
120
e
0
3 80 0 0
.....
0

~ •
~
-s, •
e 40 0 0 0
00 .
~

=
c, 0
0 0

0 10 20 30 40
Days
Warfarin

Phenyl-
butazone
CHAPTE ~ 17 211

Other (ouses of Reduced C1eorOlice

Inh ih ilioll of metabolism <lml secretion an' examples of t·lw m il~dl1~· II1t"{liall"{l plumnacoki-
net ic mteracttcns. The- lower hepanc clearance of lidoc'aim.' when ~hl.'n t o~~etl\(,T with pm -
pmnolol. a ~ '<It1 n' lIer!-rjt' hlnd.dlll!: t1 m~, is an ex ample of a ph ysiologk ally lIll"{li,I!t'(1 phur-
macnkim-ttc tn tcract tou . Propranolol diminislll'S cardiac ou tput and IWllt't, hepatio blood
IInw, whict. , ill tum. n "{!Ut1'S til(' d ('anlll<.'t' of lidnt:aillt', II dOl~ hi!!:hly ('xlnu.1l"{! by thellvr-r.
Pn-sumubk-, Silll,(' til(' dt~n't' " f ~-adn"l('rgi c blut:kadt' is it ~nltlt'(l n's!'ltlllst'. Iht' interaction
wi th lalocaim- is dt'I)(>I1(I('nt 0 11 IlIl' pllL'ima conceutmuon of propranolol.

Beneficiallnteroctions
Pt'n id llin- p rnIJt'lIt'('id com hiuatkm t h(' rJ.p~' is an example of Ih(' sUl"l'('SsfuluSt, (If a dr ug
interaction. Both of till'se acidic d rugs arc n -nally secreted by an anionic tr,mspo r! S~"!i l e m .
Pmbe-m-cid t,(llllpd iliwly illilihii s the renal secretion of penicillin tlwn'hy suh sta ntially
n 'l illdll ~ Its n 'na l deanmct', the major compon ent of total d t'amll('('. CllllSt'iplt'lllly, in the
(In 'St'llt'(' of prnIJt'llt'l:itl, lI i ~IIt'r tha n usual pla.s ma coucentrarions of pcrnctlhn an' achieved
full(J\\i n~ a nonnal dOS<I~t' ft'Wll1l'n of tilt' ant ihiotic. o f noll' is tilt' lad; of a major d Tt't1
of pt' llicillin nil prolx-mctd ehuunation. A h h oll~h prolx-ncctd is also a<-1i \"t'iy S('(,rt,It'l1 into
thr- kidlll 'y tu bu lt'; unhke pt·nid llin. it is Iipophilit· and tn{)sl l~' reabsorbed. Couv-queutly.
IllI' n 'na l ch-amnce of pmIJt'lJ("(id is low ; metabolism is til(' majo r route uf us t'!imillalitlll.
Auotln-r example of a IJt'Ill' fk i ,u interact ion is thai hl'rn't't'li lila...tati n and th e antihioti e
iuupeneru. lmipem-m is IIIt,t"lltJlil.('(1 t'xlt' ns i\ l'i~' in the kidn ey hy ;1 dl' hytlmpt'pt idlL~·, ln"
l';llt'll at lilt' hnlsh Iltlrt!t'r of tilt' p roximal tubular ('(,II. COIISt.'(I" t'lIt1y, the urinary excretion
of intal"! Iuupenem is low am] u ftt'n insuffid l'llt 10 j.,1tlarJ.ntt''(· dT('(1in' treatment of urinary
truct infect ious. Tn itnprovr- the ('ffit';lt·y o f imipenem, it is market ed in t'o lllbillalioll \\;111
dhsta lin, a t1t'l.~l.l mll('pt i t!lL'i<-' Iuhihitnr, whic h mark('(lly Increases til(' uri nal)" exen-tion of
Illwhan!-:t'd imipeucm (Filot. 1. -.,1)).

ElEVATED UNBOUND ClIARANCI

TIlt' un lltlllm] dt"tr.lI\t'(, of adnl~ can 1M.' iU(·n "L'>t'l! in numerous \lllp ; . R ilisi ll ~ urine pll
hy W\;u!-: ill'l'laJ'.ulam idl' or sodium bicarbonate increases the renul clearance uf sali(·,.Ii('

Administe red HJC,. 11-Ji. Cila."'a lin marl<.",l1~· ill'

80 with Cilastatin l'Il'a" -S lh., uri na l)-' t'\(...-tit•• of tilt'
,m l il,i" l it' im ip<'Ilt'lll loy il1 h lh i\i " lt
IlM, tlt'h~tl n'P'l>l itL..,,-· in til(' ~itlr ..-:-
..."'I...l'i l>l<. f".ito 1t .. -ta.l.~i.m . Th·
llri n ;H~' n-cov.. r~· u f umpenr-m io
••
1.\.. I.~ " 1<....
.... ...11 afk r a ."jI j(). 11 'R

Imipenem ad m ini\t .. n ",1 alt.", ( "t,,:~) anti 10 _

!:,11M"r " il l. a n 1.\'. l . ~ ", of 51_' 11111:
Alone
d lll'llili n ( (~ ,l "rl. (Rt,tl.a..." fro m
:""r1 ~ S R...... I<"'hJl:. " .. BjI\n ,,~ .
8 .• H u r m an , 1.. ..... . F,'rb l" , F .•
lI ulM·' . J.I... J"'l<'o. K II . " ;l.1I1I".
r .M.. ..:,J u.n. I·S., Kn'I'P. II., M,-i•.
in,.," , ),1... ...... ;1.1,,1 s"I."·I..tf. J(:,:
UrilW)' Tl'l''''l'ry of .'\ . fnTln i mit~ ~1
l" it'naHl~,in (M" O!"7 ) "-, ;l.ff''(1.",1
o I.)' .. -.lrni ni..tr.tit.l uf s·r..nni mi ·
,J.~~ lhit'n;l."'~'in .1..t,~. l n 'l"Tot;,Ia,, ·
i nhi h it " u . .... llti"l k r oh . ." II:,' nt .
Cl.'mt ol l..'r.. Z1 ::!U l-,l U7 , 1""'1.)
212 CHAPltR 17

ad d and otlw r ad(l~ who'i(' n-nul d ear-lllct' is p H sensitive. Gi\ing ammonium <:illo nt l.> or
ascorbic add to make 11.(' urine mo re ad tlic tncn-ec....·l; til(" renal ck-aram x- Hf pll ' S('lISilh l '
I "l~ i<: drugs. SOllie drugs Increase tht· lIleta ho lic d t·:lr.IlIl'l' of otlwr 11m"'1\;. TIlt')' dn so most
l') IIII1l(ml~' hy ind ud llg tilt' dnl ~- Il l('l a"oli:d ng e nzynu-s. hut tilt')" lIIay also ad i\"alt' ('1lZ)11WS
or n -tanl ('nZ)ll ll' degrmbtinll. (k1.1L"i o lia lly . Iikt· glu(:agoll . tIll''' Incn-aw hl'l );llil' hloc)(llIow
and t1wreby iucrvaw the hepatic clearance or drugs thai ure highly ext rurted h~' lht' liver.
(( illl ,ti<: l'C IlIS('C llIl'IIn's of an iUert'iL'i{"(lml'taholit, <:!t';tr.uw(' WN t ' d isclls.... -d ill C haps. 11
am i 12. n i l' im pliedtiollS u f tlu-sc dmllges Oil dO~lgt' requirr-ments nnd Ihe- <...'ents that
follow Iht' itd d itiull or ui thdmwa l o f dm j{ l"a us i ll~ tht' alh 'n-<I d l'am lll't' an ' li llW p rl'!it.' n!l·d .
III !{I'nt>faJ. a dnS<Ij{I' n'lQllw n adjust ment is ""(luin"(l finly whe-n tilt' dl';ar.l1ll't ' of ti lt'
afTt'<-1:t",1 pa thway is o r bt'<-'tJlllt'S a siWlifk a nt Iructinn of to lal drug ch-arunce. T!I,. s. a 1It"t",1
to d liUl!-,:t' the doS(' is antid p;ltt",1 if tilt" <:!('anllll't.' ;l'lSO(1alt",1 with a particular pathway,
previ ously 2U% of lotal clea rance . were to iUert";lSt' sixfold . b("(,llls(' tot al d m j{ d t·i1r.lll('t.' is
then doubled. :-'< 0 (·hanp;t' ill tilt" doS(' is ;lIItidp<lh-<1, even if de.ar.uK"-· ;lssul.'ia!t",1\\i tl. tha t
patll\\-dY im 'ft",l\(",1 20-fuld . if this clea mno- contribu tes Hnly I lk to tota l d l'a r.ul('(-'. An
exception anws when tilt' Illt'taholi tt' fnn m",1is l'itllt"f th e adin' spt'('il's or is to \ k·. IM-<.';IUS('
its plaxmu coucentmucn can he p;n 'a tly illl·r\';lSt."'1.
T Il(' events dt'pit1('(1 ill Fi!-':. l i - 9 illustran- salie nt ('tIlISt"fl" I'III"l'S of an ilwn "l.S(",1ch-ar-
uuee . In th is illustntti on iI patient st;lh ili7.(",1 on Olll' dm~ (I)m p; A ) also n '('('in'S unot her
(D m p; H) that doubles Ihe d l'ar.1II11:' uf D rug A. If th e t!osinp; m it- of D m p; A is IIl1t d l;UlV;I't1.
Iln-u its l'tllll't' ntmtioll falls by nne- half at a mit' dl'l t'nnilll'tl l,:,' tilt' !Ialf-lifl' of tIlt, t1m !-,: ill
thf' lm~.wncf' of Vnlf.: B (Ca.S(' I) . T he fall in conceutrationcan 1)(, a\nitlt't l by t1l1uhlinp; th e
rate flf atl mi nistmtion of D nt~ A for ;l' IOll!-,: us ()nt ~ B is ¢\l' 1\ (C tSt' Il l. lI o\\'t'\ ,\'T, a
probh-m o f t'xl'('Ssi\"(' al'<.11l 11 11latioll of I)nt~ A l'xi ~ ls if till' h i!-,:hl 'r t1osin!-,: rate is maintained
when I) m p; B is witbd ruwu . BI'('lII.S(' tlu- !Ialf-lifl' o f D m~:\ is ~I' l ll'fiIl1y IOll!-(I'r when ~ \"" II
alum', l'Sj)('(ially for a <I m~ of Inw ext ml"lioll ratio. if fnllow~ that rln- tilll(" t"I''''11 tn n-ach
a platean is IHll~1'f ill tilt' ahsence th an p fl'M'lll't' of D m~ 8 .
Twn major assum ptions wen- llIiltlt' ill l·tlll.'lt ml1:i ll~ ti ll' vu rvvs in Fi ~. I j - 9 . nallll'l)' tltat
till' 1,0'1'(1 of Drug B is 'll·h il'\'(",1 Instantly and remains constant as l(l l\~ as it is ad lllinish'n'(I.
and th at ti ll' l'fT('(1: il1l1J't'tliately tli.sappt 'ars npoll its \\i thdfilwa l. In p ract ice, bolh ll'sump -
t ious Ml' ill\1llitl.

. ·IK. 11- 9. " 1" 'n ;< 1),tIM'nl «I"hili7t..1 '''' Un' lt A II
;aI,," n.. , ·iw. Unlit H. a elm): tlwl inc:n-..,,~ tiM'l·k~;<r·
lUll'" of Unl~ ,.. 1\0.,(01.1. tI... I,la'" ' .... K.·nlr;<IK''' " r
Dn,lt" f,.]l, (Ol'" II lln~ Ii... d hIRrAh' i . d. ",hJ...1
(Cit..• fl . " ,J.,r). n or p",I ,It-", . ,( Mf.....,i\,. .... ,m",l,.·
tinn ..ri _ if ...Imini<lr.ui"n ..f I>m lt A i. nul " . I'K....I
10 Ih. ' pn~i..tJ. ""t., "t...n 1",i",,,,,,I;..,, " f 1>"'1: II
i. ,,''1 '1....1. :-.;,,,.. 11...1 ti M' lin In n·....... I'Lt .·;tU i~ k ~,
In II.., pn'S<·.K..•. II"", in l!..•;<I ,K"'. ..r Uml: R. . ..,,,••:
II.., ti"..• lot':4l<· in h"tI , tI..· pn ·.. ·.K 't· .....1 oJ"" 'K" "f
n n' l( H i. ''''1'""".. 1in h.\lf·Ii\t "l> " f U m-.: .\.

0 1 23 4 0 2 3 4 5
Druo A + DruO B DrugAAlone

Dosing Time (hall-lives)

Rate ~ J, ; -- - - - - - ~~ r - - -- - - - - -1
01 o
Drug A Drug B
CHAPTE ~ 17 INTERACTING oacs

En z:,"llw induct ion \\~LS men ttoru-d as tll(' prime cause of increased metabolic d ear-
unre. lI o\\'I'\ t"r, u d liUl~(' in dl'arall(o'(' is an indin"<.1 measure of the effect o f an in-
d \l('('r; til(' din-ct ('fT("<.1 i s all Increase ill the synthesis mho' of the drug-llIt"tahoIi7jn~ en-
z:,°llle. A(:m n li n~ly, there is " ck-lay h('tWI'C1l the di rect e ffect and its refll"<.1 io n in the
IIlt'iL\lIrt'(l rt"Splm ~ ' , TIlliS, (,\'('n if tilt' pJ.L\ IllU concentru t jon o f tilt' Inducer \\'('n' at -
taillt'(l insta ntly ami the n maint ainer] constantly, th e clea rance of the afT("<.1 t'(! d rug
would illtTl',IW \\i tl! tiuu- ll.\ tilt' ('I17.)""l' 1(" ·t,1 riws from 011(' plah 'iUl \111Ut' to anot her.
Similarly_ tln-n - is a d elay in tilt' decrease in clearance of the afTe<.1('(! dru g on removtng
till' Iuducer. 1111' tum- (l P] a~' d('I)('I\(Is, likt, ot her sys te ms in the hotly, on thl' kiuet ics o f
the d rugs and tilt' ('IIz:,"111' tnvolvcd .
\\1lt'1l elimination of enz:,'ll1e is the slowest p n K"t'ss, then cha nges ill d('anllll'(' of till'
drug llIa~' contnuu- tn O('t11r (" ·('U tlIOU)!:!J the coucentra tm n of the inducer is rL'latin ,ly
ccustan t. \\111'11 , howt" O t'r, elimination o f tilt' induce r is slow , changes in tilt' roucentratiou
of Inducer art' t11('11 n 'I1I"11('(1almost instantaneo usly hy changes in tilt' amount of ('n7)"llt·
and h('nl'(' d ear.lll('(' of tilt' afTl"CtN I d rug. Thi s last possibihty may exp lain the effect o f
plu-noharhitul on the temporal chun ges ill till' plasma conce nt ration o f dicumarol and p ro-
th rombin time. a measun-o f its ,lTl t it,( );I~u la ll t efTe<.1 , in a patient re<."t'i\ill ~ dicumarol ch rou -
ieally (F ig. I'-JU). Both tIll' fall ill the concentration and efTe<.1 o f this tlnl g follO\\;n ~
plll'Iloharbital treatment liav(' hl"l'n att rihuh"ll to the barbiturate ind ud ng the t'n7)111l'S
n 'spo llsihl(' for d il'un mrnl llwtaholism. It takes app roxilllutely 3 to" weeks for the plasma
dicumaml bot h to fall to a mhumum du ring phe-nobarbi tal admmistratiou and to n-t urn to
the p rdlilrbitu rate value after phenobarbital is disco ntinued . Pln-noba rlntal (t l/ Z of .. days)
al.\o takes app mximatl'ly the same peri od of time to reach a plateau in the hod y and to he
d illlinah -cl. l1 UlS, the ohst' l"vations a n' 1,()lllpat ible \\ith the hypothesis that till' indlll"l"ll
('1I0 °IllI' spte m responds rdati\"t'ly rApidly to changes in plasma phenobarbital couce ut ra-
tion . Fur a furt llt'r dist:'ussioll of tlJ(' kinetic llSpt"l.1s of tnducttou , 'it'(' C hap. 2.1, Turnover
Concepts.

40 40
.,
u
~
0
30 ~
.2-
~
E
20 ;:
~
zs
E
10 e
~

Phenobarbital '5
~
c,
/ '-..
0
o 30 60 90 120 150 180 210
Days
Flit. 17- 10. ," " mini' tmti" " "f ph"'H~rhi'a1 (fi(l mil: daily) 10 it palil'lll n'O';' ;n ll: ,fk-,,,naml mnlfliodl~" ( ~ mK
,bi l~' )n..l"n .. Ih. , pl..., ma '''H'''''ntraliou " f tI... aUlk..,••!t" L.ul ( e ) "",I p",' lln>mhin ti ",.· (OJ, it " ......' u"" " f its
,·ff...1 '01 ' tiM' " MK..'utralil", "r tI..· "Hamill ":r<I."''1MI.-", dot tin( (...1"1'1) ( I illWI-• • .3 0 11 M ). ( tt. .J r....n (ru m
O ..il M'11. s ,....n .m..')", ." 11 , S",u, ,,r. \1 S , all" 8u m•• IJ.: la,'",rinlt '·ff....1 <If 1" J<" IH,harh it..l ,'" pt...",,,, Irwl. <If
,Ii<.." "",ml "" Oll t1iph.'n~n,~,L."t..in, eli" , Phan naml. n... r., IH 2I1--429, 19l15.)
214

111l" data ill fi~. 17- 10 sUAAt'sl that prothrombin tunc Illay 1"-· maint ained at lilt" p rt··
ba rbit urate value by rdisillF; the dose o f d icu mam l duriuF; ph enoharhital aduuuistration. All
increase-d risk arises , however. if th e dose of ant iC'tKtj..".Ilant is not reduo-d when phcnobar-
hilal is dlscontmued. 111l" plasma dicumarol conceutration 11\('11 rises insidiously. ;L' phe-
nob ar bital is slowl)' elim inated, and may ~o unnoticed for seve ral weeks aftN di st'o lltilluin,i1;
l lit· barbiturate until. perhaps. a hemorrhagic crisis occurs.

STUDY PROBLEMS

(Answers 10 Study Proble ms ore in Appe ndix 11.)

I. Bnefly comme nt 0 11 the aC(:uroll,' of the follO\\i ng statements.

a. Drug Interactions a rc o fte n de tec t ed when an interal1ing dmg is Inlnan-d or with-
drawn.
h. Displacement of ()m~ A by D m~ B occurs when llit, mola r concent ranou of Drug
H approaches th at of the protein that hind!' Dmg A.
C, Displacement tnteracttons are g('lwmlly not tllt'rrJl'nJtlc dnl f!, j,.t,'rtletiOlU.
d. of the various rncchamsms of drug intcructkm, luhlbttiou of metabolism ill of pri-
miU)' therapeutic important't' .
e. Dm g interactions art' ~(' nemll)" WlI<!t"(l.
2. The grap hs below show tilt' conce ntration- tune rurvt-s follU\\i ll)!; tilt' lIlt'thod of ad-
ministratio n gh't' u . S!wt(·h the expected plasma concentratio n-time profil(' (If ('ad. dntg
(low clearance. brgp volume uf distriburion ) if ad minish' J'("(! again du ring tht, coad-
ministration of anot he r dnl)!; tllat is at slt'ady sta te. 111t' pa rau J('!l'r gin'll is uln-n-d
twofold, Each gra ph sll1mld d('arl)"Indicate tilt' con.S("f jlwlll't' of a d langl' in C/., \'. and
' 112 (o r il l"f)mhination ).
a, jil ill(.'I'l'iLS("'(I. cons tan t-rate i.v. infusion

~
0
4
~
c~
u 3
~-
8a,
oE
2 - 2
0
~
E
~

f£ 1

0
0 6 12 18 24
Hours
J"IJt. 17- Jl .
( HAPTff/ 17 2IS

40

o +--~---,-----,---,
o 12 24 36 48
Hours

3. Chlo nli.v~ 'PI\itlt ·. a Ill'Il/AltliillAl)int>, W <L\ a<llll i ll i~lt>n·d 10 ~i\ I...alt l l~' \ul ll ll h't' ~ (-1.3
1Il~. l .v, ho lu\ ) ill l·rn\\O\ "(·r fil..'ihio ll alone or 0 11 th~· fifth day of a tLily -IfIO"ITI~ ~ In\(' of
!wtUlUlI 'W III·, an allliflln~al agent . For tl R' pu.-post· of th is probk-ru. tilt" d nl~ ha.\ one-
e unp arnneut 1Il()lld charact eri stics . ~I l'an \'1iIIlt"S of C(o ) and t II! for dllonliil.7A'Jlfnjtlt.
an' ..1.11\\11 ill Tahlc' 17-1.
r..... 17.....

20 20
230 43 '
~ ""'""""' '"a...,..,. ..... W I/dr:l<TOOo A I
cwo _ .. n... J7'l9O-191 t Q ~ ~

a. I . Prr-pan- 01 .. t' lIliloKaritlllllil' plot o f lIlt" mean (1I1ll'1 'lltmtio ll-lilllt' p mfill'" of (·!.Iur-
tli;VA'IXI\idt, in till" pn 'S!'lll'1 ' and absence o f keroconazole. 1.111)('1 hott. llW" and
itlt'ltli ~\' !loth l·..rn·...
2. COll1plt·tt, tlu- fflll( l\\i ll~ !;11l1" .
\ \'itllI1111 Kctoconazoh- \\'ill. Ketoc onaz oh-
\ '( I.)
C I . (l A Ir)
h. (;i\ 'I·1I tlMt ('hlonlia7A'!xnitlt- is eilmiuated by luotrau..fu rruatiou in tin: hvr-r, what
p"rsilll f)~;l· nu-chan i..m (s) (Qu, f". f " T' Cl...... ) is reslxlII..i bl~' for tilt" inlt·r.K1illll of
l l·tO(1millt ,II' \\i ll. dllnnliillA.lxldde ? J lIsti f~' a ll)' aasum prious thai ) UII 1II;I" t ".
-I, 111t" data ill Tablt , 17-5 silo\\" tt.(· time COUnt· of the concenrnmon of I ht>( lflh~11i1li'
t1 l1 lin~ treatment with all oral 30U-IllF: sustamed-n -k-asc dosa~~· fonn ('\1' ''' 12 hr. O n
days fi alll i 7. IIM'dldilll' , "II llral l~' ~·lT("l.1i\1" anti.lml)1hmic a~t"llt. is l''Omllllinislt"n "'l1
{ 2ntl lll~ ('\1'''' IS hr \I arti n~ a t tilt' tim e of hlcJOlI \;llll pl i n~ 011 day 6 ). 11K-' oral ahsorpti llll
of Iht'l'PI I~1 Iillt' is \i rt ually complet e (F = I ) ami G" IC is appnnimah,I,· I. IllSuffid t-nt
information WOi-'i provided to conclude whether or not IlK"u lcti llt" aIn-red 11K" half-lift'
~If thl'liphyllilll'.
2. . INTUACnNG DRUGS CHA,PTH 17

1t n.-p1t.,tII_ e.-_......_
, ..... 17-5. M __ r
tIM M_I........ 112 hr ...... '00••, ..._1. . De_.·•.• PI. . . . h ...IetI ......

"'''''
ItfA,T/VtNT 2 3 4 5 0' 7' 8 Q 10
Concentration
lmg/U 0 00 7.0 07 7.0 02 117 125 80 55
o~ fooor,~. '" v",* J l floooo<o<o. G W , s...-.M I . ...,q....t M <li"'d"""""".A ,.,......... oo/IooctI""'~o.~
0. """-'oed n. . 5O?Q9-Xll, 1001
'Mo...... «><>:J-,,-.d It> 3 cb. 1200 "'9 -v 8 lwl

a. Give an explanation for till' (·ff('(.1 of mcxtletme (Ill t1ll'u p hyllilw kinetics . The explu-
nati on should hc.' I"l-O;(,(! Oil a d mllJ.:(Oin only 0111' of till' rol1 o\\i ll ~ pa mlllt"lt' rs : j ll . f ll T'
Cl"h" Q". Give.' til(' paramete r mvokr-d a nd im lilwdh" ti ll' din"(.'tiull of its dmll ~c.
h. Brit·fly di sc uss Iht" explanation in (lut~ti nll "a" aiM)\"(' ill terms of 111\(' physioln¢ c.·
mechanism (e.g .. (·1I7.)11W ind uction , com potuiou for ad i\'t' reabsorp tion in ren al
tuh ull', lnluhit ion of biliary tou 'n -lion ) that couk] pr oduce- the interacnon.
5, Dr ug A is ¢\'('ll by infusio n ot a rute o f 2'5 mWllf to mainta in a con stant pkeuia con-
centrarion. The da ta in Tahk- 17--6 a n ' o hlailU'11 ill a sllhjt'l1 who is infuSl'11at t his rail'
ill tlu- ah st'lIl't' alit! p n S('lll't' of D m~ B (il...~ U lI1 l· tha t it is it! sh·atl~· sta te when pn·st·"I).
O

,.ltle 17-e.
DATAJO OOJGA
PI./Irt:AU PlASM'
CONCENTtATK:lN
'" reoo e """'" ""'""
CONCE N!R.A OON
~1:«:if TK:lN
lATIA' STt.IDY
Sl Art:~1
fRACTI()N
~
..,
HALF tJ!

""" 0
20,0
"""
100
07
15
,
N ""'""
01
03
12
8

G in ' u t his illfonlliltioll am] tilt' ob serva tlonthat tilt' ('f(' a tinillt' e!t·.mUl('(· inlhis SUhjl"(1
is 120 m llmiu .
a. Dt.'h 'n nill(' if thr-re is t,\idt·!lt't· fo r DnI ~ A I It' i ll ~ st"(·N.'lt'1l a nd/ ur n'a hsu rllt'1l in tilt'
kid nt"')"S.
b. Det ermine till' IIlt"(·I.a nism (s) by which DnI ~ B interact s wit ]; DnI ~ A.
c. Discu ss the therapeutic implicat ions of l'o'l( l lIli n isft'ri n~ DnI~ A wi th D rug B.
6. Table 17- 7 contains pharmacokmctic \ 11I m 's fUf lU I im li\idu;u subjt'l1 l hlll t~]li fy what
is known about til(' inteructiou between Ijuin idint ' a nd d i ~u'(i n ,

,.ltl. 17.7.

0 75 " 0 101 500 077

075 72 51 '40 079
~"" C... <J ~ ,. 1-3~

a. Brielly comment o n how q uin idilw alTl'(:ts til(' d istri hutio ll of d iv;o1iin.
h. Using th e a pp ropriate d i ~o'(i n par,lIlll·tN \'alut's in Ta bl t' 17- 7, calculate tlu- prob-
able "lo adtug" dose of digoxin nl,,('1lt'(l when tlwrapy with t his dm ~ is ini tiate-d in a
palit'lll who is lImlt'rgoin g auttarrhyth mie tll('rapy with quuudiue-. TIlt' Iht'rape uti{'
l1l1ll't'ntr.lHoll r.tll ~l'. 1 to 2 IJWl.. n-uuuns tilt' same for <IiKu\ in .
c. J..:nu..ving that tilt' Imlf.li\'t'S o f digo\ in a m i fjllini tl im' an' ahou t 2: days a nd S h r.
n ·spt'l.1i\'l' ly. h rit·f1y di scu ss (i n te-rms tlf tilt' di~u1iill l1lIll'l'lltral ion) II\(' Ilwrapt·lltit·
CHAPTH 17
'"
umS ('tlllt'llt"t' of ad ministe ring quinidine 10 a pat it'1I1 \\'110 is rt't"t'i\illg di ~(Jxi n tln-r-
ap~· . 111is is Iht· more rtmunon situation ill \\'hk-h Ihe interaction is observed. US(·
tlu- t1i!-:(Jxill pa ranWlt"r values in Table Ii-i and consider tilt" events upon lxuh
initialin J!; and d is(,olliintling quiutdine coad mt ntstratlon.
d. Do ~ Ull thi nk lluiuidill(' would affect the dosage requirements for digoxin in a pat teut
\\111. ~'n'n' renal [unet ion impaim lt"nt? Briefly di scuss.
, . Bt' ~S lrull l 11 £II. slu dit'tl till' pharmacokmeuc interaction of the antidepressants 1I11ox-
dim' and dt ·sipraTllillt·. Fig-lin' l i -1 3 ami Tahlt, l i --8 sunuua n ....t> tilt' ollSt'rva tions fol-
liMing a singlt· ural doSt, of desipramine (50 lIlj?;l alone am l3 h r aftt"r the eighth tWily
dns(' o f IIl1o\t'tiTw (fiU 1lI~ t·at·h ). TIlt' ccucentrution of f111o.\t,tilw durillg tilt' tim e des-
ipnunnu- is lillalltifi('t! remains rdatiw ly constant (half-lift· o f lluoxet inc = 3 to 4 days
Ie
afler m ultiple doses). 111t" value of for deslpramtnc is about 0.0.1 .

100 1'-11/:. 17- 13 . M,."',I't...."'..o:tllu ·".

l ration of (It-sipralllilH' ..fto-r ;l St l- m~
"ral d,,'\(· ¢"'fl aIe,,", (I>lade.) ","I ;1f_
t ..... Ii .L.ily .1t1'M (fin mlit ,-••eh) ,,(
H"'no"i,"' (o:t ,lt'r) . ( ~ ,,"hn..,j fnlln
Bt·l'K'frum. Itt'" 1'.')1u" .... .I ~ . aud
1..-", lw·'1l'·r. L : Q"••nlifX.at iun aile!
nlt'( .....ni.m " f tI"" Ihll"""I,,,' and lri -
(')~1it· an titlc-pn'\w, t i"lt- r...1">I"
e ll". " h.an n..."". 11...1 . 51:2.19--2-11>.
1!J!J:2,)

o 2 4 6
Days

T."'. 17"'~ Ph.......c.kl_tlcs.f D••lpra.l_ 'MM. AtiI.I.I.tareti O_11y I••

Iln,l. 50..., D._ AI••• and ....., II,ht Dally Da_. " " _ • • H_-

28.1 :!: 2.1.1 2110:l:Q()()

9 ,4 :!: 54 23,9:!: 56
53 :!: 16 68:l: 1 I
16 1 :!: 52 63 .8 :!: 19 3
289 :t 168 27. 1 :l: 103
77 1 :!: 398 19 7 ... 77

a. ( ;i\"t'll that tlu- hltIl Il.Vpl'l'>ma coucent ratum ratiu of <J('sipTiltllitll' is close 10 l.O,l hat
til(' dm ~ i... uu-taboli ....t't l llllly ill tlu- Her-r, and that tilt' "well-stirred" model of ht'jl<ltie
r-liminunon applies. calculate tilt' value of e Li"l '111 in I!I£' pff"St'Il(,(" and absence nf
1I1IuWtilll·.
h. Suggesl (JI lt' nu-chamsru (comhinarion o f mec hanisms is nol acceptable) for the
phannacoktnottc interact ion observed. Document how ~1l11 arrived at ~l l1l r conclu-
simi.
 CHAP1H 17
'"
c. Brit,fly explain wll)' tIll" factor hy whit-Ii half-lift' is a ltt'rt,<1 is 1101 till' sa ult' as that of
C I1 ,...
d. \ \ l lal implicatious do tlu- nhst'lvatiollS nf tlwS(' authors han ' for til(' o uwur rvut
adminixtrunou o f tlit'st" two <lntidt'pn'ssanls? Briefly lIist'llSS.
S. Normal \1l1u('s for till' pharmacokiuetic pa mll wll·r.;: cleanuwe, frad ion unbound, ami
fmet ioll t'.'K'Tl·tl"( l llII(:hall~('( 1 arc llsn-d in Talllt· 1.- 9 for D m ~s :\ t lmlllJ.:11 <:. Silililliolls
art' pre sented Ihat alte-r tilt' kinetics of ('.1<'11 lIf tllt'St, d mg:s. 0 11 tilt' ri~h l ind it -dft·
whe-ther the value of (·ad. par,HIlt-h' T Iom uM hI.' (l!lst ·f\l..:1 In iuen-a..... (f l, dt ·c.'R o'lS(· (.1.).
OT .show litt ll' (IT no change (+-+). All drugs an- ndmtutste-n-d m all)' a m i han' \·,,11IIlIt'S
of d ishi hutio ll gn'alN than SO L.
9 . Tollmtumidr-, an nral h~p: ~l~'l't' III i<: a~('IIt, !las Iht· fo \lo....i nj.!; pharmat'okilldi(: paramo
et crs ill a '()-k~ adult: F = 1.0. \ ' = 9 1.. Ct. = 1.1 IA.r. fl · = (U n . Elnumation is
uhnost exclusivelv ..ia ondutiou to lwdroxctolbutamtde.
a. Calculate rln- ;l\"t'ra~t' plateau {'o;J('t'III ~ltinn a nd l illlt' to reach il when tu lhn lalll idt'
is ad m inisle fed in a f{' Wnw lI of n.5 ~ o ra lly I\\i('t· dail y.
St"'"t' ml dm~s in hihil till' un-tabolism of tolbnnunidc and {"<li N ' cxcessivv accumulation
and h}l)(JgI}~'t' Uli<: crises uuk-ss l ilt' main!t'niUl('t· tl(J~' of tnlhuliunid(' is rt'1II1('t'11.
b. C lveu the foIlO\\i ll ~ info r mal ion about a ('OlIIlx,til iw inhilutur: F = 1.0, \ ' = 13 l ..
C l. = 0.6 IAIf,fi l = n.o.), 1\., = 0.611I""1., calculate till' fo llo..\il1 ~:
I. TIlt' (·' I)('(:h't l llt...v an-m~(' p lillt·;U\ plasma coucentranon of tolbutamide after tln-
add ilio ll of a dosaV;t' n -ginlt'll of 1.0 ~ "'..i n ' da ily of Ill<" inhibit or 10 a panent
prt...; onsly stahilized on tolhutamidr- The n WlIIl'1I of tulhlllallli d t, is contimn-d
ullt·hanj.!;t'1l.
2. 111(' l illl(' taken In n-ach th is m -w plate-au.
3 . A p md it"i.1 nW1l1l'1I of tolbutamuk- thut mainta ins a simi lar aW·faj.!;t' prt' inllihilor
plateau couce-nt runou , when t'olltllllinish·rt'1) in tilt' pn ·M'll( 't· of tilt' inhilntor.
T nlh ulamidt , is available :tS a soo n -d 500olllj.!; tablet.
CHAPTER 17

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 CO NCE NTRAT IO N MONIT OR I NG

OBJECTIYES
The leader will be able 10:
1 lis. the oeeoc lor detet"mining when monilOring01 plo~drug concenlroliOl'ls and applying
large! coocennouco S!fOlegy ole oppropriOIe
2 Describe how popJIo1ion informolion con be osed 10 oblain inirial estmlOlM of on indivi-
dual's phofll'locobneliO
3 hrlmote the likely pOOfmocokonehc porcrreer values ,non individual patient, based on both
popukJllon and porienl choroctefislics. for di9O"in. gentamicin, phenoborbirol, and rt-,e.
ophyll'ne
4 Calculate the pkwno drug concentrotionlsl expected or the lime(sl of sampling. USing 8$1,·
malad pharmocol.inetic porometer vol~ and ~ing hiSlCWy of the P'Jlienl
5 Upon e'It'CI1U01ion of 0 phannocolinelic problem observed during chrook drug lhero~,
ascribe the problem 10 a change in bi<:xNoilobil,ry, conolcrce. clearance. volume 01 de-
tributIon, or a combinoliorl 01 these coloes
6 Revise pharmocokinelie poramelefS hom rrecsured plasma ccoceoecnce dolO acquired
under either ~Ie Of ~IotecoodiliOm.
7 Use the revised pClrOmeleiS!in objective 61locolculole any rroddcoucom ~ required
10 ensure rho. the plasma ccocenncnco lies within the lherOpeutlC w,ndow.

DOl~' art' ,Itlm illi, lt-ft't l lo uchn-ve a th t'rapt'u tit' nhj ('t.1hl '. Onl" th i ~ o!Jjc'l1i\·I' is dl'fifl('ll,
a dnl ~ illlt! ih dOSiI~C' ft~lllt'll an- d,u '>!'n fur ti ll" pat it'n t (C hap . 13 ), D m ~ Ilu-rupy is
slIh'>!''l Ut'ntl y lIIilll;l~t 'l ! .lS Sl.O\\11 sd lt' nliltkllll)' in Fi ~, I ~ I h ~c,t ll('r with shops requt n-d
tn inifiilh' tlll'mpy, Th is 1lI 'lIIa~C'lll('nl is lIS,mll)' ael,(lm plishe'l! by lIIelll i to rill ~ ind dt' ul" am i
inlt'll sily of IMIIl. tll('rapc'lll ic and luxic d Tc'l'ls . EXillllplc's of this lIw lh od of illdi\idu al i 7jll~
IIlt'r ap y an- WWIl in Tahlt' IS- I.
A1t llllU ~h pn-ferahl c, it is nut alwa)'s po ssihk' to II'>!' " d ill-"t.1 me-asure u f the des tn-d
t'lTc'l1 ilS a tllt'rapt'utic c·mlpoilli. Snllwlin it's . si~lI s of to'dd t)' iln' usc''l l .ls a dosil l~ gurde .
"nit' d nsc" of Siu il~talt"S, for example, when 1Isc''l1 in til(' trea nueut o f rhe lllllat i<.' (Iist"<l\l's. is
u flt' n inl·f(,.t\('l l Illltil tin nitus o r nall.\I'a an d \l llll i t i n~ iutcrwne. III 1Il1J(lt·rah ·-to- SC,...·('fc·
.Lstl ullatie ease-s, tht'llp hyllim ' IIMI is fn 'lluc'll tly tttran-d to a 1m,it.' e-ndpoint , Ew t"Ssivt" d r)ll('s~
of tin' mOIlII, is a l1111 ,mOIl mC" l~U rt' o f tilt' llppc'r dosa~t, of at ropine- when 1Isc''l1 'lS a
~ pa~ mell~ t i (' a~{' n t .
1111' tllt'ra pe:uti{' ('lTt'('h o f Sillil, h h's, t1u'llp hyllim', ami arropiuc, ulthough uflt 'n sllhjl"t."
tivt - allt l \' <tW It ' , (".m he: ,lsse: S\l11 a1lt1 11l'1Il1' 1Isc''l1 in jlll l~ ll ~ the Slll'{1'SS of IIu-mpy. This is
1101 SCI fC 'illlily ;l(,{111Ilp lisllt'll fo r 'lIllit'p ilep tk d nl ~s: the tl ll' rape: ut k c'lTc'l1 lu-n - is tilt' 1l01l -
fJ('{'urn 'IIt" flf wtzu n -s. Se izun 's lIlay 1)(' infn 'lltl{'lIt, am ] il" a res ul t, tlt,lays am i d iflk ·u ltit·s

290
CHAPTH 18 CONC ENIR,ATICN MQNlTOf/NG 29 .

Examine Patient,
Collect Data, and
Make Diagnosis

DefineTherapeutic
Objective

Choose Drug and

DosageRegimen
-.- - ---1

•
Evaluate
How Well Objective
Has Been
Achieved

~
Stop Therapy "
ContinueTherapy
. '11:' 1"-1. C;'·Il<·r.J ...·11<"111<" f" r iuih;di" n ..ml n n..):t·nK·nl " f . lnll: IIK·r..!,:,,·. 11..• " ....jllr t ..., 1... ;mo ,Io·fini"!: tI..•
tl,..rdl,,·uti<' ,,1oj<"1i\ ,",d ot."i".: 11K' .In'll: IlllO l ih 11, 10:<· n-¢lI l<'n. •1l"1.,,.,.]'....lin1/: I,,,.,, "..tl lll<" "t'j<'<.1iW I...., I......n
"d ,i,,,...I. \ 1"" it"";"1/: n"'I....n,· i.h i" , ..,tll!'h. t.in1/: II..· L.., t 1\\.. l"-' It. . \ 1,. ,il"";"1: 1'La." ,,,, ,lnll: n"... ·nlr. tit'"
III••· ..I.. , I..· II<"II,f,,1. ."I....iaI':-·if n I ' (11......"(""'1;,;, &1..1t.>1;,;,) ,.. ot ".·Il'I'l.lII'tifil..1. llot otlo1<i,..1. "r' ''.,.]'lIIlio'',
;on' ...' . "" I.li'I....t tl,n K'Io:I , f,....II_-Io. ( 'n ..1 lin(...>' 11,,· f...... II_ ·k , u, K...Jly .....I"i...........It·finil;,..' IIf th.· ' ... -r-
"1"·,,Ii<· "I>j<'<.1'U' • • ",·n
 CQl\K:ENTiATION NC.lNlTOI/ING CHAPTI R IB

exist in a\S('Ssi n~ therapeutn- success. Toxic eIT("(.'ls lhal ('iUl II(' rt,,(tlily meusu n -d, t' .~. ,
nystil~mus and ataxia. han ' tln-n-fore h("('11 used to :L\sisl in d t'l t'nnill in~ 11ll' lIppN limit of
an epilt'plk pati eu f s dosa~e requi n-nu-ut . :\ similar sltuauon urtscs ill till' uS(' of orul ilU-
tk oa).,YlJlallts ; the thc rapeuuc uhjt"l1ivl' is l ilt' pn-ve-nnon o f thmmlHH'ml HJlk' complications.
A~ain , tilt" therapeutic ohjt"l1i\·t' cannot n 'mlil)'I)(' ll-\s(' SS('( 1. :lIltl then-fon- an alternative,
simph-, und rap id labo ratory h'st, p rothrombin lillI(', wh id l II\t'il\ lIrt'SIhe h' nd t'lll'y of blood
10 d ot, is substu utr-d a." th e 111('r.tpt'lIti l' ohjt"l'lin" l J kewi se, for antihypt' n'hnlt'sle m lt'mk',
h}"po~I}"I'(' lll ic, and uri cosuric i\~e llt s , d inie.ll lalHJralory tests an ' t' mployt"{l altematiw,t"
tl u-rapcotic eudpoiuts. Ck-arly. tn IH' IIst'ful, alte-rnative h 'sts mu st 1)(, ~r.1( 1("t1 amI d ll~t:ly
related to Iht' true the r apeuti c e ffect.
TI ll' seriousness of tilt' first !uxil'dTt'd o l)S(,,,,t"tl is a majo r dcn-mnnaut nf \\,I\('tll('( il
ca n o r cauuot 1)(> usee] a." un e-ndpoint . TIl(' titrafkm o f ~uu n~ ad ults wi t ]; rlwlIlIl<lloid
arth ritis am i 011 salk)'latt' therapy to tilt' rxv nrn-uce of tinnitus is rt'lati \'('I~' Sil ft" as tinnitu s
is an t'IL"il\' measu red mild toxicitv. I!owt'\ '('r, t tnuttus dot's uot alwan occur befon- tilt,
mbent o( mon' se rious toxicity. particularly in )nllll~ chihln-n and paiit'nls with unpa in-d
I l('ari ll~ , T itmtiu R dOSiI~t· of di~oxi n and rf'1ah't l ~1),('t)s itit'S 10 ('iltd iae loxidl)' is alwa)'s
IlIlSilft"

T.ltl. 18-1 . " ••pl•• ., M...........

_It,........ I•• T....
Drv. TIt.,.", It, tIM lHech .....tI.cM
oe.sE'iV"1lON
oe.sE'iV"IO'l 5l.GG(SING~
SoUGGf SII\IG 1'£'f 1<SlO at CfC lI'fASI'G
CC«JlTON !'JOS,l.GI' ccsoe Sh 1 l1'f IOXlC SIGNS
Group I Drugs !'Aonito,ed by Cbmcol Signs and Sym plOm~
Sol"""" Rheumatoid omlf;li~ 01 InodeqUoliJ lEId...::tion TrnrlllU~ . "(MOO.
rheumatiC lever cJ jnf\ommofiOn "O!Tl,I,"9
cod pain
Edema c cccced E><eeUive eOOrno Fluid cod electrcf.;1e s..-.
w,rh ~~
CO,diOC foilvre.
(.irthos.i~.
d.secse
reoo! .
«ebcc-ce
cssocosed w,rn
,~

dehyd,ot>Qll
InodeqUOI8 eIeYolion Dry mouth, blurred
hypoIen~ion,
eo-d-oc
dSlu'borces

Coece 1O_;C'ty,
D.p".."""
01 mood ...;~ , decrecsed

-"""
OI!hoslohC
efIecl,~
Corbidopo/
Io.odopo
!nodeqUOIlt conJrOI 01
d;~
[),.4ine~~ .
bIepho'O$pO!>Il'l
--.
InvoIu"lOry

_~I
changes, ced
depre»ion
RespllolOry fo,llI"e

Secee depreUian
01 'enol ,,"octiOn
Hype<lhyroid,un

f>rovmlo'"" ~ymplOmOlt C N\o, ~ed pe<~ i~ l

ekNollO/l 01 use '"
eoosomeoses and trO"$Omioo loli!S ,
m,opo.~
crecnoe
~inole
Decrecsed se+'VIT1 Go!>/TOOl'lleSl'rool
~'K: oc:id ''',lOlIon
CHAPTEi! 16 ,.,
~ l oTl i torill,g of t111'r,lpl'utk- respon.'>(·s and toxicity is best accomplished when mteg rated
with kinl'ti l: l1llll'(')ltS. Iialf-lifl' de-te-ruuue-s the tune course of accumulation endhence the
development of f('sp<lllses, It is also a detc ruunant o f th e tim e for a toxic ft'spo use 10 resolve .
Tinn- is al...o il facto r in till' development of f('Sp<lllM' 10 mall}' dr ugs. even when the pla..ma
couce-utratiou i.. <'tJllstant, For example, tln- ~ponse to warfarin (C hap, 5, p . 6.1--6-1 ) is
dt'la y,'(1 he(:allst· of tht, tinw rcqutred for till' d ottin g fact ors to decline to values that
pmdul,(' an ad('(lliah' alltl stahh- dtogn'(' of antkoaglilation. Tllilorin,gdosag:I' to an ind i\i -
dual's 11l'(11s d early requi res Intcg ranon of kinetic principles,
Anothe r ap pr oach more ('xplidtl)' ineorpomlillg kindic prt nctpl es is the W' t · of pla"Ui'1
coucentranous. SlId l measurements st'l'\l ' a.. an intermedia h - 10 di slillglli...11 plmnll al1lki-
m-nc an d pharlll a<.1xl~lI'll 11 ie dom ains,
AI a minimum . lilt' pla...ma concentrauon ce n S/.'I'\.(' a.. an add itional plece of infn n nati on
10 !-.'u ide am i a..S/.·...s dmg the rapy. TIll' applicat ion o f the plasm a concentratlou meas u re-
nwnts 10 thl'm py iUHlln 'S ta"',!,11COIICl'll t rn tltm st rn tt'f!.!J. ,11e ha.s ic Idea is 10 apply a s l mh~'
10 ,whit'vI' aml uuuntni n a l a ~l·t concent r ation ti l' a targel r.lII ~l· of couccm ranons for an
im li\idl lal patir-ut.

TARGET CONCENTRATION STRAHGY

T his slr.lh ·K" is usefu l ,t.. an atljlllll1 ill i n i ti ati n~ and 1I1 1111it {J ri ll~ dOl ~ therapy wln-n a
numla-r of criteria hsted hdow an ' s atisfied . So me o f Ihe cri teria aft' absolute in nat u re,
others an' rd atiH·. ~f ost of tlu-m. howl...v r, mu st II(' nu-t fur tilt' slmlegv 10 II(' R1ul irlt'ly
1'1T11.1in '.
TI lt' ph .. ma coucentr attou of a d m~ must co rn-la te Cjllanlital i"l'Iy with hot h tilt' Intensity
an d pmhahilily o f t1lt'I'iIPI'1l1ic o r toxic t·ffl1.'Is. A direct re lation ship be tween cou ce nt ratk m
and 1'1T11.'1 may II(' illSuffidt'n l grounds for plasma conccutranou mo nito ring if tilt' tlw ra-
l'li'lltk l·ffl1.'1 ilS/.'lf is t" t~i ly monitored. whic h is fft'<lllt' nily lh t· C"J.se. The strategy hl1(1)111('S
pa rtil'lllarly allm{'!in ' wlit' li a thempcutic endpoint is diffil'uh 10 tilianlify. as \\; 111 till' lion-
Ol'(.'um·lIl'(· of (·pilepli<.' seiz ures. 111l' st mtl~' is mo st pertinent when th e ohjl1.'1 i\"t· is In
maintain a thera peutic t'ffl1.'1 hy mai nlaining a co ncentrano n with in a llmtn-d runge (C hap,
5 ) and wln-n the lil.t'!iholl(l of toxicity ca n II(' predict ed from tilt' coucenrmnon.
Ta~1'l l111l11'nlralion sl ml l'~' is also imlicated when then- is a hi,gh pOlhabilily of en-
<'111111!t' ring a therapeutic Iailu n-, i.e. either a lack of eff('('! o r an occurrence of undue
tm idly, A tlu-rupe -utic failu re is mos t lil.d y 10 arise if till' d m g has a low Ihe rJ.pelllil· index
am! a ~ft'a t va riahilil)' in its pharmacokinetics ur if till' patient is at p articular risk because
o f gl'Ilt'Ii<.' fact ors (Chap. 1·1), concurren t di S/."tSl' (C hap . 16 ), o r multiple d rug the rapy
(C hap . 1'7 ). A h ighl'r fn "-IIll'lIl'y of t1lt'mlx'1l1ic Iailures is also enti cipan-d wllt'll I'illl('r 1l011-
<'1 11nplianl.1· o r t'ffi lli<.' ilbstlrp lioll is likd y,
Ex:amp lt·s u f d m ~~ for whieh I ll ~l·t (1)lJl'(.·ntmtion stm tt1{\-' ha.s lx'(·n fount! to Ix' app m-
p riale, logetller \\i llt ~ell(' r.J information pt.· rtinellt to the ir 1Il0n itonll~, are listt'll in T ab le
f f)...2.
Fur S(lllli' t1 m~s tilt' s l r.lll~· is applil1.! o nly wh('n 1I pmhlt' lli ariS/.'S. 111t' pmhlt' lll may
hI' a b ll o f n 'slx llIS(' at lI...ual or t...·I·1\ hi ~"er dOSlI~I'S ll" a n 'slllt o f one o r lIlo rl' of Ihe
follo\\illg (1)lJd ilions: nOlll 1Imp lialll1' . pll(lr hioa\"J.ilahil il)·. unusnally ntp itl eliminalinll. or a
pharm a{1 )( 1~1 1 a lll i l' f(·si...tallt1· to tilt' dnlg, ~ 1t·ll..un· nlt'1I1 of Ihe plas ma (1)IJl'('nlrdlioll pt.· r·
mit s t1islin<.1ioll 10 1)(· matlt· among: till.' ClIIIS/.'S of tilt' prohlem . Similarly, till' (-olIlM" o f a
to\ k or 11IIus tlai respo lIS/.· al l'uslom,u) ' or lower dnsa~es may he a.<;<:crtai u(11,
Elli dl'lll liSt· of lilt' s l rah~' "'ljui rt·s p rio r k nowl et.l~l' of lilt' phann,K1Jkillt'lk' pa ra llll·tefS
of tilt' t1m~, 1111' l1lnd itiollS in which tht·S/.· parollllt'lt·fS and tilt' target (1)fl('('nf m tinllS an '
likt'ly 10 1)(· ahert·d . and if alt('ft11. tilt' ('xtt'nl of 11ll' ehanges , 111l" last h \,(l n '(lui ft'lIIl'nls
. .4 CONC f NTiA TlON MONTOfING CHAPlH 18

,.1.1. 18-2 Info Pllla,l.ft Pa rtlne ..' t. th o PI. a",o Co n ca ntra t lo n Monitoring
.f S.I.ct." Dru,.
-< i.,·,
•A'1< '" ;>.A'''';.'~
". "
"'-, ., " " , ' 1--"
''''''..I', , .' -.« 'Af> " .,.....
~ '.';" ,.""
C",c\o~p(r,~e Autoimmune E" eoS1Ye" Phenoborbitol. Sc-.e ,.,.,YIW ',, ~ RenoIlO>:oclly i~
d~_ bccod 'Q "fompin. ""J.'·W' . " fJIOto' ceeeeo-
I 'DOP'c!f>J"'~ erytfwCll"-,<:1n,
ood hboO ,~

(~Ih
[),'l0"~ RenoId,~. D;.",relia Di~,woon

:r'" cc Ioilue,
rhyTooddl~
,horoclet'lta

(;e.~ 'Q ""( I" Renoldl~ Some penlCiUiru Cenpesed 01

Ihree ;loOfl'IeI'~
N.:yt" p",<' ne E · '"",,~,v"fy Qy,rnd,l'le. lOH;d'o ·.'~o' PoIymo<plllc
AIooho/c """"" ooo-d !O I\uo.<el,ne. . ,,,.,
d" ecee
.. I <Joel
g lyc: OPI OI" '"
oo_~
~"

......""""""
P,~n'{'U<" Renal diseose. E · l<...",.~I ... Volplooc ccd SoMa"'"

-
dvoniC hepatic ~od ' corh:Jrnozepine meeobol;)Ifl
deeese ot>u"','1 omefidine
TI>eop'l,lhne I'rleumonoo, chlOl'lo( ~JfJ le f, Eroxocin. A\OO.lobIe on
~od~
o bu ~l~
ery,tllomycill.
phenoborbilOl ~"'
and ~forrm """""
"""""""
deecse,
~rb;klte,
hepohcci~,

- ,,"""""'Y
odoma
"1... ",_ •• ,.. ."..

art' n-lanve in that, I ~' monrtortug tln- couceutrutkm, adj ustun-ut s in d()Sa~I' can lit' lIlad t'
fc)r aln-red p harmacokine-tics .
A M.'nsitin', accu rate. and specifk ;l"sa~' fur the lim!, must lx- a\"aibhle. III addi tion, to
1)(· IIst'ful. the results sho uld 1)('available befon- tilt" lJ('d Il\('mpt 'utic dt"('isiun is to hI.' made,
T Ill" half-life is a IIst'fu l indl'Xof this "tu m -ar ound" tillJ(" ht'(-'auS(' il is tilt' ti nu- In une in
which accumulation 0 11 multiple t!()si n~ and d isapl)('amm 't' 011 t1i st"on l i llui ll~ a d m ~ occu r.

THE TARGET CONCENTRATION

TI ll' larxt't ('o ll('t'nlmlio ll initially chose-n is tlJ(" value or r.U1~I' u f values with 11)1' ~n'a lesl
probabtbty of therapeutic success (T ahlt' 5-2, p . 59), kt't'pi ng in mind thai the pop ulatioll
\"alut, (or m.ll~e) ma)' la- inapp ropri ate for all Individual. lI i ~h er ('Ullt'l' ntmtitlIlS 1Il<l~' 1)('
appropriate wln-n ti ll' comluion is severe. an d the converse when the ('()lI(lilio n is mild. If
altered plasma protein hill( li n~ is alltk ipah'ti , SIK h as in uremta. aft(' r su rge ry, or wln-n
di spladll ~ dr ugs are alst) adnunlsrered, then tht, targt't total concentration slltllllci ht, ad ·
ju sted to attain tilt' same unbound conce-ntration.
TIlt" p rincip les for (·sta hl ish illg a dosagt· n -giult'll to ad lh...'t - a desln-d (1)11('('ntmtioll ur
10 keep within concentranon limits an ' pn-senn-d ill Ch ap.. 'j' .. Adj ust rueut in ti lt' usual
dosage n-gi m('1J can often he anticipa tedbased O il the patien t's age , weig ht . and chnical
stat us, especially renal. hepatic , and cardiovascular functions (C haps, 13 10 16 ), Yd , ('\'('11
aftN takin g these factors into account. suffictcn t uncertatnty often remains in tilt" kinet ics
o f tilt' d m g in tilt' indi \i du al patient 10 warran t mon itori ng tl .... plasma ('oll('l'nt n llioll , From
sudl obst·r...a ttons the pat h-nt's current phennacckmettc p arameters can be estimated. and
a IW W do sagt.' rt'gi llw n t~.111 ht' dl'siWll't! to IIIOrt' dos~· I)' at'h i~ ..."(' Iht' tilrgt'l vahu'Is ].
CHAPTER 18 CONCENTRATION MClNfTOl!ING 29'
Fn '(IIIt'm) ' of lI\on i lori l\~ is a function of the presumed change in till' factors that inllu-
t-ncx- d m~ n's!'MlIl'i(·. For csampk-, ti l t' plasma conce ntration of phcnobar lntal in t'pilt'ptic
pal it'nls, whose slate of health and dmJ!; Ih{'mpy remai ns stable. ma)' ueed to ht' 1I\0niton '(!
nnly a few times a ~l.'a r: mort' fn'(IIIt'1l1 momt cnng may be Indica ted if the patient's health
dderiorah's or if t1wmpy with ol llt'r drugs is altered. Daily or even ilion' Frequent moui-
lorinJ!; of pL~~JlIa tlu·ophyllilU' concentrations may he m.,.,lt.,! for op timal n'\(' of tlll'()ph)'llilll'
in tln- treat ment of an asthmatic patn-nt in an intensive can- unit, especially if l'()n~l'sti\'t'
cardiac failun-, pue-umoma. Iu-panc cirrhosis. am! sllloking an' all presen t . T hese conduious
alter tlu-ophyllim- clea rance . which is likely to lx' quite variable andunprrdictabh- in this
sit uation.

PERTINENT INFORMATION NIIOED

St,\·t'fal kinds of mfonnunon. J!;in'lI ill Tahle 1S-3 an' IIt.,.,!t.,! to e\,lllIatt' il measun- dplasma
t,(lIlt't·ntr'dtioll l·ffid t·lltly, A hislo!)' of d m g adm inlstratlon. wluch includes d ( )S('S and tunes
of dnsill ~ is mauda to rv as an' lilt' limes of sampling.
Spl,:ifil' patit'nl population pha rmacokinette Information for Illoniloring d igoxin, gt'n-
tanucin. plu-nobarbital. and t1lt1IphylliTlt' concentrations is g1" 'n ill Tahl e 18-1 . 11lt'S(.' four
dmj.,ts art' u<;('1! throughou t Iht' renuumh-r of this chapter as esa mph-s of the application of
tlu- pn uciph-s of plasma dn l~ conce-ntration monitorin g.

EVAlUATION PROCEDURE
U sill~ lilt' dosill~ hislory and 11ll" tillll'(s) of sampling. jlltl~lIle n l is 1ll't.,It't1 0 11 whether tln-
measured \,;lhw(s) is a glxxl eslilllat{' of tilt' maximum, aVt'r'dge. o r mintmumconcentr atiou
ut sleady state 0 11 a fixed regtnn-n or of a uonsteady-state co ncen tranon ts) obtained t'illwr
shortly aflN s ta rti ll~ dosing or follll'\in ~ an erratic schedule. lI a\i ng established the cou-
ditiulls alltl an appropriate kim'lit· mode-l, a geuerally recommen ded procedure to evaluate
nllt· or mo re {'(m{,'n iratiulls is as follll'\"S:
I . Estlmute rlu- likt'!y values (If tilt' plJannal'Okilwtk parameters (F. Cl ... V, and hence
' 111) in Iht' pal it'nl !liLst'1! on population pa mlllt'tc rs. taking into account Ihl' patient's age ,
Wt'i~h l. n-uul Iuuct iou. concu rren t diseases, dmg the rapy, dosage fon u. mut e of admtms-
trution. and all)' other informatmn ab out tln- p;.ltielll known to affet:t tlU' kim-tics of tlU'

T.tt•• 1 a.3 . DehI C.llect1••

H.l.Wy 01 Drug Adm,niWOloOtl
Drug, dose. dc»oge form~. fOllIeS 01 odm i n i ~otiorl . hmes 01 odminiMfOhOft. compiloflCe. inpot.eolor
ou'po'.eO'll
Ic-e 01 Sampl,"9 Irebt,Ye 10 p'ev,ou~ Oo!ot')
Prt'$ef'l' cod Pre-ocos 101 ony) PIosmo Dr'-'3 Cooceolro!>Om
(1,0'10(01 SIotu~ 01 POI'ent
We'9ht, oge , gende< . Cond"1Qf"l oo.ng Ireoled, smoking. e/hnic;,ty, concurrent d'~loe)lQ1W l~ialiy
eo,dlO'o'OloCulOr, hepot'C. ol'ld 'enol d'~loe~1
loooo!Qf'y Dctc
~enol furochO<l (_urn creat,nine, ClOOMine cleo, orocel
HepohC furoctlOf1 lprorh,ombin I,me, !ot'Il,Im olbumi". ~ bilirubin)
P,ote,n bindng !olbum,n, IOloI pIosmo plOIeln, 1
CQrI(:urrM' [)lug Thefopy
Inrerochn9 drug~
Assay inte!ference'
Act,.-e ~boIlte~
A=J'{ I\o'oethod l'eplOOueibil,ry. ~~"''''ty , cod ~;fic 'ry)
Uwol Pho'mocok,nctoc Po'ome~~ AUOClOled W,rt>, Type 01 Poherl! in ~lQIl
8>OOv'Oilobili ty. obsofpllOf1 'ote COfloonl, ...dume 01 di~ ibution , Uflbound lrochor1 in pIo$fTlO, 10101 d earOflCe.
renol deororoce
 CHA,PTU 18

d rug . :\ maj or Intent lu-re is to idt'n tify tln- subpopulation In wilko!. tilt' j);ltit'nt ht>lllll~s
(Cha p. 13).
2. Usi ll~ tilt' appmpriall' kine-tic 1ll()(ld and the !l<U<IlIlt't er vahu-s ..1)(1\'(', t'sliTllaft' the
plasmu ('(Jll{'t'ul mlion(s) I'Xj)(x11't.1ut till' Ihu d s) of S<tlll pli n~" l aki Il R into account ti lt' dosin ~
hislo l)"of 111I' p atient .
:1. COInpa n ' 111I' Oh'il'f'\l 't.l ;l ilt! t'xptx1t'll coucent mnons. If Iht,), an ' in a~n''t' IIlI'Il I , the n
01\(' \ ('tlllfidt' n('(' ill kno\\ i ng the- p"U<lIIlt'tef'S in thcpatn-nt is increase-d. ..\ dini{'ltl t1t"l.i sioTl
to TIlodi (y the- dosa~l' in till' pat ient depends Oil tht' couccnrr ation ob st'n lx l am i Oil several
otl lt'T f.1l1 0rs i lld ll di n~" mllst illlpllrtant ly, lilt' current rt'Sj)()ll\t '(s) IIf tilt' IlOllit'nt.
4. If oh\t·n l'() and expect ed concentrations art' judg:t'(l to hI' d iITt'rt'nt, 111t'1l one may
\\hh to n-vise- th t, phanllat,(lkint'til" paramt'tt'T('stimatt's . Hen- it is 1lt"l."t's s<U) · 10 \\l 'ig;h )UI\\·
mudl (1J1l fid" llt"t, Ollt' !las ill tilt' inilial p:mllllt'ft'Tt'Stilllatt'S fm lll previous popnlatioll stud-
it's n ,lati\'(' In that ill IIII' t's limatt'S oblaillt'(l fmm the nu-asun-dplasma t'tllJ('('lltrlltion(s).
S. :\ rt'('tllmnt'l ldatillll for t1(Jsa~(' adjllstlllt' ni or pam-nt education (noIH '(llllplianl'c) ilia)'
\)(' appropriat e. III addition . comments 10 Iht' clinic ian {,(lUld aid in III(' interpretation of
tht, dnJ~ concentranon. Such ccmuu-nts ind' l<!t'lht· ue-ecl to ad j, lst tilt' tln-rapcutic wi ndow
when ;Iltt'T(xl pmlt'ill hi ll(li ll~ is t'xpt'<.1t'1.l and when a d "iIl!!:t, ill tillll' uf sa mp ling: Is llppm-
pnate.

, ,8-4. PetI Pepv.atI_ PINt....c.kl...tlc P........" ef DI•••••,

o. lcI , .IMIIn...p")"III_-
P"'M\fIUS

10 10 0 95 hyd'OU$
om ,~ ltrle
OQ(Na50irj o 9 anhyd,OU$
aminophylline
[i.v , use)
Oral bioo'lO,labMy o 75lab1eb <00 10 10
0.9 e&i>:j,
OQ51iquid-
fllledto~
Volume 01d ,)ir,b,,11On , 072 0.55 05
Il/lgl
Clearance (tlh,/lgl -, CI • 00037 0 04 '
Halt·Me (hll 44" 104 87
F,ocll()l'l e_" e/ed 07 03 013
unchallg!!d
T heropev ~, wmdaw 0.0008- 1~30 10-20
Img/ll 0002
!~J 0,001- pee, ;1 43-130 55-- 110
00025 " 0<X)' < ~

Q~"""'_ .. ~~_ ,
'"""",,, <~ -dooogor ....... - """'. . .
l>d od !dooodb,o W! ! ....... JJ so-..g aodW J Ml<> ~ ,~~ 1992

' vllfl.9l • l 8 • ~] a.. a. ..

l/l'w ~ "" <>:>A
~... _ ~ CO'dooc: ~ ~ ClII./ht\gl - 000.. • 00],,,, ... 01~"'Odooo"",<_ ...... a • a..- • 0 048, ...... a.. .....
v.,
·Awooo............. _ 01_' . < _ ~
..........,.. 004b,otoo loxbboolow"' ~b.....,."'9 ago, <1._ aod ~ '*'9> eo-- .... Iact>t,~"" ~ _ _ l'o<w>
"",, < ~ .,-

-
""' ~
"- ,eo_
....... os
cr "
"
00
"e
t

........
~<aodo<xb""
cs cr
"
os
....-r » 0 I~/a". a.... Vlw ~ 1.9
"
. ', '1 • OQQ] v /O, V and 0 --.....:1I.000o ...,..,.. < and d

r" • • 8 J1"' . .0... J '" ..too lac"" ~ ... ""'*'-,

0...-; 1_ IXl - ' .... .... _ rJ 0 :JO- ~aod oo.'f/' o:>n< ~ "'" ~ "" "" 8 ........ doM
CHAPl(. III 2'>'

DOSING SCENARIOS
CIMph '" fi alil l '; t1 mla iu Ilw hacir- n '1alioll ~ t.ip ' ","t'111'1 1 for f'\;III1;llill!! cnll n 'nlr,tliUII'
ohlaillt'1111Ilriul.( HIII,I.t11l ·rah' ;1IIt! 111lllllpl,·...lu\t' r' 1OIIWII\, TI••·\(' n ·];,tiOll, l,ips ;m' u...\
su p pl" IIll'lIh 'C l \\ i l l. f'1pl.lliom. w h id l ;m' lI'it'flll for fOllr ;ltlllil io n' II, fn "jlU'llll~ OC'C 'urrilll.(
'ol'C '!Mrio" TIW\(' an' ,,1"'11 HI'" or 1lI0 n,lIo\( " h lllis'it'1I: W""II ;I pallc'ut is ou a (u llr· llll lPs.
a"'\;I~ n1..olll11 '11 ill wh idl I",' iU!c'IYal, arr- lIut ' '' 111,,1, for (·\.;lI11pll', !oj ' \1 . I I', \ 1. , ,'i " .\1 " !J
1' . \1. ( M II ~ 'C I II" n l r~ (';1111'11 a 9-1 ~'>-9 n'!."ollJwn l: wlwlllllt' dnl!! is rt'p" ;lh'1ll~ illfll\('11 U\ ( ' f .1
pC'ri,"! o f tillll ' .lppn l,tt·llilll! ih " .M-hf,·; .lInl wl u-n till' do'o('s \;I~ ,1Il1! tI..· I"..
in c: illh'l"als
an' l'ITalic.. ElIlpl.,tsjs IlI'ro ' is lOll s"'JI :2 1l" ;tI' Mho ll I' roJl'C"t IIlrt' . 1);1r111 11 J.trl~ " II ,I.·lt-n llllllll!!
II... "1'P ro 'pri.tll- lilll 'tic- 11 1,"11 ·1 f.,r ,·,hm.d ill!! C'C llK'C'lll ral ioil! , ) al lill"'.' I ' If ....l1I lp1illc:
Fur '·;Ic·II flf tilt' \I'C 'IJ.lriO' , ,1"so rl'lIo ll is a \\llllll"ciin hi' 111111:1. ilion' u pit! lIl.11l . ·IIIn lHa·
tio1l: i.c·.. Ilw illlr:.IW IlUIIS uv .} h"l m a ppmx unation "llJ11i,,,. :\It,orpti ull tl, "(·rt' ,ISt ·, lh K111.t-
11"11 : II ,I..HIM Ill' 1.ll'·1I jlltn . M,"(1MiIIl , ,, 1H"1l 1lt"('C .......t f)'. IIsilll! II..· I,ri IK' 1'11... pn'\ iOllsl~ 1.....\ 1'''
ill e11.11" ; . l-:\lr,I\ .I\l 111.Ir l li ",'. l '"!l''' o.I...I'\\;St· 11<"''11. clu\i ll\!: ;111,1 , a mpl",!! III"'''' .In '
," hSt" t"" II ' I~ II,ISt'1 1"" tl... ~ .f · h'H lr dCJll .

.\ !tl.01ll!I. II \\tlllliel St'1'1n tlI.,1 " 1I ~"' ''l.1 cit ·, \\t.nld I!:Tt·.II I~ u 'lIlpli"lt" ,I... ''',1111.111'''' "I' ,I
1I ... a.~""'11 1'C 'IK'C·IlIr.tliu n. Ii i, 11..1 1I1,,{"l.·, lril\ -.c:•. F il!:Jln' 1'l---:2 , J.,n.\, .1 fh ' '1I.cl. "" . fi\c..[.
illlfol'\~a1 mllhll"I·.(I,~· ' 1"""'11 ill wlnch CllI~' II. ~' is mi' St '11 T" .1t"{'Cm llt fo r II,,· wis",,, 1
c lt-~ · . CII'" Ill" ..ls tc. \llhl l';tt1 lI.c· UIIK'C'n tr;l t ic"11' \pt't:1c"t:l ill tI..· Ii",. · ,.1' s.illl pli"!!. jf cIIlh 1111 '
mi s"' '11 clt- ~· ";.1 111 '1'" L,'iH'Il. fm lll ll..tl 1'\ llI'I1I'11 if no dCN ' \\i ts lllisSt'11 nlis C'.Trl"(·!i·UII is
1l;ISt '1! 0" 11.., Imnd plc' u f .ttltl lli\ily n l ('f>nn'IIIr.lliflll\ fr om " ,It·ll II.",· .\ 1 ,I II t i",. ', . I" II1Is
"\;Illlplc', ;t l"l.11l('C ·,, 1r.tlinll j, 1lH'a.SIlTl"t: I at Ii me- t I \\ i t hin ;I clt...ill1! illlt 'f\ OIl 11.., n IIlI"l. 'li t ra!iun
" \ I""(1c'1 l " i l l. "" mis "' '11 cloSt, is

F · S · Do~
V (1 • '1
11... p,lr.III1"',' r S. ' all Iortu fac1o r, i\ a 1'CII ·llid.·111 c'C,rr' "('l in!! li,r IIIl' k,dioll,II l"lIllIl 'UI .. I'
,1m \!:. It, liSt' is 11 1111''1''\\;\1) if tI... d uSt· and ('lllc"{·u t r:.t!illlls an- ' ·\pn·\\,,1 in '1I0r.lr '1IIi" .

1.5 J·ist. I ~:z . .\ """.,1,1."" I... "h~ II, ,h.' ~"" 'n,,~ ".
~
.=,
II ", fI".t"~' I "~ " "..0' ''1 rUIM" " I .. "" 11 .. · ~h ',,,,, .~" ,,,,

j\j>f~~~\
,'.t.!".'., n ..· ,1.'\,..." ..( il", ~"" 'nll~ 1\ "l""~~'nl III
c Ih.· "".., ·"rr-"",,,, ,,' m"' ''ln~ I.."" rl..· ,,,,,,,,1 ,I,,,,,
0
'~ 11..· ....I t.,I."nn ·"'r~r ..M' "r ~'l\ r",,,· f,~~ ... m~ rl..·
10 1111,,,,1.10 · In ,I" 1IIIII' J ""n 11"'11 h.· ",11111,,10,11 ..
C
B rl,,· .MT.· ,.... Iw.'" " ,I..· , ~I, ,,· . ·~Iw .... 1 ""I. ''',
c m'~.. ,lc · 1" " 1,I... """' ·IIr.~I ..", '''I".,t,,,1 "r
0
U
c
rl , II",.' h~1 ""Is rl..· ""~",,I ,~"" I"" 'n 1:'' '''' I,,~ ·
sa t, , .",.. .. ~. 11..· ,~", ·,..,,,l """,.""......., ,.., rl,,· ,t..,
0
0
0.5 ..fr,·r rl..· 1111, 1 ,J,...... 'I!J 11(' I , ,, ' '' I"·nolll"",,,I, .
c
~
E
~

il.
,
- --- --- ---
'11..· poo,..,..." Q . . ~I '" tl..' "~,,, . ~" ·Il ",,, · ' ·'1"~1, ..1
mtl ... POO'""'! III II..· ,I'I,~J\ I" , "~n.l'lo ' c'..,,· In,,,,,, , I
'1',1. -1 ..1 11 \ 1

0
0 2 4 6 8
Days
N' CONCENTRA.TIClN MONI1Oi1ING CHAPTH IB

TIl(" conce nt ration expected from ~i\;llg only a singl<.· do'i(' ill tilt' tune (If tlu- misS(,,<1 doS('
is

Clmw.d doMI - -~
F_-
V
.::5.-;;;00=
,. se _. -" 2

w!lt'n' 12 is the nnn- since the misst"(l dose . 111l' couceutrution (':1:1>1."(1('1) in the tlll' rape ul il'
set n ng is then

c-
F-5 - 00,, [
V II -.-"- hi - • I
Et ~ .k'l
3

If tw o d OM'S wr-n- nnssedtlu-u

--" I
F - 5 - Oo.. [ e ' f!
_ ~ ..
'~ - e
- i"
'~
V 11 . - ")

wln- n- t 3 is t he l illw Si lll'l' tlu- o t he r d OM' was mis sed.

9+5-9 Regimen
I n institu tio nal s('tt i n~ mall)' dru~ art' W\l.'1\ ill rt'WIl1l'IlS snnilar 10 till' 01lt" portrayed in
Fig. 18--3. Such regimens have a 24·hour repetitive or rt1-.1tllar cyck- ( 'W II though thl' dosing
Inte rvals within tilt' tlay an' unequal. TlU' ('x!x-ckt) conceru rancn at allY tum- during tilt,
day ca n 1)(· \; ('\\'1'« simp ly as the sum of till' stee dy-s nu c couceutrations rt.sult ing from each
of tilt" four daily dos('s. \\11('11 gi\'('11 011('(' dail)', lil t" firs l dose of the day is e-xpecn-dto )i eld
a concentr ation. e (/ , ). at stt-ud)' state. wn 'n by

t·ll(. 11h3 . TI..· pla.. nl<l 1I""'1>1,~1Ii l'" <.lIlt,, ·nlr.lliulI 20

, >lrlt-J ...., .. ".iVf'~' ..I . , .....1,..••1.. 1.. (2..•...It' r "1"""';"1(
pall" w ) ",ill. " "'9-1-S-9· Iyp t· of n,;; nl<'n in ;111 av·
"I'li~ n.,.. ;or.. >ld d,i lel, In 1M. l"UJ"pit- til<' ('OI It , · ,,·
,r..!io" . 2.1 1I1WL, ..I tI linK.' of tI.., I1 lOwinl( lit",,· 15
t9 :I Ml _ . ".,., Ii " ... ) " lel .... i,... ffrt1 i".. (11 1'"''''
tit.· "" 'K"_ - 7 1.) 20 mWl.l. An ;'K'""ll-''' ill II ""'.
10 " ·n..n... ,1,1 . Ie , ''''''W' ,"'I · ·.'..r. rna"
., ,,, ItnKity . 1""1 it. larl;.. dllrin lt I nin !il. !'K",,, 10
aft..r tI.... t .. .... at 2 1:Oll (12 a'lt l 36 "rl. 11K' 01""" , , 1
1" "'KiJ t'OIK' 'llI''''lion of 6.3 m,vI . I e) i, " 'I'"'rim.
1" "'''1. 11M- p;<r..l1....e r ,.,.],.... u.,..) ...... Ih..w in II...
1h....r>ll~il; lW' o:a-'" hi,'"r.... ( I mWl, _ 5 .5 11 ~1 ).
5

O +--------~
o 11 36 48
CHAPTlIl 18

when- ' I is till' tune tlllling tll(' ILlY hdwl't'n ~i\i nJ: tilt' do'K' and 1>;1I11pli n~ tilt" h loud . ·nlt'
t111l('('u lmtiull R~lIh i llg Inun h'i\i n~ onl,· tilt' !\('t.'t'lld doo;(' Oil a (bil, · n"¢lIwlI is

when- t 2 is till' tim l' bd " l 't'n tilt, ad millbtmlilm of 11.1' St't.,lIlti di N.' aud tilt' tinu- of 1,I(le MI
sampling. and so on . Thus. rlu- concentration l'xpt't.11'tl (III sud l a n.·~1l\1·1l i ~

+ . -I:1'l + e -~ "J +
6
{l -e-'1

wln-n- t is 2.J h r. rln- dosing illtN \u 1 ill ('.u: 1I of Ihl' HIlI'l' d.tily n "¢ml·us.

Intemittent Inf"siM Model

TI lt' ;uuino~IYl'tlSidl·s. e.g.. gt·utamkin. an' IIfh '!1 .ulm inb ll' R'tl t·\l.·I)· 6 10 .s ho urs I,:,' a
constan t-ra te in fusion of t'adl doSt· IM 'r :30 to (lil mill . This form o f admillist mtiull is Ilt'itlll'r
a lIlult ip lt·-<loSt, i.v. hoIus n~,,\('n 1I0r a constant-ra te infusion. hili mi llN an j'lil'nlllttnlt
lflj iu iorl n"¢lIwlI. \ \1 11'11 till" infll\ioll lilllt' appnl<ld ll~ til(' half-lifl' of a dmg. a multipk-
<.lOSt' l.v. bolus model is 110 11lIIgN adt't iliall' fur pn.'tlit1i ng t'Ullt"l·lItr.ltiUI\S ant! n'\i \i ll~
par-lIndl'r "aim's. TIll' app m p rialt' slt'ady-sta h ' modr-l, sh(I'\\1I in Fi ~, 1S--4 is

Ro ' (l - e -I:, ..., 1

C- CL (I - .-'1 • •• _jt _ '",,1
7
I II III

wlu-n - t is tilt' dosin~ inlt 'rva l: t '~f is thl' d umlioll of lilt' infus ion : n" = s . J)( N.·lt,~, : an d t
is tilt" lilllt' ill tilt' I'l\t dosin g illlN"al hdw('t'n Iht· start of the- illfu_\iou OIml tlll' \\itlllimwal
of tl1l' hlood s.unph-. Part I of 11ll' t"- pl<ltillll is tile concenrratk m l'Xpt't.11't 1just OIl till' (, ut i
of llll" infu sioll . ill rate S . V lt,,,,. Part (I is III(' uccn mulatinu fill'tnr for n 'pl'<llt'tl <Id minis-
t rution to skad)"state (S1't. Appt'lllli'l I-E). ant! part I I I is till' fn1l.1io!l n"lI.till in~ 011 po s tin-
fusion t ime, t - t ",f , afh-r 'K:hit...i n~ till' peak sh'a d,·.sta lt' cnnceut rutkm , tilt' product I . II.

Dose aad lalerval UaeqtHd

TIll' situation in which neither do\! ' lIor inte-r....alhave ,lll~' dl ~n.'t · of rt1!ulari t)" is [o'( llIl·nll,.
ob\! 'n 't't l ill t1wmpt"lllit· mlluiforing. In this situatiou. Olll' ca n simply sllln lip dnl ~ th ai
300 CHAn H 18

n-mams from pn ...-i ous dust'S wi th th t" realization tha t {Iost·s ~\"t' 1l ilion ' thuu fuur p atient
half·lin'!' a~o ( ':1Il 1)(· disft-';ilnl('(I, Si lll 't' so little d n l ~ n-mams in thl' hody from (' ad l of
tln-m. 111t' pl.o ma concentr atiou expec t ed after three lin","'!>, fur example, is

c· 8

when- D IN ' \. Dosl'~ , ami I)t )S('.1 f('p n's('111 tilt' dust·s ta!.:..-n ill l i lll4. ~ ' •. ' 2' a nd ' 3 Itt'(o rt,
s.;ullpling:.

Confidence In Esfimates

To n 's; ",,' ph a rn lal 'o killt't k pa mlllt'!t 'r valm-s pmpt·rly. 0I1t" 1II11st (,,(lIlsid N seve-ral pieces of
lnfonuanon. InfonnatiolJ ,lho ul com pliance. hioa\·ailahili t~· . lillll's(s) of sampling (act ual
versus report ed l. assay rt'pn )(l ll dhi l i ~' and spt'(i fid ly. ami t1(l'i ill ~ history: an' of pamllKMlIl1
i llllx Ht ,l!I (,{', One II1mt also .....t·ig:h lilt' n ' b lin' l'Imfil!t' lIl,,{' (JIlt" has in tilt' pa r.llllt'l e r val ues
t'Slilllakti From Hteratun- data, pn,\; ou s t'xp.' rit' Il(,(", a nd n lll('('ut mtio ll da ta . Hl"l .'1I.1I (C hap .
13 ) IIMt litt' ml nH" rl.ilroUl IC'h "r \-ahws an" thl l'\t" t"sli nmh'1l lu apply to the su hpupulalion to
which Ihe panent ht'I (}II~s . ~ l i S<L~s i ~I III{'ll t of rlu- slIbpo pllb tio n a nd varia bility in the I"X'
pt '1.it'l.l pa ra lllelt'r values a re , (If ('tIlIN". lUI\{'('nJS ln-n-.
Ad d ilio lla l kim·til: fali on; affl'd tlll t' S l't1ll6t1" lll,(' ill th t" 11M' o f a concentra tion value.
Cu usit!PT, {' . ~ .. till' ("it\( ' of sa mp l i ll~ wh ile dnl ~ riws tlu riTl I-": a ('t Ill.~l iU1 t -mtt' t.v. in6 lsiuu. A

• ·l lt· I ~ . n ..· !'....." "" u .... . ·" I,...' ;,..' " f ):1,,,t..,,,iciu . t.
pr''tlic1t't l ,lll n l1~ ;Ill '- h.." , ,I<.. h~ into-no"; ... >t..""f:, t
, 1..1<' .. ,.. I f" I1, ....;,,~ lh,' " , ..·..1<.. 1 ~",i" .....'.t..1l1 ,... 1" -g, 6
illfu' i" " "f lh,' .Im!/,. d ....... <i"'il....ilio.. "'il lo " 1'....." ..1
l.v. I.." ,..,~. "'-' -pI f" , .... , 11...1".. 1".,. \\1lt'T111..• ;ul"ll
.s
c
h"... (i" f" ' i" ,, tlunah' ..,. ' ..,1i, .. . il:Jlifit,.ul ["'<1 "f ,h.· 0

'....f·l,f,· (1,U I" ' ..·...1. il11o-n,, ;II" III j"fll,i,," C>Ul n " lIlt ~
in •• • ,... ..·,...1......TTl..- " n..... II..· j",........
"" t1 ,in tl... illt.-no-..l. n....... n tl" ,LoII, ..
IIr...., Infi.·... >n
"" ..1.-/ ;. u....l t.. t '.. 11,\.1.." , "'p""1 r<1 ,'o l1l't"" " ..Ii"".
,.;U'('1..." . 1' >11 11...
0
U
"1l
c
4

,,,,,...,,,,..,., .-..1"..."'1""-1...1 fur ,til' p..tio·lll in 1111' lhin l C

:§
..." · I,i.t"....', n ..·"'".. oI.....·" ..I .." ....·nl,...lio..... " .9 ..".1
tH "'loI'l ~ ~ n' ."I..·riml', ..... 1( e l ( I "'WI. • I , ~ II ~ I J.
E 2
'"
c
~

'"
~
E
~
0
'"
Q.
0 2 4 6 8
Hours
O -tA"'TH 18 >01

pLa.~ II\;1 concentra non oht"illt"ll dllri ll~ such all Infu ston is il funct ion n f rille ' n f atl llli ll i~t r.l·
tlou, d t·ar.lIKe-, a nd \t-J UIllt" of drstn buno n (e llllp. 6).

E\a1 uahnll of a pld..\IIla 1111KVlllrd.tion requi res klMMi n~ wht,t!wr t:k' ilrdIK't' or \'nlulIll' of
tlistri bn hon i.~ tht, IIMln' \"ariahlt, iUK I app rt"l:iat ill~ Oil wllich of t1 K""l ' two parollllt'lt'n 11K'
CUlK't'lIlrdlKlIl is I!MUt ' l!t -pt·l Kk-llt. 11K' latter lIIay IlIt" cllIu idt,rt"ll fmlll tlK' t"'t' llb llt'pit.1t"ll
in "i ~. 1S-5 dllrill~ tilt" illfusiun of a dmg:in thn-e- ~"P'lr,dt· ~illlat ic ms. III Ca.-.t· .\, IIIt, ,'a1Ut'"
of tilt" df"ar.lIK"t· allt l \lllu lIlt" P;lrdllit-lt' n art" Ih l"N" a nlic.ipalt"ll. Iht, aWroIi:t' ,.thw~. In 11K'
ceb -r two sit ua tjons, lilt, half·lift, is th ree fiult'S grean-r than tilt· awrd1tI' val ue, in Ca.-.t' B
d m' to il tllrt"t·fnk! rt'l lut:tion in t·!t·a.rdnn" an d in Ca.'1' C due- to a tll n 't'fukl ilM..Tt·a",· ill
\UIUIUI' of tli~ rihtltion .
\\l th lilt lt· d n l~ hol'i n~ ht't'll ehmtnau-d. an t'a.f1)· l'tnM.."t'nl r,lhu n i~ pn man l)' a flllK1ioil
of i nfu~iun r...lt" aIMI \ll1 u llW of tlisl rihotion. ,\["('()nL n ~', there h lill lt· vt rt ue in lakin): a
samp lt, I.'fon· tilt' lI-~l loI1llo11f-li ft· to es timate the tll~t' rt'flnin' IIIt'nls IK .... it'l l In ...'h K"'t ,
th<-rapt· u tic concentratjous. .\ sh",ul)'·st ale l'Ofll"t' n trdtiun tlt-pt' IJ(L.. Uilly 011 tl.· rdh' o f ad-
rnin istr.d ion and tiM' \a1I1t" of clearance (C hap. 6 ), .\l"('tlRlin¢~' , sa mplill): at this ti ml ' pm-
\idol'S the most l"lmfKlt' lK"I' ill l"ltim.ating doo;;in~ raw rN lllin'II)1'uh.

300 ~
-U
~
;;;
>
;;;
~
~
~

<;
200
C
11 B
~
e,
~

'18 100 A J ,e
~
0
'-' C
~
E
e .
~

0
0 2 4 6 B x
TIme (in usual half-lives)
nit, I ~ ..·.~l. ;"lt .. n",~"" t ·r""" inr,u"~ ' rn"lut''-; Pl( lho· ''''lI''Mll r.ali"n "" "III' ".. ...:I r·bf.. ,10- hlllt- In
J.....~;.I, lorho pootirnl •.,11, ... rr.". ~,.],,,,, ol ..hr- <1 u .l"'.... of .b.tnl..,I. .... c "d ,,1.
a thn-M;*I ,,"1<1l1 in cl-rar1l;'O' and ;on .... ~ ... ohm ( ,1<~nl..r. IQ. C..... B 1",..,....,.."'""11: 1.'f'A"", l ho....
p.....nh. ... 11"'.'1 p"'" h.nnKllI. h.. l•...onty. Is ~· I_ .Io-... ~. n • • Uf. "';1llt III f<.., .. ......a
I...:Jf·I.. 01. ,\ h",. " h
. I1........MlclI~ in .. oft. ,,( ..... nhortiun. ( ~ C. ill hIO, drll'l1...1 ill ...... uuwl h..oIf·bfe. " on ." ........ ;01.101
P"'"l""" 11ft'" .nf,-.rnYhl lhr final pt..r...." <. ...... IT " ." . . .+oinn!
302 ( HAYlU 18

Salllpl ill~ 1K'r.\l't'!1 lilt' t une of initialin,g tl.t' infusion .un l st('ady stall' oft t'll leads 10
im 'tludush l ' info rmat io n . At two usu al halr-li"'l" , tilt" u h">t' rvut lon of Ih t· conce-ntration e x-
1)('1.11'(1. Ct">t' A. dot-s lint nn-au tli,,! C/. a mi \ ' haw th t, ("j)('("h-tl va llu·s. TI ll') ' lll ay both
di lTt' l" ami fu rtui to llsly Ki'"(>tlu- ('sl)('t1("(!I"lIllI,· ntr. ltinli. 111t' IIl\n· r-t1.,m -t·xl)t't1t'( II'lIIlI't·II-
muion Oil h \11 usual half-li\'t·s. Cil'it' C. (1JIlI.I I)(· thlt' 10 r-itln-r all illl'rt'il",,'( 1 <'!t'anUlI" or an
illl"n';l'i('(1 volunu-, ;LS sho wn. III contras t . till' ohservation at thi s tiuu- uf a ('UIlI't' n l ra lio ll
('flual til III' ahm'(' rhc {'\lx't1('{! st('atly-statl' \'alllt', C(<;(' B. is a d t'ar indtcation that <'!t'ar.lll<.'·
is II'S\ than lIsua l. l utlt't'tl. tilt' !-:n'ah' r this di fTt'n'lw(', t11(' low er is til{' probable vnhn- of
d ,'a ralll"t' ;Ill1ll llt" ~n'a tt' r til,' needto rt't IUl1' Ihl' rate of admi nisl rat ion to ;l\"'oid Inxidt~·.
III till' n -,joll of 2 to 6 usual half-lin 's, a major 1'1l1lsitl,'ra tillll in illh"lln'tilllo": il si ll~I('
,,!l""'l"\lIlion is wln-tlu-r t:I,'ar,uw(' or vnlume of di stribution is tlu- mo rt' \'a riahlt·" Fo r ex-
amplt" d l'aranl't' (in un its of I /l l r!k~) of IIlt'opl,ylliTlt' n lril'S (!\l'r an t"iglttfold I';tng' · or
mon-, pa rtil11larly if alo":" and diSl·.t...., statt· an ' (,(llIsid,'n'(l. 11L(' r'lllgl' of \,aIUl's for 111('
vnlrnm- of d islrihlllion (lAg) is only about twofold. Tll m . t'slimatt'S IIf tilt' d t';.II';IIII'(' of
11lt'()ph~-lIin, ' eall lit, madt , frum nOl\Sleady. slah' \111m's oh tailll'ti \~i l h i n Illis firne- sp.m .
Ahl lllllgh Ill,' p n 't.'t'tli ng ('(llll1'pIS n-ga n ling es timates of paI';Ul wt C'T'S wen- d,,,,'dllp,,(! for
uduunist ration hy infusioll . IllI"y ~t' nt" rall~' a pply 10 all fo rms .uu! SI:h,'tltlies of dnl ~ adnnn-
islralion ill!t-mlt'(l to pmdlll'1.' a plan-au concentration.

Revision of Parameter Values

DilTt'n 'n ('t's ill o"""'I"\('t 1;111(1t'\I )(,(1t'tl e uuvutrutions S ll~t'sl a 1Il1l11IIt'r of possihil ilit's. For
t·\amplt·. ti lt' 1l;llit'nt''i kint'!i t'S liMy lit· di fft'n 'llt than t' \ I"I<'(1I't1. lit, or silt' may ha \l' 11t"(·u
1I01l111111plian l. Ihl ' Siun pling ttnu-s m.IYnul lIa\'(' been no!t'tl t,( lrn 1.1 Iy, or au a.SSilY problem
ma v han ' occurred.
11'1' major t1''('isillll is how much 10 n 'ly Oil tilt' llIt·.l-s uTt't1 couceut ranon rl'llitin ' to
informatjon knowu aho ul patn-nt s Sill'l l as 111(, Ullt · hl 'in~ In,.II,'(I. sudl dl'(1Sioll'i aR' IIt~,(JIl d
tilt' S('( l!)(' of Ihi s chapter hili an' H' T)· important in (1111('t'lltm!ioll lIIouiloring. Fur tilt'
pll'l)()S(' (If Illis ('ha pl N , III(' (,(lllt't'ntmtioIlS. dosill~ histo rit,S, 'i<ll llpli ll~ unn-s . ami a.ssay
pml't 'tl un-s an- (1lnsidl 'n'tl lo lx' accurate. 111<' fl(" t slt·p is then how III den-nmm- tilt'
pharm;I('(,killl'tk Ililramdt'T'i in III<' patu-ut ,
1111' IIlIKI"llIst'tl for pn 'llil"tilllo": ii I(' <'1 111l't'lllmlion(s) tnu ..1 lit, a ppmp rialt' for dt'tt-nllillill/;t
lilt' illtli\i dllal·s 1l;11';1lIlt'It'r values. Fo r l'"amp k' , if int ra\'('llflllsly illfllst'(llu stt'ady state. lile
t'xl)('t.1t't111ml't-'ntmtioll is den-nmm-d fmm C.. "" 1~, /C I." B,'arra n¢ ng, dt·itr.lIl('t· m il 1)(·
{'..timutcd [nun C I. "" 1~ ,1C .., ~t un' (1lll\p lt,\ IIllltl,·ls fo r uou ..teatly-stalt ' alit! multiple
dnsin~ sih mtiolls. ,lS tld ailt'tl aIK"...', can ofn-n lx' 'ii lll i la rl~· n'alTilll ~t'(l. 1'1';1l1it't· ill doill ~ so
and spl 't.; al pnK't'(lun's fllr situa tiu ns in whidl rt'arrangl'llIt'li t is not possihlt, an' pn'SI'nh'(l
ill Ihl' e.lSt' histo rit,S !x..luw .

(ASI HISTORIIS
Til dt'llllll\sl mlt· 111I' prill d plt's uf p!<tsn Hl t l nJ~ 11l11l't'ntmtioll mnnil l)rill ~, III(' SUllSt'lplt·nl
{' lSl' hi'ilo ril"s an' t...·alllah 'll l':'· 1111' pmt't.'tlun ' Sll~('slt'l l ahll\{', 11lt' !)(lpulalinn p.mullet l'r
t's lilllatt's for lilt· t1mgs uli li7.t·lhe info rmation ¢\" l'T1 in Tahle I ~ _ l ud llJ I't1 an ' \"allli's for
....,1,'('1 'illblXJpullitious o f Ilillil'llt S. For gt'lltamitin and di j:;oxill. SI'\'('ml ll;mUllI'lt' r \'a lllt's
d" jlt' lltl O il ,III t'..lillMIt' of n 'n al flllld inll. t '.~ .. ('rt'<tlilliut' l'!t'i1rlllll't' (C hap. 16 ). 1';iT;lIIlt'tt't
t'slilllah's uf Iht't lph~·lI illt· an' "ht<lillt't l hy llIultiplit.'iltin· f;1l1uTS. Fur exa mple, lIlt' d t".mtnl't·
of Ihl'l lpll~- lIillt ' ill a 62.~ ...'ar.(Jld, fl.'i-k~ ft'lIlall' MIIl IJ.;t'r ( 1.6) \\i l h ('( m~('St i\I' (,<In liac failun'
(0 ..1 ) all(l l'(llll"UTn'lll ly lakill~ pllt'1l~1 oin (1 .5 ) is (~.lk-t1 l all't l a.'i follows :

0 .04 x 11 .6 x 0 .4 x 1.5) x 65 = 2.5 V hr

 303

\\ llO' n ' CUI·l IAlrikt:: is t l... t ~ pi\ 'a l \"alll" fflr tllt""p l l~ll iH" ill tIll' 1II " l' m ,,~ illt:: l';tli'·"1 pUpil'
Iatiull . :\n ( ~ l m "t 1 i o ll for 11ll' ;I1!1' of Ihh adillt i, illt,!Ilt !I"l,1. O lll' p\!)I'('h ;1 c1.·erl'a\(' i ll rh-ar-
;iII n' "ill. .11.:" . t -"Ill ·(:i.,I1~ ill t I... ..Ill,-rl,' 11.11it "Il l. II f 1\\ t '\ «r,
( 'I] rn "Il l 11 ... 1111 It).. fflr ,-,II 111.<1ill l.:

pa ra lllt'!,' r \. ,111", Il.r tlU'UJl' I~I1iIl" tlo 1101 iudutlt' SlI('1. all ad jml/llt·1I1. It is import .1lI110
nu l!' IIMI mil " dl '\( '!opl'Cllwrt' MI' inlt'mlt"tllu Ill' (·\.;lIupl. ', am i 1101 In " II II II M ri/~ ' ;til tllal
is ('lI rrc ,"t l~ 1.110,,"11 abolll II... l lnlt::\ ;tlltl tilt' \t r; lte ~i .... ' · "l plf~. "t1 lIlT 11." 11I. Ct · rt ailll~ . ;I'
mun- i" ("TuMlinll is u btlilU "t l. m-w am i nnm- n ·fillt"t! n ·lalioll , IIi!)\ \\i ll t tt, fnrtlu"t 'llliut.!..
C;I\(' I.l)iK,lJx;ll. \ 1..... 1).11.• :1 .'i: I '~ '·:l r-ol d . S:!-lJ.:, Il:tt i.·nl wi llI ("I J11lo~p ..lh l· ('llrd ial'
fllilun- fllr 11ll' p;I..1 :1 ~ (· a ...., n .I" lu llllilh ·d nn .\ I)ri l Hi III I llI' 1"1'>pilal III H):IMI
bc cau...• Ilf 1I \\ 1I .....· n i ll ~ u f her .'1 ln ~.·..li \.· card iac fl,ilur. ·,,) IIIplom... 11.·r m lm i"iu n
hi ..h,l')' indi.·.l lt-d Ihal ..Ill' h;ad Il,1.1·1I 11.' r di,t.:,u\in I"bld lO.:!:i m .Lt) Ih,,1 II mnlill~ III
t he u"u:II lillI(- ( ~ :( M )-H :( M )) _ h UI h:ul f:til.·(lto tllLt· a tablet 1111 IIIl' IU('\ inn.. (1.1) (:\I)ri l
I:i l. .\ I,la..nm ..lu n lll. · IhlIIOI(1 n il hl lran n ;11 I 7:IMJj n .... u h l.lillt'd til "'-e if IIII' ..) m) )-
hlln.. ".'n' ."II11..i..lt-nl wi t h nUII.'1 ll1lp li;u WI-. :\ 1));1.. 11I:1 di J:.u\in ('1 I11("l' n l n lli n ll u f fl .!'
~ Wl. illlt! .. "" nllll ('n'nlinilll' uf IUJ IlIWdl. " l ' n ' n 'pu r11·d
SI, , ) I. f:.. /j"",I;,III ,1f:r/ " ·d .·,II'll m"'d ' ·" \'",,11'"
F rn m a~' · . ~" II, I, · r. \\.+..:1.1. ;11..1...-n nu
cn-atiuiu.-. Ih.· (·rc-. ,Iillilll' d .·.u .lIIl'1· lTa lll.· If')--2. I). 1>' ) i..

, (1 40 - 5 3) )( 8 2
CLc, !ml/m.n) - 85 )( 0 .9 - 93 ml/min
15.6 L/hr or
0 .068 l/hrt1:gl

Cl ll/hr/ kg) = 0 .9 )( 0 .06 8 + 0 .02

IO.0812l/h,{kg
Of 6.66 l/ hr)

\Ill/kgl u 3 8 + 52 )( 0 .068 (7.3.:1 l/kg Of 60 2 II

E lim ilial illll rail ' l'I lII\l. tlll ;Lll.I It"lf·li f., arc- 1110'11

k . CL/V = 0.Q11 hr- 1

'11,,· \ " 1,,.·.. "f.li a u,1 "' I" r <Ii ~"..i!l lalold .. ;<rI' 1.0 awl 0 .7.1, " ·"I" ·d h d y.
~ I ..p 2. 1':\lil/lIlI;,," "f f~'rl ll ·ttl'fl Cm l/" 'Ill rtll;ml nt Time II! S,wIJ,li,,:!. '1'1... li"'l IIH" ..IiOIl
1.. 1,,· uddn- .......1 i ~ .1...1 of II ;tppn'l"iah· killl·ti(· lIuIIII'! fu r (,...;tIIMli ll ~ 111i .. 1~ >lIn · lI l ra l ioll .
I'rt·"lImahly. till' IMlil' 1l1 I" 1"'1 '11 t;\k ill ~ t1i l,:f1\ ill fur 3 )',.;u"'. 11... dll..ill ~ hi.. t ll~' i1 11!i('ah' ..
a \i ll ~ll' , n -....·lItl.\ - mi ~1 d -. 1'1...... ;\ \ It'ady -\Ia lt· 1111 111,·1 ill( ~'I'] )Or'll ill l.( IIII' lIIi.......1 d' N '
h app rup ria lt·. Ik f..all · IIII' ('\1)("11,..1 hal f·li f,· i.. fi.1 hr " lid II". l im illl.( illl"r"al i' ::!., hr.
Ihl' 1l1l('lualioll ill 1~ 'lIn 'III r;ll iflll ..111 ",1.1 1)(· minor alit! ;, ('tl1l..l.ml ·ra!t· illf" ..io u mod ,·1
..I.. '111,1 a ppl~ . ,\ Ilc-m ,.l h ,·ly. •1 \1t';uly· "l.Ih-, lImll ipl.·.d' N · IIMIIII'I .... 11I111 111' . 'lIlpl,~ , ·. l U \ i ll ~
th.· ulIl.. I;IIII,r;clc- illfll ..iull mul..!. till' ( 'tI II .... 'lIt r;.tio ll "·\I )('l1 ,~ 1. C lf ) ( Fil.(. I ' -::!l. h 111l' 1I
C•• - C (/ , ). \d n · O t l ) i.. II... (~IIIl~ ' I I Ir;ll i(l1l "O\p' 'l1''1132 hr ..rltor adlllil1i..l r;'l io ll l ",d lllll~
Ih, · mi....... 1 Ii · 1" " '11 ~i\. ·I1 _
304 CCNC ENTl "'11ON M()NITQii:1NG CHAP1U 18

F ·5 ·Do~ F ·S·Dout ·e -I.'l

CL . t V
C. Cltll
Usi u!-t il skady·<,lah', lll illti p lt' "",lc)'i(' II\(Mlt.J, tilt' couce-ntrution j'xl'lt"(11'(1 is tha t S hr (t ~ ) inln
tilt' 2-1-hunr dm i ll ~ inte-rval (tl minus CU. ). ;lS dt,fill('(! aho\'l' (II ::: 32 hr).

111t" values an - O,ll') und lcl l lllWI.. it tlilTe n 'l\('l;' t·.\pl aillt '( II I~·I IIl · assum ption of l/l:auf!t'
..It'itt!v-slah· concvnrratiou iu tlu- first IlllMlt'!.
St~·p 3 . CO"'Pflri~OU of oh.' I'n-nl (/lui f,XPf.·(1f·t/ Conccutranans. 111t' (lhst' '''I'(1 (0.9
~ WJ .J autl l'\ !x"(1t"i1( 1.0 1 ~ WL) values an' \irtllally tilt, ~1II l(' . Sh'p 4. n ...i sioll of pa rallld N
values. is llllllt't't'!iSary . Furthcrtnon-, tilt' cluuciaunow IMs sm lll ' (."I111fidt·Il("l' l hOl t t ht' Il<lli t'nl
is h alld lill': tilt' tim!!: a s expectr-d andthat tilt' <''fll!('('u l r.tl io ll pn-st'lll 1I1i1~·1 )(· inad ('(lu alt· 10
ront r ollu-r ('tJllll:t,.,tin' (:an liae f..illln '. A dt"'(i sion must IlUW ht' IImdt' Ull IUlW much I l i~hN
01 l'u lil't'ntmtilill is 1lt't"(lt'tl, ur if t1wmpy should II(' ,1Il~llwll lt"( l \\i lh IlthN dm~s ur <:h a llgt"(l.
Ca sc' 2 , TJI~o" 'I!llIi llC' . J,T" II 6-J·(,llr-old . 22-k~ bclJ' s u fTt' rin ~ fnlfu us. h ln u und
t'pil('p"J', was l a L: i n ~ 11 lI Nl-mJ( a mino p hJ llin t' tahl('1 ($ =
0 .85) fo u r li mt·s II claJo' Hot
8 :(N), 12:{N), 16 :00, and 20 :00, 8("'("a ust· of poor (''On l n ll of hoth h i", a",t h mu lind h h
'-('bun's, II blcMMI -.ampl(. WII'" nh tai l'l(·d III 8 :00, just Ix,fo n ' the' n('d do se , for de-
t('nninilli nn of th('ollhJllil'l(' IUI<I Ilht'unh:lm illil ('u n("l'ntraliolU, The Iht·ophJo lli ne-"
('oll("('ntnllio ll wa s 6 .3 m w'L .
SkI' I. f:\t imtlti",. oj f:x,H."ctn / i'am mctcr \ 'II/un . Ttl t'slillla lt' tilt' dt',mUl('t' of thcoph-
yllilll', tlLt' IMlil"llf s a~t' 0I1lt 1 ('t m I1 I rn'll l l l nJ~ lltt'mpy Ilt't"tl to hI' conside-n-d. 1111' d t'am.Il('t"
iT<lhlt, IS-I J is then

CL ,. O.OA x 1.6 x 1.3 x 22 = 1.83 Vhr

~ olt, that till' d l'Milll('C' pc'r ki l ll,,~r.lIn ill till' fi-~l 'a r-oltlll( ~' is ildjmft"t l by ,. f"(1m of 1.6;
~llU Il~t' r cluldn-n (1 10 " Jl'un; of a~t·) art' adjllsh't l b~' a fador of 2.-1 (Tabh- IS--I ). 11K'S('
numbers an ' d ll'( ' In lIlt' values t'.\I)("'(1t'tl for atljll..lult'lIl ll<l-"I"t11l1l surf"l't, an-a (Chap. 15 ).
111t' fm.1ur 1.3 is all adjll stllll'l1t for ti ll' concurrent admmistratfon of plll'nuharhillil. wl.idl
ind u('t·s I ht'tJph~ ll i .1l-' mdahlllislll. VOIIIIIII" of distribution (0..5 I A ~ tunes \\l'i!':h t in L:~) is
II I.. Elimination rail' con..taut and ha lf-lift, an- tlu-n 0.17 hr " 1 ;I11t1 4.2 hr. n 'sl)("'(1i\1:,IJ',
Valt..,s of otln-r pertinent pa r.lIllt"ft' n; an" F ::: I , S ::: n.s.'>.
Skp 2 . EdillUltitlU (If f~If"t1l't1 Couccntmnon at 111111' of SfIJIIll/i'I/!.. U..i ll~ E'I . 6 . tln-
UI Il<'(' IIIr.t1iu lI al "):on is

" vimilar situation is dt'pk1t'tl ill Fi~. l ~ .

Slt'p 3 . C"'"/J(/n'ifJII oj Ob.~t'n"c'(/ mul F,J.'/1f't11'l1 G'l/In 'lItmtim•.s. Tltt' obwrved coue en-
ImtilJll (6.3 UlWI.) is tlm "(' tunes !!n'lllN than Ihat (" I)('t1t'tl (2.1 mWI .) 0 11 rlu- assum ption
Ihat lilt' illflln natillll un com phance. dO'>ilJ~ sclu-duh-, Silmplin!! history , ,U1d ,lsSily is ,11'(' 1-
mh' .
Slpp" . 1l" I · i.~iflll oj Parunwter \ 'fl/I/l'.~ . Appa n 'lllly, t'ithN volunu- o r dt'Mlllll't', or lxx h,
Ilt't'tls n -vision. Tln- flllt'stiollS an': \\1.it-h IlIw ? a ml llllw mild. ..hnultl it II(' n-si.St."tI? On('
OWTE~ 18 30'
,lppru,l('h Wtlllld lit, to ;J.'iSUIlll' that Ihl' volunu- term is corre ct and cha nge th t' value o f k
(o r CI.. Silll'(' k = CIJ\ ') iu th e equation ahovt' un til till' r ight side o f the equation is equal
tu 6.3. TI I1' flllln..~ill ~ vahu-s an- dcn-runned:

01 66 21
012 43
010 02
008 91

Thi s proccdun-, 1·" lIt",1 itrrntnm, is IIM't1 fn '(lut' ntly in di llil'al pharmat't,killl,tit-s. Xott' that
till' mo st lik('ly ".thw of k, tu exp lain all ohservation of 6.3 lIIW1.. is about 0.10 hr " I . a vaIm·
no t tuo t1ilTl'n 'nt fmlll tha t t-\llt 't·II'l1. U.!'i' !lr - I .
A similar 'lilalysis ('{mid Ill' l'm ril'll n ut a.ssllming: that tlu- value o f clearance is th ai
I'XI)('l1t'll ami tilt' ohst'l"\-atiulI is a n-sult of an nuexpected \ulu nl(' o f distn bution. In this
caw.

tJ-18J >t 20IV + tJ - l U >t 16 I V +

11 - 6 -1.83 >t 2.. /"1

By in-rat ion. tln- fonll..~i n~ vahn-s are t1d t'n nim'll:

VIU
11 21
20 40
40 5.7
00 04

Xnh' that a la 'll:I' ineTt',N' in \ ' is 1lt '<.'(· S'i.;II)· to account for the observed co ncentration.
Populat ion da ta on tl ll'llph yllillt' st.ow th ai ck-arance is much more variable (large r coe ff i-
('i1'1I1u f "'I riatiu n l tha n volunn-of distnhution. ACl:o rtlin gly. th e prudent decision is to adjust
d l'ar.IIlI'l· and nol \UIUIlII' of di strihutiou ill thi s p;ltil' nt.
1111' pr ocr - dun- wlll'n ·hy till' .....nsili..i t~· of the oh M.·r\"l'l1 measure ment to ch an~l's in
paramete-r \, tlllt's is ;1-~ st" SI; 'l 1 is <'11I1t ..: l .~ f'll-~ it i r lty tJ1wly,'fI.'f. It is accomplished h)' sp tt"llIati.
m lly suhs litlllinl!: various values for each par,III1l'ter, ill tum. int o till' appropn ate kim-tic
IIlIllll'l. Ti ll' l'()lll'l 'nlr.llioTl i, iUSI;'l1siti\"(' to a parameter when large d lalil!:l'S in Ihf' parameter
prodno- small ( h U1I!:I 'S in ('tm('('ntmtillll and the ('()n\"('rse. \\'", ('(md udl' from suc h an
;\u;lly>;is. anti fmm our 1!:1'1II'm l kunw ll'lll!:{' uf th e popu l;ltinll phann ucokiru-tics of theoph-
yllilll" thai dea r.tIll,(' (k • \') in this pat iell t is alx)1I1 1.1 Lzhr. The couceut ratu m is S('llsithl.'
to d l'Mmlu', ,I.'> onl y a small dl<lll~I' ill ils \';.I.h lt' ( U j to 1.1 LA Ir) p n xlu('('s a th f('l,·fllid
Ilif!l' n 'lIl'l' ill ohSl;'l"\l'll am ] expccted conccnt ranons.
Sh 'p .';. Ik OJm llU'lIfltltiflll f or :\iljfl ,~ t "U.'" t of IJos(/~e, 111t, maximum courent runon I'X-
Ilt'l:h 'll utte-r 11 11' d ow at ::!O:OO is thl' trnu~h \,,1111' u mcs e .. l · U , a value rk-riwd frmn tilt'
maximum limi ng: dl'lH d\"('l1 bv a fa<.1or u f (' - l · U . III this rase-, tht> b -st es tilllah' of the
maximum l'tml'l' l1tr.ltit;n is 21 II1WI.. 1111' roncentrution mll~{' ht,tW('t'1l a In lllF;h of 6 .3
mwL am i a pt·ak o f 2 1.0 IlIWI. n-uders concentrations outside till' recomnn-nded tlu-ra-
pcut ic .... tndow . A Tl-gill1ell of 6- lu m rl~' fh''ll dust'S lIIar not 1)(' practual he n-. A mort' Inw ml
st,luliulI is 10 s\\i ld l 10 a ('()Iltrn lll'll· n ·le;l<it' dl)s;l~(' form . 11)(' p ath-nt 's daily need is abo ut
400 111~. A 201l·m ~ dosl' w-rh an appropri ate controllcd -n-lease product. to Ix' taken twice-
d.ai ly, is Tt't'(lll1 l11t'ndt'l l hen'.
 CHAPTU 18

Ca.... 3 . l..-nlt, miC'ill. \l r . H.G ., a 2.1-)','ar -o ld , 51S LoR patie llt "itll a Rra m -lle gati, 'e
p nl' u n" m ia , "'a<; lx'inR treated ",ith Kenhunidn and ampicillin. Gen ta micin had
been WH'n "!Ii a ll Lv, infu"lion ( ~O mg) UH'r 45 m in e\"l'r)" ~ hr. Blood !'Hmp le !li "'l'rt"
ofJlah'l"'l1 j u..1 lx'fort" lind 30 mi n a Oc r th e end o f Ih l' fourth infu",ion 10 prt"" e lll
hnicilJ' a n d In evaluate h i", Ihl' rapJ', The Rl'n lamicin ('onl"nlralio n l; re port ed "'l'n.'
0... an d .j.9 ml¢ L The seru m cT('alin hw in lh l' patil'nt "'a '" 1,2 mwelL,
Ste p I. f:..';lIlIlli",. of Paramet er " allll,s , 1111' ('rt'alillillt· d t'arall('t' in thi s patit'nl, e-sri-
liMit'll Ir oin tIlt' patk-nt's a~l', \\l.-i~ht. ~l' m lt ' r , and Sl.'nllll en-atiuim- (T able 16-2), is 79
1II1Jmin (4.• l A ir ). TI ll' dt';mUll,(' of ~t 'lI t a lllidll is appm, inmh'(l 1Iy r-n-at iuine clearance
(Table- l b.- H. TIlt' \Ulunl(' of d btrihutinn i.. 12.1; L (0.22 IA R X ,').~ kg). 11 lt' t,!illlinatinll
ral t' l"fllll;tallt a mi half-lift' an- tlu-n (J.3' IIr - 1 illlcl l. 9 IIr. rtOSpt'l1i\'dy.
Sh'P 2. f: \'fj/lltJIiOFl of Er pf'("t'(/ Gllln 'IIlrntilJll' at Ti"U'., of SlI lII/ l/ili/!, . 111t' Sitm pltOS are
ubtahu-dunder slt'ady.stall' l1l11d itiollS h-' lll'l1t'll half-lift, = U) hr ), anti tilt' dm~ ls con-
sta ntly infll'i('ll tAl'r a )"It'riod of lilllt'. .t.'i min (f).' S hr ), appmat"lI i ll~ tilt" ha lf·lift' , 111t'
lntcnutttent in fus ion 11I11(11'1 ( El l' • . F :: J) is appmpriate 111t' concentrat ion just before
till' TIt"" inful;ioll j<; ('1ll1ivul('lit to tln- \OIIUt" at tht· end of tilt· dosill ~ fnte rcu l (st't' Fi~. 1&-1 ).
Thus. tilt' reuux-ntrations 3(J min aftN tilt' end of tilt' infusion (1.2.'i IIr aftN start i n~ til('
infllsill!l) anti at till' (·1It1 u f tln- IS-IIr iute-rvalcan II(' calcula ted fnun

C .. 80 11 - e - 0.37 )( 0 751 . e - 0 371,- 0.7051

4 .7 x 0.75 (1 _ e - 0 37 >< 9,

111t' t'Xlx'(il'l ll1ml'l'ntmtitllls art ' " .S ami 0,4 mWI., n' spt'l1i n ,ly ( ri~. I ~ I.
Stt'p 3. C"mlHJri~m. of 0/,-~( ·,.'t:4 'd ami t:X/II'(1I'(! COIl n'IIlml/O/IS. Sill('(' tilt' nbst"rvt 'l! a nd
('xllt'l1 ('l1 values a n ' \i rtually tilt' satm-, tln- est nnatr-d pa rault'lt',. values a rt' i\.s"'Ulllt'l l to
apply ttl tllis I'alit'nf,
<:aq' .j. PllrtwlHlrlJila l. \ In, J.p., an H2-J·t·a r-o lll, 5.'>-10." paUl' n t wtth K M' i7.urt"
d iserder, has bceu n."('('hing 100 lOR o r plll'nobarbila l at lx-dtiml' Ior J·t'an . Sh l'
IUmt'<i into a nursing homl' o n Fl'hn.larJ· 17 a Ol' r ha \-in" a M"iz u n.' on thl' I Sth in
ber own Kp;lrt ml· n t. On th e mo mi ng o f Fl'h rull r~.. IS , ",hl' 'mel Kb lond sample taken,
"hi('b showl'<i a Illa "lma phl·nohllrhihll ('oll('('ntrntinn o f 12 mWI.. lI er p h' 1>ician
Increa sed h..-r n iglltlJ' dose 10 200 mR b ta rt l'<i0 11 the 181h), On F,'bn.lary· 28 a llo lht'r
b lond !'Hmp ll' wa-o; oh ta lned; a l'OlK'l'n lratio n o r 26 ml¢L wa.s th en reported .
Sh'p I. t:~li mllti(m of Parameter \ 'nl/f('.~ . Clt'a r,lIIl1' and \ 1 11111\1(' (fm lll Tubk- 1.')--1) a n'
('l;tiTlHlIt'l! to II(' U.20 IA n OIm1 3(J L, Tt'spt't1in ,ly, 111t' Tt'sliitin l' elimination rateconsta nt
am i lIalf-1if(' \ 111111 ' S lin ' 0 .1I0fl' hr - I und J(H lIT. F allll S a rt' equal to 1.0.
Stt'Jl 2. f:~t i "'ati"'l IIf f :X,I1"f'1cd Cm lH'lI l m l imn (It Ti mes of Snm,xi"r!.. It is uncertain
wht't h('r ti lt' first l'(III('l' ntmtillll is a ~ h'iltly.sta t(· \ 1111l1' , a.. tilt" t'tll}("f'ntm!ioll o btailll'(l 10
l b ys (2·10 IIr) liltN is lIIort' th all ,,\i('l' tilt" first vallit' , (,\'('n w11t'1l o nly 2..'5 (,qt!'t1t'll hal f·
1i\l'S han' t'lapst'(I, If th t' first hatlllt'l'n a slt'iUly.stal (' va hlt', tlU' l"fllll'('llt ratio nl';llk-lllat('l1
for lhi ~ fim t' is

F · S ·Dose lOOmg
qtl! . Cl . t .. 0.2 V hr ' 24 hr .. 21 mg/l

A sh 'illly-sta!t ' l"flllstallt-ra tl' illfu.sinn I1Itl( lt'ln m~' lit, 1ISl.'1I II('t.l.IIst, of tht' short dnsill~ in -
h' f'\~tl (I day) rdatin' to the half-Iif(' (4 days ) OIlltl llt'l ' lUst' tht ' hlll(l(l is ~tlll p it'l l ll('ar tilt"
mid point uf t ht' dosing illlt'l'\'a l. 111t' '\("t,lIld ]t...·t'! (~J Il II(' ('lleulalt'(l fm m a hol lIS plll.s
l"flllsta llt· m!t' infll ",ioll IIItltlt.J,
C HAPT E ~ J8 307

1 day
200 mg/doy x 24 hr
0.2 V h, (I
'" 36 mg/ l

Step .1. Cm/I/Hl n .wlII of Ohwn:('ll (I/UI F.x} H'Cktl Concentrations. Clt'arly, tlw p,atil'lIfs
oh"I'I"\ ·( '(1\ alut,s an' well lx-low tilt' p n -dicn-d oucs. Hevision of Illln lllwtt'r values is ill order .
Sh'p 4. Hl'l' h io ll oj Parameter \ 't/l l/('.f . As neit her ccuc'e nt ratiou is a steady-state vahte,
nOll-.slead y-"talt· lIll'tl.IKI" must 11(' U\("(1. Two appnJlrodw" nught 1)(" constdered . First. tilt"
lllCKll'1alKln ' lIl i ~l. t 1)(· 1l<;(,( 1.
I f tilt' vuhn- on ' h.t~ nTlly m inn r ' ;'lria hilif)' wi thin Ill(' adult population. It'' is IIJ(' case for
plu-nob arbital, tln-n the vahn- of d l'ilr'll!("(' can lx- calculated by iteration as in C l<it' 2. 11Il'
d t·.ar.lIll'l' \<111Il' nbtai l1l'tl is U..1 IJhr .
1\ llutl lt'r a p p n- MI·" 1'(11111''' fru lII ll lil" " ha lallt'(' ('(" wt"pts. TI lt' lid ra te of dlilll!!:l ' o f d nJ~
in tln- IKKly (\' . dGMO is IIIl' d ilTen ' nl,(-' 1)('l wft'n the rail'S in (F . S . v.. ~"d'( ) and ou t
(G/ • • C ), that is

de F - S 'Dose _ CL .C
V · di = ,
III t, mdit iollS in which the couceutranou d Ja n~es from one value. C (l I )' 10 another C (12),
rl e Mt can lit, apprll';illl<ltt, 1 by ( C (t ~) - C(t. ))/( '~ - I . ) ami G I,:,' (C(, . ) + C(' 2»12. 11lt"
l'(I" .ltioTl 1111'11 !)( '('(mi I'S

q'd) := F · S · Dose + CL. 1q lJl +

'11 t 2
On n 'a rran ~t ·n l(' n l .

F· 5 . 00•• _ V · Ig',1- g 'llI

CL =- t 1'2 'I!
ICI'11 + C(r,1I
2

Suhstitut ion uf III(' vnim-s fur t'al'" ~Ylll bul n il tilt" right sit!t· of Ilw t'(l" alioll ~n's

200 30 X (26 - 12)

Ct . 24 - (240 - 01 .. 0.35 Vhr
(12 + 26)
2

a '~I I ..(, r-krwtotlu- ('~li m alt' fm lll rho rirst mr-thod. In hoth cases, all t·slimatt· o f \ ' 11;111 In
1)(' IIst'(l. TIll" st"(' IJI( l lIwll.IKI is all «pp r odmutlon. with (ul1sidl' l"dblt> errur whe n e (f ] ) a nd
(.'(I ~ ) an' d ust' til ('a d l orln-r ( (C ( f ~ ) - CU, ))1(1a - t I ) ca u then 1m.....' a high error] ur wlu-n
e (f 1) ami Cl t 2 ) an' far apa rt [(C(, . ) + C(t ~ ) /2 is Ilu-u nol a ~I K )( 1 t"Slimak of l!J(' a'·('r.l~t·
\'a lut, o f C dll rill~ tilt' Interval ]. III !-:t'lIl'raJ. tilt> U('ra li\l-' lIlt'tht KI is pre fem-d
30. CHA.PTE ~ 18

Otllt'T appnl;\t·!lI·San' 1I0W availabh- tneuupu ter pn'h'T".ulIs th at tucorponue population

mean and \~lriahi l ily iuformunou ill ti ll' pa r.lIlldt·r values ami tlu- charact eri stics o f ti,e
kinenc 1ll11l,!t'! ll-S \\l 'lI itS tllC' thud s) of salll pli ll~ and dosi ll~ history .
Step 5. Ik o mlllwmliltiorl f or Mljusl" wI/t II! lJO-\fl1!.('. If ti lt, , bny , Ill\(' of 200 Ill~ is {1111-
nnned, a sh'atly-sta h'I't llll'('n ITitlillll of 2k IllWI. is t'X!'ll,'(11'(1(F · S . [) ' W'! t . Cl •. Cl . "" 0.3
lA,r). :\ d;li l~' duS!.' o[ 11M) 1l1 ~ tlu-u ~ \'l'S a (:u rn'spol1t l i ll~ vu hn- of 1-1 mWJ .. Bolh " a1I1!'S
an ' within tlu- therapeutic window. II S('(' TI\S ap p ropri ate In conchnk- th ai th e patient has
a Il i~l lt'r (50 %) dt'a nllll't' than ('Xpt'(:h '( t itlid th 'll silt' hat! ht't'u compltant be-Fore admission
to till' nu r.;ill~ horne. :\ t1t'l;sioll IInw is Ilt't't lt't l o n li lt" pmpe.'r d INlV;e.', Bt't.'llll ~' silt' had 11
wtz un- O il IUO mWtL1Y, a daily tlllS(' be-twr-eu 1511 a lltI2(J( ) m v; see-ms appropriate.
:\rv;u;,h ly, ill ;111 four o f lilt' Iln'C'('t lin v; exaurph-s, d nSlIV;I' ('(mid have ht"('n ;jtlj llslt'tl so ld y
hy t ilralinv; to li lt' d Tt'C'ts observed. :\ poinl in fll\ u r o f ('(lIl(l ' n lm lio n measun-meut is t ha i
an ;I.\StosSIllI'u l could be.' mlKle.' ;1.\ to w hy tm:it:ity or a b <.o k o f I"lTe.'(1 occur red. T!le."St' mea -
sun -ments ;jlsu pe -rmitt ed fadll" lind rapid es ttmatiun (If tln- pal it'nt' s dOSlIV;t' n 't lu irc. ' lIlt' n l ,
whid l o the.' I'\\iS(' mi v;hl han ' required a (,(lIlsid t' mh lt, d t1!:r('t ' o f readjustment from o hS('ninv;
t!le.' e fTt't.1 s alone. 111t' fillt'm'ss o f tilt' ;lIljllsl lll(' lIt \ \1l-\ a! SC I 11111( '11 v;n 'a tN wnh tln- plasma
concent rat ion data than it \\lluld han ' ht '('11 \\; tho u l tlu-m .

STUDY PRDBUMS
(Answers to Study Pro ble ms are in Appendix II .)
I . Lisl and hrit'tly <il,..t:ri h... t ilt· cri teria for pt 'rfonnillV; dmv;t'o Jl('(' n l ra lio n lIlunito rin g ami
llppl~i ll V; t a ~t'l l"tllll"t'ut mt ioll Sl m It'K\,.
2 . An s,,>-\.;V;. H -Yl'a r-nld f('m alt' patil'nl is r('t."t'i\ i nv; 120-1IlV; dust's of V;t' lIla m idn in sho rt-
n-rrn. constau t-rat e infusions ("'l' r 4.'> lIlilll'\l' ry " h r. TI ll' patlent has a serum ('r('ali ninc
of 1.2 IllWd L. Plusuia s amples wl'n' ohlaiJu't l jm t ht 'fort, an d 4,') m in afh-r tln- eud of
tilt' fou rth d ust ,.
a . E sl im ate ti lt' \'alm 's o f clearunce, volunu- o f t!isiribillion. ami half-lift' l·l pt't.1t't l ill
Ihi s palit'nt.
h. E sli lllalt ' til(' ~t 'll t a lltid n ("t Ill("t;' n ITil!inll ill p l,I-' 1l1<1 t'XI:N"t1t"t! " I t,,,t'l i o f tlu- IW1I sam-
plin~ uuu-s.
3 . The plasma ("t mn' lIl m tio ll\ a t t ht , tunes n f 'i;lIl1 pl i ll~ in tilt' p;ll it'lIl in problem 2: \\ l 'f\ '
2.5 ami , .2 IIlWI.. rt'sl:N't1 in,ly.
u. Usin g Iln-se I"tJll('(' ntmt iu lls, n-,1St· lilt' tost im a tt"'S o f d t';ITiUlt1.' , vohmn- o f dist ribution,
a m i h al f-lift' in this pa tient.
h . Is il pos sihlt' to adj ust lht' doS(' (t Slllllt') to kt't,p l ilt' t n ltlv;h <~ ltl("t ' II I Tillinn 1:N' lnW 2:
1Il ~I. a nti t ilt' I:N'a k ill:Nl1."(' I) Ill~ L?
4. ( :i\'('11 Ihl' IIsu,,1 para nlt'ft'r values fur theophvlltm- (T ab lt' 1~ I, p rovtdea pharma-
("tl\.;il wti e inn-rp n -tati on fo r ench of tln- f(l llt l1.\i n~ Ih t't lphyll illt' ("tlll(1.· nt mtiu llS, u h laillt'tl
ill Illrt 't, d ifTt'rt'nl adult patu-uts dlirill V; a n in fusio n o f ;u nillop hy llillt, a l a lu ns tallt mi l'
o f 'Pi lIlv;fhrllv;. :Xu Iht 't Jp hyllillt' W ,l-' p rc. 'S(' lIt in Ilw hCM: ly lit tilt' st art o f tilt' infusion.
In yo ur in te'rpn't al ions ind nt!t' lM: llh a l'tl m parisc lll o f o h\(' I'\"('t1 and t" I:N't.1t't l pl;I-\ lIlli
t"t JIII1.'n t m t i(ms a nd a n t'sl imatioll o f tilt' \'a llltoso f d t'ar, UI("t' alit! half-lift' in t'lIl'lI pa til'nt .
'-\ SSlll llt' Ih at tilt' H IIUlIlt, o f tl ht rilmlinn (lj ft'rJk~) is tilt' SlUl\t' in all thrt't, p at it"llls a m i
Ih a l t llt'Y a n' lJC m s lllokin~. ht 'il1thy ad u lt... t" ('('pt fo r Iht'ir ;l\ l lu n al it' ("t )l\t!iliClIl.
TOW CA I'V&'M IHfOPH'o'UNf
~ C(lr'-C £N1.....1lQN
P" lf"'l lI>oo.n _"""""'1 1""91\J

,
I

3
3
16
30
35
18
6
CHAPTU 18

5 . Mr. ,".J. i", U 70-1.:~. f)'~" l·ll r ..o ld u ",th m utk llalit'nt "''''ith t"lJU~l, ..th l· cu n litu." Iall-
ure .He i....tarted on llm ino l)h, lIine Illh ld.. orally a nd hn'" 1l 1)lll"'lIIll llll'·n p l., 'lIillt..
cnn~'nlrnti on mea..u rcd a .. noted in T able 11t-."i, Il l' ",nlOl.l·'" 2 pill'll." of ci~a­
reues M d ll" ,

...
J- '
".
1800
22 00
1Wf WHENI'V.Y,O,A ~
lSOIl' "","",OM

14
~Al 0051: I"'{II

400
200
J_ 2 8 00
1200
'"
10 300
300
1800 "
PIosmo $ample 00I0,r«!
C-18mg/1

a . E",li malt · tln- \~tI Ul '''' Ill' d ,'am llt't·. volunu- Ill' di \lrihuliulI . alltl half· lifi- t·\pt"l·lt-d fur
tllt"llphyl1int· ill Ihi'" patn-nt .
h . Est imatt· lilt" t'lIIt" 'IIlra tioll (,'[M'dt...1at III(' timt' of sm ll p l i ll ~.
c. Cmnpan' tilt' llh~ · I'"'''t ... 1and t·",limatt..l concr-ntmttons.
d. Stall' w"i{·h pamll1t·!t·!"'i y' lll thilli. IIt"l... 1 to 110.' rt",i ~ ...1 am i hy how mILl'll In ;U"'ltllli
for am' di lTt·n:·m ..·IIO.·hn...-u 1)1)\('1'\"(...1 and {·s lilllall... 1 (, mt1·lll mlitm",.
f). ~(r, D ,\'·". a r.H' , 'l·" r -o ld . 7".L.~. a lco ho lic, l·p ilt.·I)tie l),ltlic n t. h a ", been ta L.ill";
phl·noharhih. 1 (2(M) IU"; at bedtbue } fu r 3 , e lln. lie lu"" been Free of ~' b un'"
for HI Il'a ",1 1 , 'c ur. lie "'Il.'" lIt1miHlod 10 the ho,,"pilal 011 Ja n ua ry' 10 " ilh a hu. iH
and general cemral n en nu", ",)·..tern dep re..",ion. without KIt."I.hol on h i", hn·Kth.
A p la sme phl'noharh i ta l cnl1~'nl nalion o f 51) m Wl- wa ", nu.·a ..ured in a hlot"1
sam p le drawn at I I :Of) of th a t tla , '. nil' tlru~ you" discontinued (i n el u d i n ~ no
dO"l' 011 Jllmuu." 10). a nd a no ll ll'r hlot"1 "'iImpll' Wit'" nhlltinl'l l un Jllnullry' 16 lit
10 :00 to determine if Ih e plltil'nt Wit.. metllholi zi n~ the lim", more ~.Iowl,· t ha n
espected, a ", the IJ.ldil· ut hacl ..i~n", of h epatic C'irTIUl..j ",. nit, "l"("Imd concent ra-
tion wa", 16 mWI..
a. E\'aluah' tilt' d ata in tilt' ~ 'l jl lt' ll tial lll a ll llt ' r rt"tltlt's!t"'! in probk-m 5 .
h. ( ;i\l' 1l Ih" l d" ,m Ult"l' is tuut-]! mon- variahlt· tha n \ll lUIIIl' uf t1istrihuliun (T" hlt·
1:1--2), ",talt· tilt' li}.:" I" {~Il l~' Ilf 11 11' Ilb~ 'I'\·lIliOlI'" 11M' I,· ami prm;t1t· a n "'''llllltllt'mblilill
for hi", future ituti t·pilt·plit..· tllt'mpy with plwlIllharhital.
r • ~h . K.I>•• a 10-1.:,;. &I-'l·a r . .o ld we.. adm itted to the hm'l)il a l a t 13 :30 nil April n
ht.'<-"UU"l· of "'hol1nl·.... of hn'nth lind \\hl'l'7.in~, ('.on~l·",t h l· C'llrdillC' fa il ure a nd
a ..lhma Wl'n' confirmed h,· clinica l "" m p to m .., To tn'a t tilt, Il..thma, ",hl' WII'"
nd rnini "'len'<l 300 m,; of a m inop h , 'lIinl' in t nl\ l·nou",I,· 11.1 U :OO. a n d a n in fu",io n
of 30 m whr " ,a", begu n immt.· lliatd" . At 18:00 un Ap ri l 10 . Kpla ..m n "-Km p lt' wa\
ohla int'd, TIll' t1ll·ol)h,.lIilll· l"IJIIl't'nlration ",",'a .. n'pm1tod In he 20 IIlWIH(hi AI)ril
II . h c r ph, ",idan ..wilchf.'C:1 hl'r to o rnllhe nll)" , TIlt' infu",ioll WM'" di ~"Imlinut'll
a l 9 :00. a nd the fint o r al do"'e (200 m it l'H'ry' f) lt d W lt\ "'~ H'n Iii 13:00. E\ a luatl'
Ihi", C'a~' u", i n ~ lilt' 5 ",I("p'" recommended in thl' tc ).1.
 Section V

SELECTED TOPICS
 · : 19

DISTRIBUTION KINETICS

OIJlCTIVIS
The reodel' will be able 10:
I $late why the oeecoeponeeot model is sometimes inadequate ro descnbe kinetic evenl$
within the body.
2 . Compare !he scm olrwo escceenscls wirh the compartment model lor leprMel'lling pImmo
concentJolion dolo showing dislribuhon kinetics ,
3 . E~imole clearance and the holf~ile 01 the phose ossooced with the mojoflly 01 e1iminotlOO
gMtn plasma concenlrali()n-lime dota 01 a drug showing distribution lineta.
4 , Define 000 8slimofe the distfloollOO pc-ceeers: ,nilial diluliOn volume lV,1. volume during
the terminal phose IV), ood volume 01 disll'iburion 01 sleOOy slale IVJ.
5. Describe the impocl cl disll'ib..lion kine/ics on the inlerptetotion of plasma concentratIOn"
hme 0010 follov.-ing administration 01 a Single dose.
6. E-.pIoin the inRuence of distribution kinetics and duration 01 odminiSlfolion on the tilT'le"
COUl1e$ of eeeeeeeceeo in pIo$lTlO and amount in ussce during and ofler stopping a coo-
slont1ole infusion.
7 Descnbe how dislribuliOfl kinelo ,nRuences the Ruetvotions of p1asmo and lissue Ieveb with
lime during a mulriple-dose regimen .
8 . Explain how dislribulion kinetics con inRuence the interpretation of pImma concenlrolion"
lime dolo and Iefmincl half·Me when clearance is cnered

TIlt" first fuur sect ions cover mo sl of tilt' Iundunn-utals o f pharmaco km ct jcs. Section Fin '
110 ..... exp ands on ~ lt"l1t'(l topi('S: it l)('!Q lls wnh chapters 0 11 dut nbut ion kine tics lind pbur-
m'll."lllo¢c "-'SpOIl<;(', Su b<;('ll lll·nt chapters deal ..\ith lI11'talxllitt· ki'll'tics . tiose anti tiuu-
t1l'Pl·llllt·nd l·s. turnove r ("l)IJ('t' pts and tlialysis. T hese topics du nut h uild o n l·a(:1. utlll'r ll-S
extcusivcly Il.\ do Illl' p n ....-ious topics . ~(Jta"ll' exception s to this stat e me nt art:' fOllnd in
ap plica tion s o f dis tribution kin et ic concepts in the chapters 111\ p h'lrJlIlll'llhlh'il' "-·sl)lm....·.
turnover coucepes. anti di lll~'!i i s ,
Purt m~i n ~ the 1)lI(!y as a s i n~lt· ('llmpart lllt'ni is uppmprtate- for ('stablishing: 11ll' fU IllI'I-
men tal prin ci ples o f phanuacokincncs bill is ;111 inaccurate re presentation uf t....ents Ihal
follow d rug udmfubtratlou. A I ~l-\ k' assumption o f lilt" l'(llIn'pl of a one-compa rt ment n 'p-
n-sentuho n of di stribution is that equilibranon of dOl~ between ttssues and hll)lI(! II('\'u rs
spullla llt'lJllsly. I II (('ali!)-'. dtst rtbnuou lakt·s tune. 111l' time- required depends 0 11 tissiu-
I)(·rfusioll , I)(' mll'ahilil)' characn-rtstlcs of liss\It· membranes for dmg:. and its partitiolli ll ~
1)('1\\'1 '('11 tissues am i blood (C hap. 10). lj.,trIo rin,gdi stribution kim-tics is n.·a.';oua blt· ...., lo ll,g
a.s tILl' error incurn-d is al'('(·ptahl(-. Th is error la -couu-s un:w('t.· ptahll· when Ihl' (JIIt' -<''l''lI-
partmout represcntanon fails Iu adl'( lualdy e xplain uh ....-rvurious foUowin/ot t1 m~ atl millis·

313
". OlSTillllJTlON 'TICS (l-W'TEi IQ

tra lion; tll( ' f(' is a { lall~('r o f S i~lifk'all l mis iuterpn-tation of tlu - nhSt: r" atio!ls; and major
di scn-pancies rx'eu r i ll tilt· (-'l Je ulalioll of dnl~ t1osa~e . slid , sit uations a rc most Iil.:d y 10
a rio;(' whe-n ('i t l wf substantial " IIlI UlIl ! S an' chminntedor « 'SpO Ils(' O(:l:Urs before di strihution
equilibrnuu is ad li("\'t'(1. Thts d laph' r deals wit h the pharmacokuu-tic n lllW( l lIl ' llt't' of di s-
tnhutiou knu-tk-s. TIlt' 11I11)<ld o f di stribution ki lld k 'S 0 11 plJann al·'OI (~ t' « 'SpOilS<.' is dealt
with ill III(' m-xt cbapn-r. I'lm rm al1I!Ilj.,rie Ht·sl)(IIlSt.·,

EVIDENCE OF DISTRIBUTION KINETICS

E, idt,!It't, of t1istrilm!iun kindit's is IIsually inferred (m ill an early rap id ch-clhn - in p];lsm a
(h lclIMll ('U lI( 't 'lll ral io li (oUtl\\; u j,t an i s . bolu s d oS(' ; \\"1lt"1I littll' d m ~ has be en elim ina ted ,
am i fro m tilt' ra pid o nst't a mi t1t'(:lilJ(' in Ihe pharll\;ll·oloJ.~il- t,lTt'<.1 of sonn- dnlhry> d UrillP;
Ihis ..arly phase. Dal a in Fip;. 19-1 , which show tjn- rmu-ent runou of thtopc-ntal in various
ussue-s aflN un i.v. ho llis d ust, IIf this preoperative p;(' Ilt'ral ,t!ll'slhdk to a t!op;, I)m..ide
din-ct ('\i tlt'lll't' of d istribulion ki m -t ics . Thiopental is u sm all, h i~h ly lipid , sc,lublt' t1 n lp; for
whkh d ist rih llliOlI in tn t'sw nti <tlly ull ttssue-s is pt' rfusio ll ratl'·l im ilt'(l. l1lt' rr-sults see-n \\ilt.
Ihis d m p; an - the n-fen- I)llitw dl o f IhoS(' ohst 'r"'t'(l u ilh lIlany other sl1lall lipop hi lit· d rugs .
:\nt il't· rhat Ih ie l!)('nla.l in liver , a hip;hly pt'rfust'(l organ, n-aches d isl rih lliion t'(llIilib rilllll
wit h Ih al in plasma hy .5 m in (the fi rst Obst' 1'\11lio u), and the-reafter, the dt"C:lillt' ill Iiver
1),;1I1(lIt,ls that ill pl'L\llI a. Tln- Sll lllt' hold s true in ot hl' r h ip;hly perfuv-d ttssues. illdud inp;
bruni <tlld kielrlt') 'S.
Ht1.l ist rib utio n (If thillllt'ulill from wt,lI-rl(: rfuo;("tl ttss ues 10 It'ss wt:ll-pt.'rfu '\t-d tissue-s, sud l
;Ls muscle- and fat, p rim arily accounts for tln- subsequent dt'd im' in plasm a l,(lIlt't'n lmtion
(lwr tjn - Ill'" 3 hr: It'ss than 20% of rlu- d oSt, is eliuuuan-d dllrillP; thi s period. Dill' to a
comlnnunon of poo r pt'rfusion am i hip;h partiliollinp;. t'\'(' 11 hy 3 hr distrlbuno n t'f jllilih rilllll
in adi pu'\t· tiss\lt, I..l.'> nol 11('(1'11 I'stahlisllt"tl. Ana.l)'Sis of the sitn atio n Indtcat es that th is does
nol occu r for SC,,\'('ml lllon ' hours. at which tune tilt' lIlajority of thiopental n'maini ng is in
fat. RI'<.·all: TIlt' WI'alt'r til(' 1),;lrti liol\ of a d m g illto fal, (I T into ,lll~' tiSSU(' , the longt'r is t il l '
lillll' required 10 ad lil'\'t" dt srn buuon e-quilibri um (Chap. 10). 1I1J\\'l;' \'l;' r, nnly if the ap -

100
-a."
§.
c 50 Fat
0
•\
~
~
u
•
c
0 Liver
'-'
;;; --------==::: Muscle

'--==
c
~
~
0
•
"
~

6
Plasma
0 2 3 3.5
Hours
. " l(. "I..
19- 1. ...·u" I....:-ontl""I(· 1'''14 " f tI..• e'''' I(~'U( rail" " .,( tl,i"I',·" t.J ill "",;. " " 11\_""" "".1 <m" (e~ "' ,n..1 lir...)
f,~1. ",-j,,~ "n i ,·, 1..,1,.. ,Ie...• " f 2.') "'''''''II: In " ,1.11(. :\. 0(.' tl..· ,~..~ ';<t. ,mel f;all " f lhir' '''''I;aI in II..· " ,·lI'I', ·rru<t..1
h' , ue" <0-, 1(.. h" 'r l .tn, 1 in l"al' mu« '!c' h'''M·. :HI,·r.1 hr " "M'" "f II..· ,Iml: n·m..",i" lt in tl... I...." , i' in .. 101" ......
h.., ,,,- < I "'Will: ., ~ I J.l" .. olt1<lt ). I H,..Irawn fmln Bn ..I..-. B B" 11oo·""lo-ilO. E.. " rMI Mark L : 11M' rolle' "flnly fal
ill li''' ili'' l: II..· 'I" . . d ir'" " f ",,1it," "f l !tit, ,, .. ,laI. J 11"lOu""ul t:, I" TIM·r.. 105A21-42ti. 1 ~,)2 , C Willi""" &
Willin, ( l!l'i2U
CHAP1E R rv DlS1R18UTION 1(lNf1l(S 31S

pa n 'nl ' "olumt' of di slribulion of a lissnl' (}\." . \ 'r ) is a major fmd iclll of tlw total volmne
u f tlislrihutioll tluc's IIplakl' Into that tiSMW suhstantially afTrt1: (' W il ls wtthln plasma. With
thiopt -ntill. whk-h I. 'l~ an atl ipmt '.It )-p lll~ lU<I pa rt ttion loclt,fljdt'nt of 10. fat (Il l 2 lA g) (OC lTl-
slitllh-s appmxima ldy -10q. of tht' total , u lu t1l{, of di stribut ion (2.3 lA g). Al'(ocJrtlingly, tlw
plol'llla euuenr ranon o f Illinpt'l\la! not (lilly falls markedly , h ilt drstributton takes many
hou rs. For orlu-rdrugs. disrribunou may tak(' ('\1m longer if parti tioni ng int o tissues is mo re
t'xlt'llsiH' th an for thiupl·ntal. In routras t, distrihution is complete wi thin 30 min after
adm inislral illli I,f I l l t~)p hy l1i llt · (Fig. 3-1l. Eitllt' r t ht~lphyll ilw dcit·s nol ent er poorl~· Iwr-
fllS(~ 1 tiSSI\t"S «r if it dCIt's ti lt' partition {"(1t'fTicit'ltts an ' ' ·t·f)" low . It is i lll llt lS..~ ih l(. to t1istiltguish
IIt'h'·I'l'1I tlww 1'0.'.(1 !ltlssihi lilil's hy IIlt·a.su ring tht~ 'phyl1irlt' only in plasma, ilS t...a-nts lu-re
Illay poorl y n ,lIt'(1: th ost' that might occur elsewhere.

INTRAVENOUS BOLUS DOSE

Presentation af Data
Sum of EXIMllll"n t ia l Terms. TIlt" t'arly rapid and subsequent s1m..,.r t1t'('lillt' in tln-
1'I.lsma {"( lIlt"l'nlralion o f axpiriu in an imlhi dn al slIbjt'(1: follos' ing a f).')O-mg l.v. bolu s tloS("
(Fig. 19-2) is t~lli(";ll of many dnt~s , Had uo s amples 11t't'n taken dllri ll ~ tilt' fin-t 10 m in,
tilt' n-munalltm-ar d,'("liTW of till' ph sma eonceutratinu when plot ted on \(·milugarith mit·
~ra p l. pap!"r would ha \"(' lx-eu cha ract eri zed by a mnuoexponential equation. and one-
l'Ulllpa rt llwllt d is!lt)sit ioll ehar.tt"!t' rislil'S would ha" " bee n apphcd to asp irin. Rl'l..t1I: The
llltlll(It'\ !ltlllt'uti ,,! t" lliatio n is (;(0 ) 't, -b, when- k is tile rate consta nt with an assudalt'tl
half-lift', gin-II hy o .69:lIk , alltl (;( 0 ) is till" ant icipated initial pl'lSlllil d rug conc entration.
~ \"I"n us tilt' iult'n:"pt nil tilt' plasma concentration axis ",11t'1l the line is ext rapola ted b ack
tu ttnu - I.NO . Fur aspiri n k is {) .o.')() m in - I, tilt' l'Clfn'sf>l. lIId ing hal l- life is 1-1 min , am i (;( 0 )
is 3.1 mWI.. C:()i ll~ further. tIlt' \Ulu nlt' uf drstnbunon [[){)S('/C(Ol] is 20 L anti clearance
(I.. . \ ') is ().~ I/Illill.
Xotit'C , th at tln- t';lrly pt.lsnm tUllt'l'lltmtions lin' higlwr than those anti cipated hy ha('k
t'xtr;llltliat ion of tilt' tenniual slolX' urn ] th at tht' earlie r the tiun-, the grt"illt' r is tilt' di ffer-
euce. \ \1It'l\ ti lt' d iITt'n-lIl, " al t·'Il,.. I, sample nnn- is pluth 'll 01 1 Ihe salllt' gr aph. 0111 1111.'
tlifTt'fl'lIt'l' \"ulnt's f,,11 till auuther sl mi~h t line , which ca n he characn-nzed hy " 1Il 0 1lC1t' X'

Hit. 19-2. \\110·" ,ji'l'la~1 ...1 ...·mi l"ptitlnll it-..J~".

tl.., raJ l ill II... 1',,",111,;1. n ll" 't'ulrltIi" " "f ;Bpi ri" i. ini-
Iiall~· I"lIpi.t h.ll Ih.·" s1o...., aflo" all i.v. 1".1.., .1..... ur
·· fi,,'j() m!t I" a .ul>jt'(1. n .., .l.'(~il '" ill , ... I('t'l'Ir-..lit"l

",\. \'''1
··, , ,
.,

\ G;e - ~Jl
..
((...."....1I"linh ) . ..11 I,..dlar-......"ti,,,l lo;.' tI,,· .um cor
I,." ..'I" ....."liltI h'm.., C ,r - ~ I' 1•••• 1al lt l C~ - ""
(--- ) \ I ' 'WI-- .5..511 ),1l. (R... lra"'l' (rum R" ",t.,..I.
),1 . a... 1 Hit,.,4man, S.: 1'I'am"....ld ' lt 1i<... Ill".'tot;oi .
"']~ii<' .,.1 a" d sallt., ii<' "" d ..rlo' r inl ra.. '.".,,~ ...1_
m ;nhtl>llitlt' in mal]_ J- 1'I". n n Sli . 5:":1313- 1319.
I!«>'t.)

/~.
G1e - ~ , I \
.
o 20 40 60
Minutes
316 D1SmlUTJON I(INETICS OWTE i lQ

(lIiIlI'uti,,1 t'<IUilliu ll . B (lI ~ - ut . WIWH ' U is lilt' d, '<.'a)" rate constant ami 8 (0 ) is the ro rre-
spc mdi ll~ 1~' n Hi "lt' Intercept. FelT a-spirin. u :::: 11.2.1 min - I. '1/2
= :1 0 min. aIll 1 8 (O) =
fi j lllWI..
Bt'(,UlS(' all tilt" plasma concentranons at tilt' later tunes ("lU I 1)(· fiUt '!;II') ' one equation,
G(0 1f' - lr a nd h"'{',IlIs(' a t Ihr- earlier tunes. all tilt' di ffert'lll't' values can 1)(· fill('(1hy allotlwr
l'flll<ltiu li. B(Oj(' - "', it follows tilat tln- eunn- pl...\ ma dnl ~ concentration (el n 'NUS time
dat a ca n hI' fi UNI hy lilt' .\ 11111 of ti lt'S(' h \1) (·1.lx)IIt·lllial terms. That is

C - 8(Ole - '" + qOle- t ,

For (''(a mplc>, tilt' h it' xpo lll' lIlia ll'(jllalio n C =fii'c, -U 2.1r + 31.· - uc"",. , WIWH' t is thl H.' in
minuu-s. ad c"IIIlOlIt· ly t1c' MTiht ' s till' d c'(.'lillt· in tht· pL,sma aspt nn (''OIlI '(' n t mtio !l follo..\in~ a
fi.5U- IlI~ holus do...-. SOllwIi IlIl"S. when lISi n~ this difTe n ·lJ("t· p r oced ure. 1:1I0\\1l commonly
,l~ llit' lIu 1/'ot! (If n ',dl llUlk a slim of three and ol't'iLsiollally four esponennal te n us is n '-
quin-dto ad ('t lua h ·l)' fil tln- nh...·.....a-d coucentranou-nnu- dat a. SiUl't' III(' pri ll(.iplt'5 in ap-
pma('hin~ Sil l'll data an" tln- s.:IIIW us those usedto aual~7.t· and Interpret I··..onts dt "l'ril x'tl
h)' a hil·xlllllll'ntial l'(lllati on . 0 111)' tht' simpler {'il>;(' is ('tlllsidt' f('t i further ill Ilris hook.
Tn fad litall' th l' di M'llssioll a more uniform '....1of s\l l1lxlls is lll'('(I(.'(1. Hur ln-r than us i ll~
IIII' difTI"f('1l1 S~l11bols u um ] k, tilt· ~l'III· n d s)'mixli j. is uS('(! to dellole till' 1·.' Jlllllt·nli,,1
ux·fTidt·1l1. TIlliS, Etl . I rau he rew ritten ,I.'
2

when- the sllbM'ripts I and 2 n-fer to til{' first ami Sl't.'tllld exponential te n us fl'slx'(1ivl'1y,
am i C. and C 2 refer to tilt' l't l rrl'sllll ll( li ll ~ ze-ro-time- interce-pts, or l't x~ fTid('n ts. 8)' couven-
lion . IIU' exponentialterms an' amUl~('( 1 ill dl't.·n·a.,iu~ onk-r o f A. For example. in Ihe case
o f aspi rin C I = 6. IIIWi-. A. = U.2.1I11in - ., C 2 = 3.1 ul/dl... ;lIId A:z = O.l).')() min - I .
\\'ilh as piri n . 1\\1) l'xIXl!Il'llti<l1 tenus ami lu-no- two pll;N 'S an- st'('11 wla-u plasma ('011-
l't'ul ralioll-lilllt· dat u an' tlispla)'l't l o n a M' lII i ll~l ri l l ll ll it' plot. COllllnonly, IIIl" last phase is
called tilt· t"""illtJ1 'I'ww. \ \ 'jth a."pi rin and lIlallY ot her d m gs it is a ('{)ITt'(1 ck-scnpnon.
SnllwtillWS, IItr.n ·w f. then- is all addtnonal, still slm\l' r p!l;l'l', illt li ('ilti ll~ thai dislrihu tioll
t'tillilihrill lll ha... unt bt't'u al'i lit" l"ll with all tissm-s. TIlt' Il'f1nillal ph:L\(' is ofh-n misst'l.l
IX'(';II Ist.· IIII' 'l, s.:ly pr ocedun - l'lII plo~l'( l is insllfTil'iI'ut ly S('lIsilh l' In meuom- tln- dm ~ cnu-
l't'nl ralioll at ti ll'S(' later tunes . Tl lis l1·rtaillly \\':L" tlu- ( ': t\(· \\i l 11 mll i llo~~IY(1 IS idl'S and SOIllI'
,ullillt' dru gs Ix'fon' til{' advent u f mon- S(·m ili\ ,t· 'l,s.:l~"". \\'ill l iUl'n 'ast'(llx,!t'lley o f lIIany
lit"'· l.'lllnIXlIIllds. <tll,d~1ieotl S('llsiti\i t)' cont inues to Ix' all Dl1.-a-, jonal pmblt'lIl ill t1 m~ de-
n ·ll/p llIt·1l1. III Iltl' Sllhst 't/l1l'1I1 t!istl.ssiu ll, till' Ohst·....'{'(!lt·n n ina l ph;l'M ' is ao,slllllt'(l ln 1)(.'
t'tIITt't.1 Iy dt·siKlJa!t'(I.
Al tim(' I.(·m IIII' anlk ill:L!t"ll phsm a l'll!ll'l'nlmlioll is. hy "-,fl'n"lIl'l' 10 E ll . 2 , t'tillal to
lilt' SUlll u f Iht · l'll{·lTidt'nls, C I + C z. At th at timt· ti lt' alllollnt ill tht· hody is tlw dUSl·.
IIt·II('(·. hy dt·fillilinn. lilt' m lulIll' inlo whid . t1nJl-t apl ll'a ro; to tlisirilllllt· initially, tilt' illitial
f/ifutim. w /umf'. \ ' 1' is giWII hy

Fur 'L'p irin. Iht"alLlid p<tlt't ! initial I'tJllI'{'lIl mtion is lOti ( = fi7 + 3.1 ) mwL Sll Ihal lilt' init ial
d iluti u ll \llt.Ullt· Df ,!-'p irin is 6.5 Ih
It is imjxlrtallt 10 n'ali/'(' Ilml lilt' tinK' for l'tlll('('nimlioll III fall hy Illlt'-Ililif is u llly t't ilial
lu a half·lift· dll riul-t lilt' kfmillal ph a.S(·. lX·fuft, Iht'll. lilt' pl,l~ll1a l'lJ!lI'{'nl ra!iulI falls in h,M
ill a Ill'rilxl uf It·s.. than (lilt ' !t·nnilli.llilalf· lifl' hnl morl' 111.1ll lIlit· initial Ilalf-lifl'. 11 1 L~ i_~
CHAPTER lQ D1STRIBUTON KINETICS 31 7

clearly evide nt on co mparing the fall in plasma aspiri n concentration in the ea rlier mom ents
wit h the decline of th e first expo ne ntial term.
A Co m pa rtmen tal Model. Although for the majority of situations in pharmacokinetics
the des ired info rmation ca n be obtai ned directly from modificatio n o f Eq. 2, it is sometimes
co nce ptually helpful to represent dispositio n pictorially. Figure 19-3. a tui o-compartmcnt
model, is a co mmon form of such a representation . Compa rt ment 1. the initial dil ution
volu me men tion ed above, is also frequently celled the ce ntral co mpartment because dm~
is ad ministered into and d istributed from it. As mentioned, the initial d ilution volu me o f
aspirin is 6.5 1..; for many othe r drugs it is muc h large r. These values are clearly greater
than the plasma volume , 3 L, and therefore this initial d ilu tion volume mus t be composed
of additional space s into which drug distributes extremely rap idly. These spaces must be
in well-perfused tissues . which probably include liver and kidneys, the majo r eliminating
organs. Elimination is the refo re usually depicted as occurring directly and exclllsively from
the ce ntral compartme nt. Drug dis tribu tes between this central compartme nt and a pe.
rip he ral compartment, co mposed of tissues in to which d rug dist ribute s more slowly.
Several poi nts are worth men tion ing he re . First, th e model is de fined by the data . The
num be r ofcompartments or pools required equals the number ofexpone ntial terms needed
to describe the plasma conce ntration-time data . Thus , a th ree -compartment model is
needed whe n the da ta are best fitted by a triexpon ential equation . Next , the mode l depicted
in Fig. 19-3, o r any other model for which drug eli mination is portrayed as occurring
exclusively from the central co mpartment, is not unique. Three two-compartment models
can adequately describe a biexponenhal plasm a concentration decay curve: the one de -
picted in Fig. 19-3, one wit h elimination occurring from bo th compartme nts. and one with
loss occurring exclusive ly from th e peripheral compa rtment. No distinction be tween the se
th ree possibilities can be made from plasma concentration-time data alo ne, and while the
mod el de picted in Fig. 19-3 is the most favored one , based on such ph ysiologic co nsid-
e rations as th e initi al dilution vo lu me exceeding the plasma volume , e lim ination ca n some -
times occu r in tissues of the peripheral co mpa rt ment. Moreove r, occas ionally the live r (o r
kidn eys ) is not part of th e ce ntral co mpartme nt. For example, the initial d ilution vo lu me
of ind ocyanine green, a dye used as a dyn amic tes t of hepatic fun ction . is only 3 L, the
plasma volum e . T he major perip heral tissue . in this instance the liver, is also the pri mary
site of elimination via biliary excretion. A two -co mpartme nt model, with elimination oc-
curri ng only from the peri phe ral co mpartment, ther efore best describes the disposition
kineti cs o f this dye. Last, d rug d istrib ution within a compartme nt is not hom oge no us.
Altho ugh the concentrations of drug within and among such tissues usually vary enor-

~
Fi g . 19-3. A two- com pa rt ment mode l of the
hody. Drug is admtmstercd into and ..limiuat..d
from compartment 1 and d istri blJk~ h.,I\Wt·n com-
partme nts I and 2. TIle rate t't)l "tan t~ f"r the pro-

0
k" cesses are indicated.

k"

l k"
Elimination
311 D1STfrBl/OC)N KINETICS CHAPTE f IQ

IIIl11lsty. tissuc", an- 11I1lIpc'(! h '!-:{·tlw r int o it compartun-ut h t '(".III S(' til(' nun-s to ;It:h i("\'('
di sl rilml ioll ("<!1lilih rill lll in r-ach tissue art' similar.
In Fi.!-':. I ~.h1 m (J\ 't'lIIt ' nt o f dnl~ h !.'t\ \ '11 'U comp art ments <''<11I lx- e har.Ki t-ri:t.l'(! by lm nsfc'r
raft- {,(lIIslanls, when- k I:! rk-not e-s the ra il' const ant ,....sodnn-d wit t. lIlU·..t ' IIWIlI uf dnl~ From
('UlIlp'U1lJll'l1t I tnto corupartnu-n t 2. and k ~, is tIl(' rate cons tant ;Ls''i.n l'iah'1) with the n-verss-
p n K1'SS . TIlt' (;.111' ('u mla nt lo w is ;Lsso d alt'(! 'lith los s of d n lg fmlll (,( llll lla rtllll'lI l I hy
metabolism aml r-wretion . 111( ' uutt (If all th n -e mit' coustauts is reci procalumo.
Hate equations t-an 1)(' writte n for 11I0\"(' 1111' 111 uf amou nts Iwhoo't'('11 tilt" ( ,(l lllpmt lllt'll l s
and fur dnl~ l'iimi lliltiuli. F()I1I1\\ill ~ an Lv. holu s duS!.' till'S(' r-quations an.'

Role of change '"'

of a mount of
drug in
4
compo rtment 1 Role of movement Rate o f Role of movemenl
from compo rtment eliminotion from comportment 2
to comportment 2 to comportment 1

Rate of change ""

of amoun t of
drug in
Rate of movement
5
comportmen t 2 Rote of movement
from compo rtment 1 from co mportmen t 2
10compo rtmenl 2 10 comportment 1

wlll 'n' A l uml i \;l an.' tln- amounts of d m g tn cenupart meu ts I alll12 , rl' spt'l1:i\"dy. In!l'g ra lio n
of tilt' s!' run- l'fillations Im " idt' s a hit'xpO!lt'lItial''flnatin ll, of till' sa u l(" form ,IS El l' 2, (or
Ill(' dt·di ,l(' o f dmg (mill plasma, ('Xl'f'pl thut tln- (1)(·ffid ,'nls am i , 'xl")(lIw nls lin' recast in
It'fl ll S Ilf til,' parunn-ters , Il ·fi ning III(' compart mental mo d el. EIllli\"alt'nl n-lationshlps be-
hn'f,'11 thr- h i!'xpulIl' lIlial am i " \'O-{'fIIl1p<lrt nll'lI t lIultlt·ls an- hsn -d in Tabh 19--1.

r , ,. I~.I••I..., ........ahl,......_ ........ 11. . . . . . . . . . 1.... rw.·

( part M ....I.·

PIo!o/TlO ccoceorronce
IQ [~ . (_21
V, 1i.2
- ;',1] e.' "
'<d
-+-
V, (i., - i.21
1
[ ~ . [.1: 2' - ;' 21 e - ' .

1/21l_,] -+- ' 2' -+- .1: , 01 -+-

, ll ' 2 ... l 21 + .1: ,01' - 4 ' 21.1: ,01

Inll_,] -+- ' 21 -+- .1: ,01 -
, [-,2 -+- ' 21 -+- .1: ,01' - 4'2).1: 101
'< , '< ] .1: ' 2 -+- .1:] , -+- -'0
i. , ]
'2' . ' ,0
Ceoooce tell
""",/(C + S) V, . '10
"' 1 . .]
hllol d ,lul,on -..clu me [V,I Dose/IC, -+- C2 )
Volume cJ d'SIf' buf,on IV] ClI;']
d uro ng \e<m,na l phose [V]

~1
Volume cJ d,s/f'bvtoon 01
sleOdy ~Ie [V.,I ""'" [¥t +

.
[C, + S
"
I'
 ".
A ltlloll~1J l'xp n~..ill ~ (Llta ill !t'TIIlS of a ('u m p;u"tlllt'lIla l lllllclc" and a.~\lJ(iilh'( I I'/;lr. lll l(' ll' ~
milY a ppc'a r 10 ¢n' J'rl'a h-r i nsi~hl into til t· data, caution sho uld ht' t' w n;i M"'l1 in t1oill~ MI.
HI'IIl C'IIl!M'r that the cotupart nu-ntal mudd c how-n is " flt'll not 1111111111', alltl Ulil' (';.Ill rotn ·ly
ll..s i~ l a physiml or phy"iolu¢ c' nlt'allill~ 10 ti ll' vnhn- o r lUly Hf til(' mh' (1lllsfanls . Accord-
i ll~ly. 11111('1. of ti ll" SlIhM't I" c' n l di M"1lssioll is n-l..ted to CII'M'rihi llJ.: dOl I-: di slx )Sitiu li ' ';'" till'
sum of ('llpullt'nlia k II0w(,\'('r. phanniK1,kinl"fit· o h"'t' rYal iolls a n' di M1IS"t"t1 in h-rms ur 11 11'
{'UlIl jlMt llw ll lal lllo cll" WIIC' Il th is p R IC:'( 't llm' fad lila lt'!i ~( · l lt' mll ll ll ll'f'i la ll( li l1J.:.

PltamcKokineti< Pororntten
C IC'K rn m.'t.". Elimina tio n IIl'\'1' " at all !iII it'S . Ju st i tS pla \lllll {'1l11l'(' nfmt iull is hiJ.:llt'st
im lll('(lialt'ly foll( J\\in~ an illtmw llOUS hol liS tllN ', so is mit· of ehnuuarion (e I. ' C ), Sill...
st'l lllt·ntly. bot h plolsllllt ("Ilnl"l'nt nltiou all( !("Ilm"'polltlin ~ rate nf ,·lim inaliull fall mpitlly,
To (,;tk'u1a t,· 11ll' amount di mina!t'11 ill a s mall uuil of Ii uu-, tit, n'1, 11I that

Amount eliminated within interval dt - Clearance ' C · dl 6

when- C • tit is IIII' l"llrrl'Sjltllldinl-: sma ll a n-a under 11u- ptLslJ\a ("I Ill("I'lIlnllion-linw ('u rn '
wi lhi n lIlt' in h-r...a l tit . TIlt' 10t;11 amoullt t'l imi llah "ll. tln- tin...• admiuiste-n-d. is tt. t' MIlIl of
all tilt' s mall amoun ts ,·limin;IIt"l 1 from tiull' ".t'Ol lu tilllt· infinily. Tl u-n-Ion-,

Dose - Clearance ' AUC 7

wlu-re A t 'G is tilt· tottl1 a n 'a under till" phslna d OlIl: t"I lIK"I'u tmtillll-li nlt" r-urvr-. '\ I"I"Iln !-
i n !tl~" ll-S wnh till' stmpler 1l1ll'-("I1111 jl;,lrtIlWllt Illtll!l'1.d" a mll("I' (C I .) is IIlllst n 'atliIY" slim a!t'11
hy dhidin~ Dt N' h)"" t 'C, 111l'an-a lIlil~·I ll.· dl'l" nnilll'l;! [rmu till' tmjll.·..~ lidal 011,· (App" lIl1i,
I- A) or . mo n - ('u llw nit'nlly, hy n'al i 7j ll ~ th ai tln- tol al art-a Ulldt 'r1~in~ "aell t'\jltmt'uli al
n-rm is tll(' n ·Ol- lilllt· inh' I"(" pl dhi dt'l;l h}' ih (:nrrl'spond i n~ t" llt lllt'lIlia l ('C",'fTi d " IIt. 11111S.
lilt· 101;11 area nJrn'Spond i n~ 10 El l' 2 is ¢n'u I,:,'

AUC - S + f>
i' l
Area oisociolec! "
Area cssoected 8
with will,
initial te«n leit lerm

\\ 'la-n illst·rtinJ.: tt.,· apprnpri att' \,t lllt'S for IIu- il-spirill t· ~t m plt· into Ell . ~ . lile' \'lJ llt' of At 'C
It-sstllialt'l;l ....i th tilt· 6."j( )- 1II~ IlIN ' is 95 1 1lI ~-lIl inl1 .. stl illat Iht'lol" l d t'a mllt."I' of 'I-spirin ill
IIIl" indi\itlual i ~ 6.').1 m IJllli n, S oli l'C ' tlml dt·lImnl't· is conskk-rablv sma l er thau ti lt' val..t·
(<l1(11Illh'l;!lt"SI"nill~ a IlIlt'-("I1111!Mrt nw lIl IIlt"I!'I, 9.\.'5 m JJ lIlin .TI II· L ltt ·r is an tl\ 't' n'sliltlah'
o f Ihl" t nu- "aim', 1 ll.'(~.lIIw mon- d ru g is dimilt<lIt 'l;1 dll rill ~ tilt· a Uainllu'ul tlf d islriblltiun
''lluilibriullt thuu ,1('('tlllll!t'1! fo r Ily I h~' lilSI It - nn . 1f inslt'ud (,f tht, first ph a'it' a later pllOl-st·
is misst'l;l, tilt' e mir in t...ti ln'IIi ,, ~ dt·a ntlll't· is 100 rgl' nnl}' if t hl' misst"li ltn 'ij is a majo r fn ll1iull
o f tilt' l"t:.1 art -a. Ol l\iollsly, !Ow n tilt' t·..\t · n f t'st i lllali n~ tol al a n 'a alltl p n J\i tll'l;llhat hltlllli
sampl i n~ li nlt'~ an' illit'llua tt•• lilt' 1m, ' \01111" fur d,':tm lK't· ~I ltlllitl al.....ays ht· ('al('u b lt'l;l.
" olu!Ue of I)hl rihuli un, Ollt · JlIl'lXlS{' u f a \ u llllllt, It'nn is to n'!alt' ph smOl ('UIlt't'U'
Imli oll to mtlo unt in lilt' Ix Illy. TIlt' initia l tlillltitlll \UllIlIll' fulfills t his P"llx N ' inilillll}'.
SlIb'il'l;IIU'utly. lllJ\n"\t· r. ,I-S ( I m~ t1isl riln ltt' s inl u tilt' slllw ly t'l ill i lihml in ~ h SSIlI·S. tilt' p);I-SIIM
t'Olll'C·ntr. l!inu d t'1,lillt·s ilio n ' mpi d l}' Iha n tkll'S lilt' 011111111111 ill tilt' h' llly (Al, :\'''l'C lnli n~ly.
as illn sl mlt'l;l in Fi ~. 1iJ.-t lilt' l' lTt'11ht · \111" 1111' "f dht rilmtio ll (,Vel iut·n .....t... \\id l timt·
'20 OWTU1Q

un til d istrihutiull t'i lllilih riUlll bt,iw("('u d m~ ill pJ.i.\Illd and all tesues is <1(' 11' ( '\1."1.1; this (It'('\I"
durill( the- h-nninal pI.a....... OIlJ~' dWII dut"5 (Lt.·dillt· ill all ti....\ ut"§ parallel that ill plasma and
is pn lpmtiollal i~' IJt'Nl"t'1l plasma concentration anti amount ill hudyachit"\l-d.
11... ".111111(' of tL\lrihution durin~ tl.t· tennmal pl........ ( \1 can lit" Olbktt."C1 as folk""" .
I> n ri ll ~ rlu.. plla....• II", ('u ll('t-Il' r.lIin n is !ti\1"11 J~' CI' - l.Jt t Fi~. 19-2J. aJl(! C'om"'p "tdi nd~"

Amount of drug
in body d uring .. V · C • V · C2& - ;2' 9
terminal pna:r.e
IIt"lwt " t':dmpCllat iTl ~ Il;.ll..k 10 tinw ze ro , \ • . C: rum! lot· ti ll' amount ,..-('(It''(l lo ~\l' a p L...\III;l
("Il11("l'ul m holl of C2• hat! (ImJ!; sp(l ntallt,() II\I~ ' distrilmlt'l;l into ,lit" \'Ollllllt'. " . 111(' amuunt ,
, ' . C t _ remains In ht" {~.tI<:\l lah"( 1. \ \ l w ll plat't'tl into till" lu ly. tlw amount, \' . C2• is ('\l ' n -

t U;lIl~' lIlatdl('t1 by lUI ('(I"a1 amount t'liminah '(t As tln- amount n 'mainillJ: 10 h(' t'liminah'tl
is tll(' pneluct of dt'll r.lI\(1· and area . and a\ C2 1A: is IIII' il-ssu d a h "'t! an-a, it ro ll uwli that

CL ' ~
i,
Amou nl in Amount remaining 10
body "be
e1imincled

'"
V
- Ct
i,
11
VDtumeof Total deora nce
distribution
Terminal ellJl'O'*1tiol coefficient

A 6
100 30 v
~
c
.2
0 ~20
.sc; 10 ~,

,
c

'"
~,...,
~
6
0
E °10
-e: E
~
'v,
~
<5
>
1 0
0 6 12 16 24 0 6 12 16 24
Hours Hours
flit, 19--4 . s.-.~ ....... h 'l(o" fi.u.....O(.,... i .,,", .... " ..~d._. .-l. . I ~ ... ,,( d"'Il:frtl... ,.... Hul'&l d1hrtlnn .,.ft.....

,,(...md. ~ma it • J-1 . iI 10 .... "'h mmlRahon (",," I I(~' -.I d1otnhut.>n in to I.... nwIn' drMfy "'I"'h.
hnhO( ""'un n... fall In ,nt of drur: in I ~ io thrrrf lIutW~ h tlwJ !hr faD in t.... am""nt in ,....
,nm..J d11"hr'" •.-.Iu.... ( ~' ''fw.n d1otnt.uhon ,wlil>n um h&.'",,", .il rd do Ihr drd.~ ,n , ."..,..nh in
I.... IOmai d1hlt.'" .d" .... .".1 in ~ma ~ /umr "''f'''') t h..t i" I ~ . ." . n-flo"l'tl~ II ~rnll. It.-
apr;arrnl ..,Iu (i dtot:nhuIIlIn (A,IC ). ..hid! ju<t aft" (1\;1>( If. ."... f'<1""" lho- in il'&l d1luhr'" ....aUITM' (\'1 ).
,..""'..._ .."IIh I" "l'P".....-f..fIll:. h,,,,,,..,; .-.1... (\1. .. hid. .u"n .. flnI (holnhubun ""lwllhn um it . -h........l
( HAPTH rv 33.

H('l tlming 10 tilt' example of aspirin, CI. = 6.').l l1l l /min and ~ = 0.0.'50 mi n - I. Ilwn.'fon.·
its volume of d istrih ution is 13 .i L That is, if during the terminal phase- tilt' plasma l1111-
ce ntratton is 10 1Ilw'L- then the amount in ti lt' hody is 137 m ~. Sinct· 65 Ill~ (10 mlifl. X
6.5 L) an' in tilt' initial dilut ion volume. tln- f('Tllaill ill~ i l 1Il~ mu st 1)(· in the tisSlll's with
w hich aspi rtu slo.....ly equjhb rates .
A compartsou of Ell. I I ....ith Ilw one that has lxx-u used in all previous c hap ters II)
define the- volume of dislrihutio n ( V = Cllld shows tlWIII to he the sa me , n't.'( lj.,lJIi7jn ~ ti ll'
('fI',h'lllt" K't' o f k ami A~ , Iht' n-nmnal expom-utiul coefflcteut .
TIll' reno \'1I\' ~ \'('s an es timate uf tlU' dt~'t, of e rro r in p redicttug tilt' iuili,ll pla.~ lIIa
concentratio n lIsin ~ a on e-t.'IllllpMtm(·nt model. For e xample. for aspirin. ....i th \11111t·S for
\'1 and \' of 6,5 and 13.'j L. n.ospt't.1in ,ly, tilt' error in pn'llil1:illF; initial con cent rations fr om
the plasma couce-nt ration -ttme data dllrin~ III(' le nninal phase can IX" n..lativt'1)· largt" Tilt'
emir ca n IX" ewn larger when pn'l lil1: ill~ comhtious ht")u nd the measured final p h;l"t, if a
still slower nne exists. T his la..1 e rror is o nly o f co ncern if there is an app n'l:i,I" Il' accu -
mul anou o f dm ~ in this phase dllrin~ chronic admnustration . a point <'111lsidt'f("t1 snbSt·-
ll'lt'ntl.y in thi s chapter.

Distn'butio. IOnetks and llimination

DlIrill J' the initial r.lpidl)· dt't.·li lli n~ phase, mon- r-hmtnatton oc curs than would han ' hl ~ ' n
t'xl')('t.1:t"t1 had d istribution I)("('n spllnlallt"t)lls. Addi tion .u elimination is d ill.' to Ill(' partieu-
larl)" hiJ'h concentrations of t1mg p n -se-nted to tlrv:allS of clinuuatton d u ring th is pi-nod. For
IIl;Uly dmgs this iu<,'n-a-"t'ti t·liminatin!l is smal l und. ....'ith n 'Spt't.1 to elimination, \it.....i ng Illt O

Ill)(ly as a single <.1l1npa rt nlt' nt is adt~ l nak, For othe r dru gs. the addi tioual elimlnution
represents a major [ruct ion of tilt, adlll inbh'rl"t! doSl.', and appmxi m at i n ~ th(· kint°li<.'S \\ilh
a one-compartment IlIiKIl'1 is iuuppropnate. Area conskh-ratlons are iI h'l-~ is for makin~ tlus
dectsiou.
Rec all fmm Eq. 9 that eluninatton wisot.'iaft"t! wit h IIIl" coucentranons dl'fillt'tl hy IIII.'
t erminal exponeuttal term, C ( , - ),11, ~ \"t's un amount equal to Cl..' C 2 "-1. ExpTt'ssin ~ tllb
amou nt as a fr.l<.1:ion. f 2' of I~I.' admi ubh'Tt'(1 tlUSt' and ut iliri ng Iht, relation ship in Ell. S
~ n's

Fracti on of eliminalion c ssccioted , _ C2 f;. 2

, AUC 12
w ith lo ~1 expcnenticlterm

Till' n-maiuing fr.l<.1:io n.j" mu st tl ll'n 'fon ' hawl x-en l'1iminal t'l l as a result uf conci-utru-
lions alx)\"(' IhoS(' I'XI)('t.1:('t1 hal l spll" tm ll~ lu s d istri bution occurred , i.e ., those coue eu tru-
tions dl'fill('{1 hy C l Ot. - ),, 1,
A ppl)i n~ EII_12 1u tln- <'1l-'i(' of aspirin. di mination o f 69% of the l lt ~' ts ,l-'i MKi ah"t1\\i lll
th e tenulnul slol')('; IIIl' n.'mailling 3 1% tllt'n 'flln ' mu st ht, assoctan-d wnh plasma <.1J1ll't'II·
tnmons allll\"l· thu S(' eXI)('t.1:l"t1h"d sIXllIlml("tllls d istribution OC"l'U fTl'I.1. Al.thulIgh d islri hut ioll
kim't il'S ea nllot he i~ IOn.'t1, till" majority o f ll"pirin ('lilllinalion is d e arl)' 'l-'i SofJl.i a!t"t1 \\i lll
ewnts d l'finl."tl hy thl.' h' nninal p ha.w , wh it.'h h,l-" a half-life of 14 min. Ba'il'tl 01 1 Iht· samt'
f(·<l.'illllillg, ti ll" It'rminal lmlf-Iif(· is tilt' l.'Iimiuatioll half-lift' for IllO!it ( I nJ ~s . TIU'T1.· an ' Sof lllll'
d m~s , hu...."t'\·{'f, fur whid l Iht' <.-ak ulah"t! valllt, off l is low , Ge ntarnid n is an l.'xalllpil', ( h l.·r
98 % of ,lI\ i s . Illlllls tlOSt' is 1.'!illlinillt'tI IK'fon' d isl rillIItinll {"tluilibri ulIl ....ithin tilt' htKly h,l-s
!)('t'n i\l'!Jil'\ "t"tI. In this {'a-\C, lilt' n ',l-'illll lit's ill a l)('rnwahil ity-Iimilt 'll d istri huti on u f ~{' n ­
lamil'in into <''t'rta in tissllt's. C I l'a rl~·. for ~l' l\ l a lll idn mltl similar dm~ , tilt' i1ppmp ri;111' half-
lift, (Ilit'xpOIlt'litial ll1l11II,I) dl· r. l1i ll ~ l,lilllilmtion a fte r a hollIS doSt~ is O.69.VA1 ,
322 CHAPTER 19

AMath.mati<a! AId
Fo r a ll h ul tln- math"'lJlHt i("ollly illdilll't1. ;iIlalpis a lltl pn-dicrion of pla.SIll;1 ('olll't.' nl r.ltion -
timi' data for a (I m~ Ihat tlisplaY!i lIIultk'x(XIIll'llti,11 disposition (,l.ara l1 t·ris l il'S an' diflil,lh.
A lIM·fulm;llht' ma tit".l1 uid to fuctlitan- sud . all aly~'s ami p n ·t! il1 io llS is 10 imagim' that 1"K·1I
1'\)'ll:JIII'lllial n-nn arises Imm till' indt'))('nd t'llf iulmillistm tiu ll uf 11 difft'rt'nt dnl ~ hil\i ll~
(l1\(' -(''UIIII'lilrtlllt'1I1 dmmt1t'ristil'S, alld tim! the- sli m of tln-ir im lhi tlu;II I"llll('t' n l m t io lis is rln-
nhSl.'lv l '(I IIIlt'. Fo r ('Xilmpl"" illlah';Ill' thnt a bil'\) xJllt'lltial ('(llIatiulJ. CII·- k" + (,'1, - ).rI.
;U;S('S From lKlmiuistmth m of rnll h)lXI1!lt'fit'll lim p . D m~ I anti Drug 2: Drug I pnllllll"l..,.
tilt' rurve C ,I' - k a nd )) n l~ 2: pnl(lul"l.'S lilt' t'lrn' Ct · - ).:1. Furthe-rmore. It\\Ulllt' Ihal (·lId.
"
h~ll( )t1lt"t i<.'al d r ug h,lS tilt' s ame clearance. CI.. Therefore. hl't"illlSt-· t hl' two d nJ ~s haw
difh-reut ra te constants , ),. ;uu! ~ . till')' hil\ \' d iITt'n'nt \1I11II.lI's of db t ribunou, w t.i<.'h an '
~\l.· n hy CIA. ali(I CIA 2• n 'sfll 't1iwly. To eomplete- 111I' analysis . tilt' tln....·s of t ht· hn 'M l-
thetk-al d nJ~s an.' needed . TI)t~· an.' u hlaillt"tl [nun an-a l"l lll,idt'r'lttio ll' ,l\ fn llllw" . Si lll't·
dose is the product of clearance and an-a. III(' n-spective t! US(,' S an.' CI. · (Clli••) and
C I. · (CAl. Furt hermore Silll 't· CUG .!). . + C IJ-z. ) ("lllIals l l.(·lllial do....· "dminb l(·f("li. it
[ulIllWli fnun E(I' 12 tllitl ! . · dn....• and! 2' diN' an' l ilt· 1,(lrn 's l'M Jlll li ll~ d o ....·". Ih ·)I("I·. tl u-
tllial oh....-rvl"tll"llll('-·n lmlin n is W\l.·n h~'

. Dose e- l ll
ICV~1 1 +
'2'ICV;'21
Dose e-
l2
'
13

A lt holl~1J tilt' aileI\'(' equation is a de-vi ce t ha t cannot , for (·x<Implt'. p n-chct t" 'l'nts ill s lowly
("l llI i lihmli ll ~ tissues. it n·ad ily fll'nn ils l"itlculaHIl Il of (·\l.·II1s in ph\lIl<l nuder u \'ant'l y of
circurustances . :l\ suh...... j1lt'lltly Sh(1\\11.
(ON5TANT-RATIINFU510N
Fi ~ lrt· 19-.'5 Illust ra te s till' lIlIlidpilh"l1 t'lTt"l.1 Hf clet nbunon killt'li<.'s OTI tilt' pl.l\ ma ct tn -
rentration UPOII stllpping u coustant -ra h- infusioll at \1In OIiS tilllt's a1l1nn ~ appmad l III plu-

. 'llt. 19-5. 1-:" .,,10 in pLa.. n\;l (u .I" l li".. ) ..,..I 100 Slowly Equilibrating Tissues
in .I<owt,. ,..I" ilih ....ti,, ~ Ii.".... ( ) .I"ri nl( ",..I ............... '..
..ft,·r ••"{'pin!.: Mn ..l.l..nt·...ot.· infu.io", ,-\, n",· . .
•..."t ....lk'" in tI ..• .It ...,~· ' ''I''llihnalin!.: Ii , ...... ri.. ..
, llLrill~ tI..· illfu.ic", . ,I..· ,..'! 1'"I" lo.·,..) " f tim!.: ."
..
'"1,10', II.....• tI...., .. tI.......·.,·.... . C, m"" I'''·'' I I~·. "" Plasma
10
" "Pl'in~ tI..· infn.ic"I. II..· .h. lri l",h"n Ill,.....· in
,-,
I ,-,
\
I....." ... (---) "'PI........ . I..JI<....••. tI ..· " ..,re· I're..
1<",I('..t II..• i" f".ic"l _. '"• • impli<il~'. ,,,,I~ tI..• .10··
I
\ ,, , -,
d i,,,· i" Ii..".· .."",-'(·.. 1..",.... , ..t ""I' ,I..• i" f" .;'-", i.
I
\
,-, , -,
, -,
-, -,
-, -,
"'W ~ I"I pt.1...... i, .1"""Tl, .:'1 ;21; . ,lo. TiI".. II,,·
\ -, ,, ,,
pL.im... (~" ..'('f'. r.II" .. ' .I"rinl: ..., inf".k -\1 II,,· 1 \ -, , -,
,·,..1 flf ;u ' inf".ic "1 " f ' "mllk''' t . tl,,· (~JI "l·" t ..a- \ ,, -, -,
, -, , -, " ,,
' '' ''I. Cit ). is .I..·n ·f, C:oolflO - r ~ l , , ) + I l ( 1 , -,
- r - lt' j j. •"lI rt l..• -. UII " "{'pilll:: il..· infll- ,,
-, -, -,
,, , -,
\ie,,,. tl..· I'I....." '(·" I ,...., " 1(1" ',, 1,>' C oo trl ( I -, -,
, -, , -,
- r - l " )_ r ~ l , ,_ + f J(I _ .. - l'·) _ r~ ""_ I . -, , , -,
..f...no ,_ tI..• lim.. ..f,
is 1''1''1'':''1(tI..• infn," "'- 0.1
n..· la.t '''ll ldl.. 111 ('lUI 10.· ·nn d n,illl!: th,· nUllo. 0 6 12 18 24
'·"' ''' k:. 1....1 (t:' l. 1.1). n ~ ..,.l1j "", f..r '....."'rlc-.
lIo.at / l • Coo ( 1 - r ~ l l ' ) ii,I..· n 'I ....tkJl' ..' tI..· Hours
.....I ..f tI ..· inf,t.ic,,, ;ll; I ith tI..· fin! r1.........
;u .. I.. ~ l ~_ i, tI..· .um"I Ii"1:f....<i i-.... n ·n..un -
i'1j( .. l lin ..· ' ,.....
CHAPTE ~ IQ DlST~IBlJTIC)N KlNETlCS 333

n-au. At t 'a rl~' urues. a pronounced distrihution phase- is seeu upo n st oppi ll ~ all infusion ,
because dtstrtbuuon eqruhbrium has yet to b(' achteved between drug in blood and thai in
1Il,IlIy tisSllt'S. \\'illl a mon- p mIOll~I '( 1 infusion, umre d n , ~ enters tilt' tissues. T Ilt' h 'llIlt'II('y
u f dnl j.( 10 tnove- From bloo d to lissUt's is rln-n much rt>(II1('t>(1, and tht· distribution phase
appl'a" l1Iut,h shal10\\'('T UpOIl stoppi llj.( lilt' lnfnslon. E\'('II al plat eau. !lO\\'(,\-t·r. SO!lW di s-
trih lltioll lIlay still ht, St't'll upo n stoppi ll~ lilt" infusion . At plateau , rlu- mit's of drug ent ry
into and o ut o f the lissm's art' t'flual. Upo n st(Jppi ll~ the in fusion, e liminatio n o f dnlg fmm
pla_\l11a. alollj.( \\i th u SIlIlst.'IIIII'nt full ill plasma conce-ntration , en-are s a ~'md ien t fOT return
o f d nl~ [rum lissues. Inilially, tilt' mil' of r-limlnanon fru m plasma ('X('('t>(L'i tln- rat e o f (·f1l m
froru tissue-s. am i pl.LSll1a t'Olll'('lltm tioll falls rapid ly. Eventually. ho wew-r, Iht' ra te of ret urn
fmlll till' tisSHt'S limits Ihl: mit' of c·liminalion from plasma. nit' hody then acts. om '(' a~aill .
,LS a si n~I(' (,(llllp<trt rn('nt; plasma con centrat ion and amou nt in tilt" tissues. and ht'n('(' in
Ille h' I(I~' as a whole. r.lll with a hal f-lift' ('{Iual to thai seen du ring tht' temunul p!J;LSt'
fol ll )\\in ~ all i.v. 11()11IS dust"
Tl« - adnal ('Wills SI't'!1 afn -r slopping an infu sion at s lt 'atl~· state depend largd y on lilt'
kim-tics of distribution . If distri hut ioll from tissues is slow ",Iali vt' 10 elunination from
plasma. tilt' phSIll;l ("HIlt"('lltralinll falls sllhsta ntiall)' II('furt· III(' !t'nnillal p has'." is n ·adll'tl.
COllW'Twly, d i\ trilllltioll lIlay II(' so fust that , Oil stoppin ~ lilt" infusion . dnlg: in IisSIl(' alld
ptLsm;l slay in virt ual cqntltbrtum and oll l~' lilt' terminal monoexpouential dt'c ay is seen.
TIlt' latte-r silllalillll cnutmst s \\i lll ('v('nls that would hl' SI'('n follll\\i llg all L\". II(Jlus doSl' ;
a bie xpOllt'lltial (111'W is ill\"llriah ly SI't'n if blood is sampled ('any (·Ilt m~h . As a gu id ing
pnnciple-, a frank luphask-curve, nil s l oppi ll~ lUI Infuston al stt·;ltl)· state, is SI't'U wln-n f:z is
small. i.e., wln-n Ih(' majo rily o f tlm J?: in phlSTlla (and mpidly t'tilli lih mli ng tisslU's) is elim-
illalc'(l ll(·ftln ' di slribulion e-quilibri um is .It'h it'\"(.J.
Hf.'lllmillj.( 10 events tluriTl j.( infusion. 1\\ 1) baste questions remain: \ \lml ('(mlm ls lilt'
plate-an ('o nt't'lltm tion? How long dot'S it take to reach platt'all?

hents at PIaleau
Pla teau Plas m a ('..o ll('{'lItnit io ll. T ilt' plate-au is n-ached when mit' o f d m J?: ellnunution
matches mil' o f infusion , Ii,!" Tln- plasma concentra tion . C... is thr-refon- n'allil)" gi\"t'n hy
tilt' familial' equation

c _ RQ
14
... Cleara nce

T hIlS, as lo tl ~ ,lS d t'a r;U1t't' is at1.'llI'ald y det e rmined , Ih(' rate of infusion I)('t'tlt'tllo produce
a ~\"t't1 sh' ady-statt' eoncentnuion ca n be calculated. Conversely. clearance can ht'dt,tl'T-
millt'tl fmlll tilt' ("(JIIt'(:nlmtioll al slea d\"stalt' ,
\ 'o lu lI1I.' uf Dj\lrihuli on nt Sh" nd~: St nle . Although Iht' \u llllllt' o f di slrilm liolJ, V,
Il Sl·fll ll~· n'lales amounl ill hody to pt lslIla ("OIlt't'lllrdtioll duri llJ?: th t' h 'l'lninal ph 'l'it.', its
\1\1111' is iullllt'lIt'('(1 by {,lill1in;ltioll. As SI't'1i in Fi!?:. 19--6, tilt' fa~ le r a d m Jt is t'!imin ah'tl. the
~n'a tt'r is lilt' r.llin of tln l ~ ill slow ly t'fluilibm ting lis.'illt,S 10 that in plaslIIll d uring III('
h 'n llill,,1 ph'LSI.' am!' t11fr!·slxllld illgly. tilt' large r is tilt' appan.'nt \u lu lIlI.' o f d istrilmlioll. A
Ilt't'tl, Ilw refnn '. ("isis til dl'filJ(' a \"(Jlulllt' l('flll to rt·He('f purely d islributioll. n lis \,o IUlllt'
k rill applil's 10 sle ady ~tah' when d m ~ is infuSt'l.:1 al a ('(mstalll mtt'. T his \'tllullll' It'n ll.
\'nlllml' d istri but ion at slt'ady ~tale , \ '••, is (\1'un{>(1 by

Amount in body 01 steody stole

15
Plasma concen tration 01 steady stole
 CHAl'lt1l IQ

COIlCt1)tuaJi/.alioll u f tli is volume TlIay lx- Ilt"l pt'tl by tUllsi de ri n~ till' two-compartment
1II000Id dep il1t"(l ill Fi~. 19-3. At stt-ad)' slate, tile r ates at which d m~ enters am l lt'avt's ti lt'
slowly t"'llIil ihrnti ll~ tiss\lt'S arc t'X.;lI.'t1y matelu-d. It then fellow s from Efl' 5 that tilt" amount
in tilt' slow ly ~ '( I\l il i lmd i n~ compartment at stea dy stnte . A.. .2 is ~vt' n hy

A11,2 • 16

T ile amount in tilt' 1)()(ly al slt·mly state, 1\ .. . is till' SIl IU of A.. ,I and 1\ .. .2' Therefore,

17

Finally, as A...1 "" \ '1 • C.. and A.. "" V.. ' C.., it follows th ai

VU = VI [ I + ~J
Volume 01 18
d istribYtion 0 1
steady stc te

In practice , as amount in the 1)()(ly l~.lII n{)t be de-termined physim lly, \ 'u is usually <:1I1-
culated fmm tile dispositiun pa r-tlllett·rs (C l , AI' C2 , a nd )-2) f()lIfJ\'; II~ i.v. bolus ad mi nis-

A 6
100 100

6100<1
'il. / -
~
.s 10 ,
c
I
/
Tissue
.s 10
c
I
0
I .g , - - --_! isslJe
~
"
~
I

"
~

~ ---- -----
-- -,
u u
c 1 c
0 0
<.> <.>
BlOOd

0.1 0.1
0 6 12 18 24 0 6 12 18 24
Hours Hours
.'I~. 19-6. t:lilllin;otinu inlll.·l.~" ...tUUll" or.Ih lrihulio" .1" riujl. II.· l"nni,,;o! pl.,...... T" ;apl'n ...-i;,I.· d ,i. o.f;a!t"Ill""I.
nlll,itll-r lhrdiltrillllliofl (J( 1I. 1Irul( ht1>.o~'f'1l 1>11.. 1(m I1l1I1t,. \ '8' 5 L) and II. him.. (m lum,·. \ 'r. 2u l. ), Furt llC'n lllJn ' ,
Irt "'" - I. .. , " ..I IIit' cc" . Tfll rolli,,,1' ill ,,;00.-1, n ''''l''' rt nlt' nl at "'lm],l,Ii"," ~n' rt l'...I if "" .,limi"ali"" ,,,-,'Un (;\1.
11... ".t"TlIt' of .ti-trilx,til", at ""I"ili l,rtu", i~ tilt'" 2.5 L. Wid, ..Iiminalio" of ,Inl~ lilt· ,,,,.'O ·nlr..litlC' in tilt' Ii~..... ·
(---J b !:"1..·I,ind 111.11 in 1.1.. -1( - - ) .tUrillg til(' t.. n nin,,1 ph.a,_,·, 111C·,,'1,:,' !Q\111l( Ii...· Ill . hi~lC'r "1'I"' n'1ll \..:Jut '
..r ~, K. (8). C...........I'It·"I"'·. till" ;q>pan'n l ...tUlII" Hr c1t\ llih"liun ( \'8 + 1\ • \ 'r ' i< i'. -r,·.... ..J ;alit.... • th;al
.."l......1,J'ti"....1o.r Inl(' t"jllilihli llm CC>ntlih ll. lI. \ '8 + K., . \'1' ,....,.
 32S

fr..lion (Tab!., IH- I) . 'l1w in!t' r.n· b tiom hip' hdwl1t-u \ ".. '1 l1tl utlwr pll;IrII1.It" l illl ·! ll" pa-
r.u rwtN" .m- 1..'\ 1 IlIltl. ·"toocl (m ill IIII' 11lm " pl (If IIW'1Il n·,id.'lIu ' tillw ( :1..11' ::!·I.
Tum".. tor ( :OIl (1 'p " , ,11111,\ PllI-Hili, I -I) ).
111l' \ ";I IIll " of v.. lit" IodWt"1I lilt" initial diluti ull \ H III IIl '" \ ' , . ;llIe l til" \1> 111111 " of lIi,!ri·
huli"u durilll:: tl lO' k n nilloal ph ;l~ " v. III c:c'lw ra l. lilt" d iffc' rC'lIll ' l.du l l 'lI tlu- .. ;&1111"\ of \ '..
;ultl \ ' i .... mall. 'I lid l d"I" 'IMI, 1111 Ih.· di' I11 ...iliull l.jud i.... uf till ' .fnle:_11... t1iITN' ·Il.' - h
b n:,·r. ,1"' l,.'T,·ato·r ,I... p\ h'lI l «f ,·lilll ill;t!i,," h.·fon· t1i' lrihutiuli ''' 'lIilihrill lll i\ .ll'!li'"\ n l T..
;Ip p n '('b h- I ll i, 1.1'1 pc.ill t . (,ITI\j, It ' r thn ..· clmc:\. ;(\pinn. ~Ji(~ Ii(·.u:i<1. .IIII! c:,'nl.llllit-in, '11",
t1i\j Mt'iitiull l illdit-v. Ilfln nali, .t'. 1 tn 'I 11In'l1l ~ j\ .I...III\ II.......· f"f.1 7n , " ~ \ llhjl ....1 M , ' .1'I" ri IL
C = H.7" II '" + .'i l.· l ..; ....llil... lii·,II-itl .C =
IO ,~ ,· - l ... + ~ '; I · U:'II ; ~'· lI t.ll l11d li . ("
s 7.1 " U ~.) + ni l") •. _ UUI \\ It,· ~,· C i\ illllllV l. a llil li lll(' ill 11l1l1f'> . ~1l1 "'1lI 111i"1I of III.·...·
IlOlr.ulII·h-r \".1111'''' ililn th.· n p. 'I1i\t· ' ''III;IHfllI\ li\Il ..1 ill T ah'" I !J-I ~i. · ll k li ,r ;I_p irill. \ •
.= 13.0 I ... \ '. . . lOA I .; fur , .Ilil...lil · ... i l!. \ . "" 10 .5 J.. \ '.. ::: I n.~ I.; a llllll,r ~1 ·1I 1 .lIl1il'ill .

\ . = :\.1.3 I ... \ '•• '" .'jfi 1.. :'\lIt ;n ·. f.,r axpiriu and 'IaI;(~ li{·.Kid. 1I!.1llhc" \alll, .... n f \ '.. an- \ I'~
\ illlil.lT; IIII ~ .m· la" t l. •• il k p n .... I..llli ll.t!IIIY h"ulld 10 alluunin, am i ;M..... n lill~l~ IM\l' \111.111
\ulm lll'\ of dl \tn imliflll . Tle- ~n ·.I l< ·f \'aill" of \ . n ·I.II ~ ,' til \ '.. fo r .I\)Iinn ri........ 1.., ·.111...·
;IPIITt....i .lhl .· .·lilllill-lh"l1 lC / . :: ·11 I AIT I ' .." If'> I..-Ion- di \lrihllt icOll ''' llIilihriulII h .M',"it...,.. L
for "'11ic.:7' lil' ,. i ll. tilt' , h lT" " ' I"-'1' 1I"lw' '' '1I \ . aft(l \ '•• h \ lIIaIl 11ll·<.':.lII • o f .l It,""f d",lf;IIK'I'
,C/. :: ~.-I l A id . f iIM!h . for ~" II I " lIlid n \ . i\ 111111'11 b~"r Ih.1Il , 1....·.11 1...• IIH",I IIf l ilt'
;.llIIillhh' r lllmc i\ , ·li·lIIilult..II ..·f.. re- t1i\tril lllliull ' ''lllilihnllllt i\ .11t.1; 1I'''''1. III " 11'h rs r -
1·1I11I\1.llle'l· ' lill ... lil\~ \ '.. i\ \\ ,.rt ll" 1,i1,· if. Ior allY n ·'l...m. , li\p'",iti'l1I kir ...til "" we-rt- .lllo-fl ..1
.1/111III... wi\I 1 11I ;I\\ it:tl lilt' dl.lIl~' ·I " ah ,"n .. 1, Ii\t ri llllholl ur ,·lill1ill.lliulI. ..r In I.. "h
.-\ lIul lll.'r \ i l'\\ o f di \lrihutioll ;II \ h'at l\ \ 1;11t· i\ 10 ('1 IT I\ icJ" r IIIl' roll in of ;l1 l1l l1 l11 t ill 1.. ..1\
1.-\.,1 1" am",,"t ill II,, · illit;.,1 tl illll i..ll \ .. luu... (.- \.,1)' 111t' roth.. i\ " " (\ '1' Fn r .l\ pirilt .11 111
"' lli (~ Iii ' 'M·ill. llli \ ral it. i\ "PIII,.,illlalt ·l~ ~ , illtli,:.. ting th"l 11 · ,ln ll......m · ' ''lu.ll1~ ,1;\lri l' IIIt..1
hl'lwl,,'1I 11..· iu ili.ll ,1,llIli nll \ 0 111111" ;1Ilt! tilt' n-a IIf Ih.· I I~ . Fur ~.· 1I 1 .1I 11 id li II... r.llin i\I ,
i ll t!i l ~tl i llg th.ll .11 \11';111, \ t.. llt · 1II1Il'I. lI111n' o f Ih i\ 'llllil. i" h l' rI'\id", ollhill, ·. 11..111 ill\idt·. l ilt'
initi'll ,hhilit'li \I,I 'II11t·"
Fi ll"Il ~ . ;I UlIIlI''''''li,," 110'1.. 1\ tn 1M' III.ill, ' 1" '1'\\ 1'1'11 \ ',. and tilt' \ u llllllt' "f dl \l nllllllulI " ",..I
In ''II!1\i ll.. r III" il1111lt'IlU ' u f p l.. L\lrl;l "lIt lli\\Il" hillcllll~ nil t1i \l rihlllioll . " .lo:.. , .... \ '/' +
"r'JII1Ur 1<:I." p . 111 ). 'l1wy ,m· I ·\'ot · Il I j;I II~ tI... .... Ullt'. ·11 ... 1t'T1!I \ '., ;lpp li,·.. lu a IlIt ..l,.] ill
\\ !lil·h IltJ , ·lillli llalitlll'M't'II'" alJ(l,li \ lril 'll l iem 1"llli lihriult1 (..Il ·;lll~· , t ill ' ) l la\ I.. ·t·n <ll·l,it '\ . .... 1
( Fi ~ . lU -7 ). III p f;1(1il 'l·. .. lilllillal in il ;al\\~l~ " tM.. ·I\'" and ('11l1fllllnt l\ 1111' 1'\ lill1ali"n t If " I'll n · l~
. li,1 rihlltit.lla l \ t,lllll1I' II' Tl lI: , .••. ;lIltl lll li , . (11, lrill\! II,, · " ' fllli ll;J ph;!'ot· j i\ II,, · 1·lt ,...·' 1,·,t i'l l.Ilt ·
of il.

nm. to Reach P1aleau

)(' 'l 'all th 'll fUf p m t'! il'a l 11" '1)0... ·\ pl.l""all h ...lid In 1)(' n 'adlt'l l "'It'll
lilt' ('1I1ll't 'n lf"lhlll i\
!Jllll " f C " . B' '''a ll\( ' of tli_lril'llli"" killl'li("'!<. lilt' lilllt' III n ·..d, p l..llt ·.m .lifT.·,.. l 'd w.·. ·11
p"" IlIi1 ;lIld li \\ II'· .
E " 'n h in )'1' (" 11101. TI ll' h'nnil"'! h;llf· lif(· " f lilt' alllih~llt ·rt' ·Il ,i\I · age'lIl lIIl'ardipilll' h
. l ppfll\ i llla l d~ 12 lIT. nlt'Tt'I<,n·. nlli ' \\'II" ld lI"nllall~ " \1" ..1 .) t lll uf II... p"'to-.i11 1'1.1\111.1
t1 >l1I .. ..nlr;lli"lllu I..· n ',ldl''III", I ~ I.r t illrill ~ a l'I lII..I"I1I'TiIh· illfu \ ;ull . III' k al1 illaLt'\ 0111 \
1 Ilr ( FI~. IH- '; I. .-\ 1"" . ~JU'l •.r'lh,· plotlt·;U1 i\ n ·"dlc.. 1by appn l'(iIlMlt'l~ I.') lar iu ,lt'ac! o f lil;"
1·' I)/...1 I..l llI l. r (.1..1 . , 1 2 )'
n li ~ t1iff,'n'l\('1' ;Iri ·\ 1.....~ l l l ....... llic.:;mlipillt' \ d l\I " "' lliulI Lillt'l K.....m " h ipl..l\i (·. \\1111 \111.·
\ la llli'll ,·lilllill.lliUIl ' Irrill ~ t1l1nllt: till' fjf'>II" ..I-... •• \\ h id l I.~\ ;l ll;l[f· lif.· of .lpp n ,'illl.l,, · I~
ulI l~ ::!i l lm ll '11... r" "lIlt i\ ;a r.lpidl ~' ri\illC; IIl1ti"!I" IT\I' f..I","l.. ll ~ ;l 1IIll('" \ I'I\\I' r appn ~I('I I
I" pl.l!t·.III.
". CHAPlf P 10

. 'ill:' 19-7. B.~' "I 'I ,n"i rn"h·l~ 1 I..

20
ln lu .. ~"'· h r . .....>l.ml ·. ..,, · i.v. tnfu-
.in" ,,( 1lH;'>lTl lipi ' ''' (11,5 I1IIo0.r1. II..•
I"t..... a "''''.....n l ..II..'' 11;&\ rI..-" ,..
5l"l'l lOr II..· p!..1to;<lI
"''''1''1<' iI 1. -nllin..J
."" It' 0 4 II-Wl.l
Iwlf·lif., "f 12 I,.
11,L. r.api<1"'PI' " ... t, 'n
pUh'"'' i,
ll"Sull .. f o,\,..nh in pi....,,);!, h.oillK
fTWril) ' t'<"' I",IIo.. I I ~' an h, i1i;1]
"ri·..

pi,........
....;Ih .. l...Jf·lir.. ,,( 211 ,,,In. ,I" rin"
",I 'K -" li",.. . iJ(Ili finltll ..
•• un'" r. "I< ", ;, ~ .. 1,,>1...
h"""..ti""
,1<..... 11...
\.

\
,L'l " ;,. re- II " ....." . of 3':' Iwlw-n"
,,;11, lII ilo l-I """Io-,..h· h~ I•..rh ·,,, i,,,,
t I ml\"l. - :2.. 1 IlM). IK,.. I,,,,,,, (rum
C•• • . K . C1ifl'.'. C;.<:.. Bio·rn .......
<:., \\ i ll;;. " ,•. R., S"I11I",j, S .. \1."·
M"' """ . C;., c:....,..I)'. S.• 1.aI. C ,. \ I. , 2
Q u.. n. C.. '\ II,I,,",, 'n. C ,R.• T II. l..·
p;<~' . r .. ;U"I W"l1 m, JI>. 111M1"'"
o 24 48 72
(·.... i "t"! ~'S. r"arm.. ,<. I~·".."'i<'" >1,,,1 Hours
mini",,,,,, "fT...ii\,· dm io;...l , ~ ..... of
InlnnM"" " Ilit·..nll l" ' .... e llll _ 11...,..
m;o(,". TI M·r ., -I;:711f>-71'l . 19'Jl1,)

111t' impo rtance of liot 11I11) ' tln- half·lin ·s but al..o Il.t' n·lal h l · ran-.. of , Ii..tri lmlio ll ilm l
elimination Oil till' appmad l of th t' pt L"IlI;1 couceut mtion tn plate-au ea n Ill.' appn"l.·i<lh"l.l hy
tilt' events dl·pil1t"l.l in Fi~. 19-h. for whit-h till' values o f i ' l ami ~2 an - fht"tl und li lt"
Iracnoual tenn a.....ulo.;;IIt... 1 \\i tt. tilt" n-munal p!l'L'i(·.j;2' is varil...I IM·I\Wt ·U (I.U! ami I. \\111'1l
I1. "" I. d m ~ distrihul es sp' lIllmll"'lIlsl)' rt·latiw 10 d illlinalio ll: till' ' '' Illy lIppl·"r.; ,LS a sin ~l (·
compart ment lIllll. a \ t''' p'>(111I, all th t' d m~ is l'Ii llli ll al l "tlll ll rin~ lilt' h'nninal (and ollly )
phase I II this case. it takes I n-r miua l half.lift· (lI.fil.),'lIi'1:) and 3 .3 vuch half·lin "!; 10 rt ' oK·1i
50% ami 90% of tilt' plateau. rtOSpl"l.1 i\'l'Iy. Jl owt...x-r. at Im\'('r valut's of f l' mon- d m~ is
l1 I m 's l)( Il l(li l\~I)" cltnnnatr-dlx-fon- di..trilmti on equilibruun i.. t· .. tahli..III..l. As a re-sult, til.·
tinK' to ac hit'vl'. t· . ~. 5( )'l;f, IIf th t· plateau oc curs t'arlier until. when / 2 = 0; till' h llli ' n-quin-d

. ·i jt. 19-'1. " l'p r" ,Ol'" I" 1'1.. 1.·.." il) pt.,m... ,lllrill!!, I,
a l, . " la" l·r..I.. l.v. i nfll~JI1 . Ii" a ,ln1ll: 11,..1 ,lhl,l ~, 0.01
Ilit"'p'". ·" "a1.I"p'.. ili,,n Id nt"ti<.~. n .1t" ,·nni n"I I~.- 100
Ih.. n ·I " .. r.atrs ,,( ,I,"' n l>( ,ll"'" ..".1 ,·l" " I"..h..... I"
Ihi "'1>1.0 .1","..,''''1'' " " 'IlIW .".·ffir......'h ).1..,,,,I
~.on' 1..1" .,,"....." 1{....uh A. l • Ill~ l. ;uKI tI,,· fr...·•
li" llal ..Ii"'i'....liu" k rill ..., .. Il;...h~ l ....ilh II..· h 'rn,ill;l!
1"......../2. i. ,-..lit..! fn,," 0.01 I.. 1. \\l...n ,IRlll: Iii' ·
llil",.,.. r.apit U~· (' ''lIi''' n~ 1 ....ilh .-!imin..Ii" 1I ifi "'..
rn.... ....
~ I I. II... It'n,,i,l;l! """f· li f" I" 'l n ~ . d..' Ii " ...
I" "'1'1""_'" IJ
pLat.....,,_\ \1 ..... I. ...,,"10M,. .. ,!t-. OJ}I .
" "M1nl/;..liml".. li"" .lOt, ·,," ",,'"' f;l,\I" r Ih.u, <\".
lril.'lio.... II ... "1'1:""......, I" I";I,I'~"" i. ,1t".. n "I'Ol~ 1
I'n", ..nl)· 1':1' ).1 ' 1 , ,,~,.It ..1 f,,, n.f'·.........-.· b; .1,,' ,·0·
1"'..1...11:'1.1,. f,,'1 ' II,,· "RlI: •."I,ihils''''' ''rnl...rt . 20
" Ol'nl d 1..ri' lit'S if! .. I I. in .. -h it~, I 3I1'l-
;u"IIIl ~ u( II rLoI"'II' an- n ·;o(......1 ~' I ;1",,1 J .J
I,·nn; , l """r·I1, n "P'''1i\.. ~·. Xu,," 11...1 Ii"... i. o./----~-~--~-~
....! '" I in " "ih of I,·nni,...ll..,]f·!if.·.
o 1 2 3 4 5
TimeJ(Half·Ufeof Terminal Phase)
CHAPT£i 19 321

is lilt' half-lift' o f lilt' firsl p!J;l"l.', f).59-VA I • 111C bod y OIlL'C a~ain acts lIS a si n~It-l'(J m part me n l ,
but ,,; 111 a smaller volume of dist rihutkm. \ ' 1' For most dmgs/2 exceeds 0,8. and so till'
It'rm illal half·lift' primarily ck-tenmm-s the time to reach plateau. Fo r uicanlipiue, sip lifi-
can t eliuunation occurs lx-fon- distnbutton cqutltbrtum is achieved and hence the O!JSN-
vatiou ill Fi~. 19-7, Fo r ~t' lI l a lll i<:i ll . ,,;l h/2 dow to O. it is the half-life of the first ph 'l"l.',
nsually 2 to -I hr. Ihal primarily detennim's the ti me fur th is alll i ll(~lyt:osidt' 10 reach pta!t'all
ill plaxtna.
Anlltl lt'r vie-w of events in plasma n-lates 10 rln- l'xpall{li ll ~ volume of di sl rih ut ioll 0 11
appro.\(·ll 10 d istribllliull equilibrium ( Fi~, 19-1 ), A plateau is reached when th e mil' S of
infusioll and elimination an ' e-qua l. \\11('n distrthuttou iuto the lissut' is slow, tilt' (-ffl'l:tiw '
\Ullllllt' of dist rihu lioll n-malus fur SO lllt- ti lllt, dose 10 tl.t- iuitial di llltiull volume. \ ' 1' so
Illal for a ~\"(, II mil' uf iuput tilt' plasma concentrat lcu rtws much faster th a n if di st ribu tion
in to tissu t' is rapid , Tln-n-fo n - lLS mit' of elim inatm u = Cl.. · C, it follows that. for a ¢\'t.-II
dt'antlll't' value, til(' appru.\(·ll to plateau occ urs earlier, till' slower the dis trjbut ion to tis-
sues .
The phsmlt coucentratton al any ti Ul(' on app r oach 10 plateau e m ht' caleulan-d usiu~
prt'st'nlt'l l ill Fi~. 19-5. Hem r-mber for a dm~ with one-compartment ch aracte r-
{'{lllt'( ' p is
tsncs lilt' conce-ntration at any tilllt' d ll ri ll ~ an infusion is WH'n hy

Fo r a dm~ tha i exhilnts hit'x!,MJIl('lItial dlsposltion chaructert stlcs . II\(' corresponding {'(111<l-
lion is

19

'"
20

Tln-se n-lations lnps follow hy ima¢ning Ihal to tal conceutranon is tilt' slim d{-ri\"t"{1 From
h \1J h~l'Mltl lt't kal dmgs, t-ach \\; Ih the same clearance value. infllSl.'l 1 al rates I I . l~ , anti
fl ' !l", n ·slx "(1i\"t,ly. E11llliliollS ls an d 20 em phas fze- tilt' impo rtance Of l 1. (and 11('11('(.' C I
and C~ ) a.. well a-" Al and "~l in d('l en nilling 111(' t'\1.-n15 in plasma foll{J'\\; lI~ a constant-rate
infu sion . Equunon 20 al.so permits ready calculation of the pe rcen t o f plat ea u reached at
a uy tinu-. For exautple, if the half-liws associated with the first and tenntnal exponential
te-rms an.' I ami 12 hr . n 'slx"(·tivd y, allt l / z = 0.5, tln-n at 5 hr , the co ncentration is 64 %
of plateau. The converse, t.c. tilt' lillie n - quirt-d 10 reach a ce rtain 1)(-n'(.-1I1 of plateau.
('JlllIlul II(' calculun-d din"{11y. IX"(.'llllSl.' then.' a rt" two exponential te rm s (,()Il taillill ~ tilt' lin-
~1I( J\\l ' , time. Ti lt' tinu- cau II(' ck-n-rmtned by iteration (C hap. 1ft), i.e., hy sllhs tiluting
dilTpn'nt lim ps into EII_20 uu til till' rigllt unswr-r is reach ed. In tlu- ecun pk- all(J\·t" th e
time taken to n-ach .')( )f}. of plateau is 2.7Sll r,
En'n ls in Pt' ri phe ral T iss ue . As illust rated ill Fi~. 19--9 tilt' tilll(' 10 adlit'\"(- plateau
in slowly ('('l ll i l ih ral i n~ tissues is p rimari ly dete rmined by th e terminal half-lffe. irrespect ive
o f tilt' lime rcqum-d 10 ll(·hit'\ ·(, platea u in plas ma. To app reciate this point, co nside r c....'Cuts
in terms of tlu- two-compartrueut model de picted ill Fig. 19-3. \ \ 11('11 distribution occurs
rapidly, dmg ill tissm' for IIIml of tln- tune is \; rtua lly at N luilib riUIll ,,;tll d m~ in p lasma .
T lml is.
 CHAP1U 19

k2 1~ .. k12A 1
Rate of drug Rate 01drug 21
lea ving liuue enlering lissue

and the rcfon-

22

which slll,"'S that the amount in tissue par allels tllilt in p!;l"Ill11, \\1I('n. !JIIW t'\'N , dist ri-
hu tion is slow relati ve to clhntnatlcu. li lt" concent ration in pla..ma appmacla-s its plate-an
!)t'fore much d mg has cnt ered tln- sl(," 'ly l'(llI il i b l'd li n~ tis sue. 111t' situation is the-n aual o.
~nus 10 a consta nt- ran- input into 11(1)lIIpa rtllle llt From which loss IX'(1 11'S. Accumulation is
dctcrmtncd by the elimination half-life , whk h in thts case is a"slxiatl'(l with k:Z1, tile exit
rate cou staut fmmlhe slowl)' t'f l ll ilih rJ,ti ll~ tissue . In real ity, the situation is s()lIlt"what mo re
co mplex 1>t'(',IIIS(" of tilt" n,\"('rliihlt" 1II(J\"("IIWllt o f <I m~ !>t°tv,"('("n pI.lstun aml tissue. :\011(>-
theles s. under tilt'S(" ctrc't nnstano-s. the con stant for tran sfi-r oul of the slowly l'fi ll il i lmll i n~
lisslll' is a major dlolt'nnillanl of the n-rl1linal mil"coustun t, "-1'

Bolus Plus lnf.sion

Lidlx-aille is IIM'lIlo control ventricular a rrh)1Inllia.. in t'lIIergelley S('lt inl{s. A b olus is J'in' lI
10 rapidly achieve an effecuve concentratkm and is foll(,"·t'(l bv a constant-ran- infus ion to
lII11int aill' ti ll' couce ntranon. Althnugh rhe infu sion l'\ 'l'Jllllally' ill'hil,\"('S ti ll' 1a...1 object ive .
tnutally it ca nnot match the f all in pla.smil concentration assodun -d with d isl rih ut ion into
tlu- tis.sue s. porennally I('ildi ll~ to a period of il1(,lTl"<:ti"lo couceutr aticus. TIll' r-wn ts an '
,1,"pk'll'(l schematical ly in FiF;. 19-10. A large r ho lliS dnsl' u u tlld overcome till' problem
but wuuhl IUSO inl'rl'll.,*' lilt, likeli!l,xxl uf Io.'<ilily be cause- of tilt' initially hi!-:hlor couce-utra-
tions. A (.U IIl IllOU prdl1i<.~dl solu non is to J'i\'(' supplementary bolus doses or an initi;uly h i!-:Iwf
mh o of tnfuston during this pt.·ri,x l of pott'lilial defici en cy . A men- elegant solu tion lil's ill
~hi nF; a supple mental, exponentially dt'(:linillF; infusion . T ilt' n!Jjl-'(:1 o f till" suppk-nu-ntul

Fi ll:, 19-9. slw...... ;U'f' t· .....'h in

pLo..tllll llIKI 5"""'~' t" llIilihr~li llll: li5'
5U.. fo,.. l"oo~) dn ,JC1 161 IKlt h t.Ii~' ' 00
hit-':po:Mlt''' tW (1i~p<lSi lioll 1o:ir...tx;s, 90
n...,. h., lho· ",.. ,ll!"..s for .....·10 Plasma
nf till' l'c" llilil ,~ ..·ffKic·"h c)'1 I, = 0.9
.....1k,;l hUI clilT." tn tI.., ,;n nlc1hutio n -- - - --
of ........ pha.... 10 t'!.im;llllIXIrI. ' ;jl;lIi ·
fi..c11'Y II..• ,;d,... of!!. For "0" clmR
!, • 0. 1, for Ihr uti.....f , • 0.9, t», Tissue
5pil.. clilf..I't'1K~" seen in pL..lIIl1. re
I'ruchK"t't1 [rmn t'il!: 19--It, II..• IIp"
pn""l:t. I" pLoIl'''" I" It.,- s.....iy
t'll" ilihr.dinll: Ii..", ..· ( 0) c1urinR II
' ...." hu'l ·nd.. I .~ . inf" "",,. i'l'ri"o;U"
;1\, mulrull...1 I...· II... I,'nnif...! Iw.If_
lifC'. ...hx·t. is tl... "'n..· for Id"
,1m ",. S , ltl' Ih..1 ti"... is l" pl1;'S.\t..J in
" 'n " ina! I""'f·lr....., n ho>ti:lllonlll! 1 2 3 4
tLo..lll.J li"rs 1~,rn"P' II O.5O'Illllll Timel(HalHife of Terminal Phase)
1l()Il of tho· plal"'"1 pll<llIil ,"..K"t·U·
I .... lion ,
CHAPTl ll 19 0I5TI11BUTION KUTlC5 '29
illrusioll is to match tilt' 1It't rate or movement into tissue . T his rate is hight·sl initially. when
110 l!m~ is in tissue. However. a." th e tissue conce nt ration rises towan] plateau . the net
1I\00'('IIlPllt into tiSSIIl' pn ~n'ssi\'dy declines .

AN EXTRAVASCULAR 0051
Oftl' n , ubsorpttou is SIOW N th an . list ributio n. so a pp roximatmg tilt' lxl<ly a.s a single (.'(1111-
pa rtuu-nt ark r au extravascula r dose is reasona ble. Occasionally. it is not . as illustrated wnb
t1i ~oxiTl in Fi ~. 19-11. Follo"i ll ~ oral admin istration. digoxin is absor bed before much
distrihut ioll has occurred. ami conseq uen tly, the distribu tion ph,L<;(' is still ('\i l!('111 beyond

10
~
t' !t. 19-10. Altho:lURIl il l.lIus (\ '1' CJ ) ( , I. · Riwn
10 inilially "..hit" , · II ,,";,,,,!, pt."'''ll lielo..a; (UK.....•
§. Inll ioll of 4 ""W'l.. CJ. (..n~IIl" 1 i"fu ...." " I " rat.·
n o.
c
0 8 ' lui 1 10 maiolain It:.is .,.] .... (1'>11. , • CL , Col) fails lu

~ do hI tiM' .~. '' '' If'lt'f)b , "",i,,~ 10 .li.lrih" lioo Id_

Iwli.:s . ~,ott' 111..1 f1l(' ol_....ed pi " (u"" " lntlio"
"
~
y
c
0
6
B
(- - . A) l< I"" ,"mof IIwt
(u >l<......1"..lid Ii....) (f.tt, 2) lUltl tlwt
i.Ill
lIh 1.... ' • •1".
,.;..t ed "1111 tI...
'"c
~
4
( 'OIut"" I· I1lt.. i" f".ioll {u >!." n '" dou.,lli".. ) ( ~:'-I ' 20 ). A
I"'W'T "1I1~ do... ('>lIl . . . 1Q'o1'" 10 p
.i3 .... 1 I.... UII M'("O-

0
e
A .. ' .' 1.....t1o", f,Ulin~ ..·Iow 4 l" Wl.. I"ll tI ,"" Iholt hi~ lui-
tial pL...m..(Ufl(Tnl ..... tit"", ( - - . B ) ""'~' ilK..,......... tiM'
:::; 2 .illlI..... "i lnxit:ity ll mWl, · 4.3 J.t M),
~
E
~

i1. 0
0 100 200 300 400
Minutes

10 HK. 19-1 1. n.' lit1....is ll ... mi k~ lllInieplot of

Ih.. TOf';oO 1.....lieMl of , IIl:1rri o f,lIl"Wio~ 0 ..5 IO~
...Imi"i"..·....!. " .11)' (tv.....O , 2.5·m~ lahlt..s. e )<I'MI i.v,
\_ 110 fOOf. ,>l" nItTn , llor. :. " "h...rpl ie,n is m OMii
fioUl..,. Ih .." ,li' lrih., Ii<"" .. hipl ie ('''1''1-'' i, ctill .. , -n
alt..,. ..U;oinnlt'T'1 or t"" I''' 'a!< u nlCO·nl r.. lie lll f"l1,,,,,··
; n~ t ""tlnol ,lo- .... l l mlifl , · 1.3 ,, \I).(Tak.... fn""
H " ffman. 1),11 . ilntl !u-llrll " ff, J.: Ahsurl' tiuo .. f
,mJJ:. jtiw" ~m n pn,.......diorn . JAMA. 2:l2.-u57_
A," 9fiO. 1972. C"''1~Tid'l 1972. An...ric>ln \1...11t,.] ." c-
""."iatitlll-l
,I ~",
I--...e
I \
,
..... ----------....-""'1---..

0.3 +--~--~-~---< f----,

o 4 B 12 24
Hours
330 CHAPl'Ei IQ

tilt' 1)('111.:. ('(JII('t'lItmtinll. In th is situa tioll tilt' 1)(';\1.:. conc entration ami till' !iIIit' of its 1I('(1lr -
rt'1ll1' rh-pe-nd 011 li lt' killl, ti t'S IIf hnth ah sorp tion and chstnhutnm and minunallv uu dimi ·
nation. n it'implira tion o f tln-se- PH 'n is In dm g t1wrJ.JlY;!Iltl m llll ihl rillg:dt'llt'ml" 011 wln-ther
tln- sill' of .u-mm n-stdcs in 01 mpitll ~' nr 11 slnwly ('fillililm ltiu g: tisSUl', D ign\ in dbtri huh-s
slow ly iut.. tlu- ln-urt. IIU' largd 1IT'K<ln . :\ ('\,(lrtlillg:ly". it is il\;\p p m priilh ' In n-lan- plus ruu
(''O lIn'n l m lio ll In j,lTt'1:t lIul il di st ribu tion ('(Iui lihrimll is ;!l'hit·\l'11. fi lrr is 11 <'tl1l....-r...a tive
('st irnah' fo r th is <1 m !!: in llIosl patu-nts . Ht-fon' ,IIt'Il, res polN: illt'n'il" 's dll(' to it risin g
cardiac ('( Jl 1('(' 111 ration. ( 'W II w ll('1\ p!,lsmll (111Wt'lll ra l io ll is t1( 'd i llill~, lI1a ki n~ a ny Interpn-
laf ioll o f tlu- p l''-'IIl,1 {" ll('t'u l ra lillll t''''tn-nw l,. dillku lt (C hap. 211 p..').'),1) ), III (' IIl I r.l~ 1 10
d iJ.:O\i ll. lIl,m,. t1nl~~ t'l p lilih ra!t· rapid ly wit I. Slid . 1 1i~l l l,. 1)t·rf uS4;"(l lisSllt's ,tS lu-art ami brain:
tlu-n pl a.s ma ("tIll(" llt ral io n ("tlffi·lalt-s IXlsitin·l,. \\i lh n 'sl)tlll....• ill a ll lm i Ilu- earlir-st tiuu-s.
As with tilt" si m p ll' 1I1l1'-t '1I1l1l<u1111l'1l1 mudd . bio;w"il..hili fy is Wn' l\ II,. F = CI.. · At'CI
Do....', a nd n 'bt iw bioa\·,tilahilit,. is t'slillla!t,! h,. t' IIllIl<lli \C lI\ Ilf ..\ L'C \ a h lt's fn llll\\ill!: dif-
ft'n'nl Ionunlarions o r 1'l1ll!t·S (If atlm ini strat ioll . ('( Irn'("!i ll~ fill' tin....-.

MUlTIPLE DOliNG
T he illll);lt"! o f t1islrihlllioll kun-tics 011 t'wllis d urin!: muhiple- tlllSilljl is illustraktl hy tilt'
dala ill Fi ~. IH- 12. " I,t ai l"'l l fol lU\\ill~ a ll S-lullIrl,. i.m . n "';lJlt'1I of ~t' " l am id ll admi n is!t'n'( l

~
§.
10
100 ,.
is 5 3
50 g
~
E •
\
3
9-
g 1 '~entamicin in Rapidly
8 EQuilibrating Pool 10 ~
-._ .
0.5
c
:Q •
"'-..
5 "n3
- --.---
E 11 11 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 r
r 11 3·
" 0.1
~
~
Gentamicin Doses. 80 ma "3
o
'"E
2
!X o 2 4 6 8 10 12 14 16
Days
n". 19-1:!. 1),1',,1,, 1 An ' "'mil"~:ari ll, mK' plu", "f ,I..· ·1. "f 1:",,'a"'K'" ill II..· I...." ,..",nTi,,!: ,Iurin" " ,..I
Afk. LIll . "' hnini.t.al....' . 'ol) til\,(. ,J",..., ..... · I~i .. I.. I I "' 1".1"...".1I,:!' am""".) ' 0 a 1';,h' ·" 1 rur i'''' '''''r '' ,Lo~,, _
11,,· hil' k ,I...~ " ... in .. ·..."n """,('T,'r"l ~", , • .1 " I..'T' .. 1"'ini. I.-" '....' "-a' 'h~'1 ... 1" .... fi ll,..I I" " ".. ""·1 11",,
..." " " ,10", l:" "'a",it~ " . 1i,'nl..," ·. I...." . .....' ;a.I. ", I~· ' '' Iuilihral inl!. " ""part" ..·" , a,,,I .. r"[>i<I~' ' '' I'' ilih rali''" •• "" .
I", rt",," ll f....." w"io.~, ..lilllill..litll•.• ·"' ir..l~ I ~ WI...! ,·"·0'1io..,. ' ''.''" (.. . . Fi~. 1\j.....1 1. 11..• lit "... tI"·I' O'..lidn l
.. "".·" I.-..Ii.." . (•• 01.,",,1 Ii,,,·. "·f' ·h",..1" Ii,...,.-). II..· An.."",1 in ,I,,· .-..pitl~· ''' I,,,I,I''''hnl!. ,,!"" rt "....'1 (n ol...... 1
I" ..·. "j(t,,·IM,..1,,,,1,,...1.·). A.-.01, nhl.u, I I~' muh ,p1~llll!. II..· .. ·" " n .. ..".·" , .-.. lit",I ~ 11..• tim.." ..JInih.J .bl"lio..,
..·
,, ~, ItI 1tI"·p"..1"1,..I.." ,,,, ,n , "'~ ,,,,, "lt h.-Ah"l/: n ""I"'rtlt..·" t l'.....·l li...·. ri0'1 ·1......1,,,,h ,,,,,,,' ). I .iIl~
..." ,,,,,1,,1 , ..,,[IIa~· Ih ,,1' lio .... "f [1 "" 1/: ' '' ' 1 in ' ....' nM al,,1 Ill<' ....., "r II..· .-.q...IJ~- ' . Inilil"""illll: 1"'...1. I"
.. ",1.-..., . ,I..· «... I a", it~n <I(", ~'. , .. ,I ...." ·n ·~· ","''''L I'... i " II..· .I. ", I~ ''' I''ihhrahllll: 1....>1 duri"l: tI...,1!. ",1"'In ·
i. lrall. ", . "ill, hlt" · ,h..1,,.<l it.., wilhl"" ,I. inll: Inl t , I,,;al' ..·.......... • nf dllll!. rn ,,,, II..· .I. ", ~' ."!u ihh.-,,"l'!:'l .,
i• .J." [.., d''I'I>I''1I: 1o:" "I"lUit~ " , 1 ), ," ,,~ ", Imml-I.-..I" " '. ,I..· n n"" " luh,," ill pL...,,.. aflo" ,I..· :'Ii ll, 11
I..· ...lo..,L" . 1 f"",, tI..· f"rm " l..

" I..·...· " " I, II..· It ..." '''', ........ • , ",w " ......r;.. t . f i. tl..· h" ..· .i "..· 11... la.' ,....... a...1 \ ., i. II..· inili,J ,bl" lit" ,
" """"',11,i. ' . I" odit.., ...", I,,· 1"·ri 1u\in" II,,· m"lhp!<·.. I<...i""'. I".,Ii<",' _\ I, ,, ·t.. I'~ 1_1>1. .....,""'i nl/: lIld .."I;u ... ..,.
.J...,'1"...., 1,10,· "",II,,·n,..I".,.I u l lp _322 ) ( I mli'."l. .. I." 11\1). (" ,lap" ..l 11'1 " " Sd....n'~ JJ , " IKI Ju. l ll. W-J-:
H''T ,al I·..·...-at • ",..1',,,,1<' ' ''' u'L I;,II, " f « '''I''llI'''''' _e lill 11''' ''n", • .1 11" '1,, ;2.t:lf;.l ~l7tl. lilT;' 11,1'" ..1,1<....1
,.,110 I",·n lll..it.., ,,( ( :y \1, I ~ .J
Q-IAPTfR 1Q

to a patit'nl for the t rea t ment o f a serious inf('(.1ion for /) days . St't'll are large lIul'tllatiolls
in concent ration n-'s uhi ng from thi s regimen ami a lon g terminal half·life o n stopping
therapy, In 1'OlIImOIl ....i th o tlu-r a minuglyt:osides. genranuctn is polar, ami while it distnb-
lilt'S ra prdly into the e llr.K.'t.'lIl1la r wate r space, approximate volu me o f 15 L. it enters cells
\1'1)' slowly. Accordmgly, althou gh ~c n tam ici n has a long terminal half-life'. 87 IIr in thls
path-nt, the majori t)' of a tlt)S{' i .. eliminated hy 8 hours. a..sociat ed with the .. -h e half.lift·
o f the- first pll a'\{' in Ihl' pa lie nt, Indeed . as a reasonable approximatio n. tlte temunal p h,I-">('
can ht· igno n "(l with rt'Spt't1 to t"\'t'nts in plasma. a.. was (lt Jl1t~ pn"\i ously w hen considering
gt'llta mici n dosing (C hap. 18, Co ncentration ~I on i toring) , The n-asonableeess of thi s ap-
p roximation is horne.' ou t by the obsen'-"'l! rapid establishment of a plateau ill plasma ami
by the co ntinuance of large fluctuation s in ccncentnunon, a n-snlt expected for a tlnlR wit t.
a half·life of .. hr wh en it is gi\1'n 1"\l'I)' S hr. Asso d atcd ....ith th is regimen. oo....'t"\'t'r, is a
sm' but continual eccumulatkm of dru~ in the slo\'\ 'I), t"llllilihr.lIillg ti.\SIK'S. when- it takl'S
apprtedrn ately 12 d ays (3.3 terminal half.lin.'S) 10 n"'eteh plateau. Howeve r, at plateau. at..
cu mulation i.. 50 exte n...bv that mon° gt"ntamici n exists in the se tissues than. 0 11 It\1.·rdge . in
tltc rdpit.ll)· t"(l"ilib rdting pool. Furtbermore. Jntle flul1uatitm of dru~ occurs in tlK' sl(,"1) '
t'~lll il i brati n~ pool. because of slow distri bution,
Accumulation . both ti me-course and exte nt then-of an' clearlydependent o n sitt"ofme-a-
Stlrt"IIK'UI. For RI'Tlta mici n litt le aet.'l mulationoccurs in pla...rna, and a pla tea u is n'achtod ,;( IU I\
aIter initiatiu Ktbcrapy. In centrast . e xte nsive accumulatio n occurs in the slawly t'c"I"ilihrdting
tissues . ..... he n · it takes 111m'" km~l'r toattain plat eau . In C hap. 7. ba....-d on con...idl'rlltion o fthl·
minimu m lImuun t of dnJ~ after the first WlM! and at plateau {p, fi7 ). a pJUPOMod index o f ac..
cumulation wa s 1/( 1 - f.' - it), As a reasonable approximation . th is tndexcan also he l·IIlI)~'t..J
he re u...ing the approp riate- exponenttal ('O("fficienl. For exa mple. in plasma (A.I = O.171 Ir- I;
t 111 - .. h r) ....itl. t • 8 hr. the accumulatio n index for ~'n l arn icin is on l)' 1.35. wh(' rt'a-~ in th e
slowly equrhhnatin gplXJl (~ = O.()()f) hr " I ). it is as IIII1C·1. as 16,
Tlse e....ents 011 stoppi ll ~ ~('lI tamici n ad min i...tratlon an' predictabl e. 11K' plasma C'()f)('('ll-
tretton falls rapidly fo r the fin.t 2 days . .....it h a half· life controlled by the fin.t pb asc. Even-
really, h(I\\'l"\'-'r, elimluatkm of dnl~ from plasma i.. rute-llnntcd b)' return from thl' sl(I\\'I)'
l"(ltli l ibmtill~ !iSSUI-'S. Except for the hi ~h dt."Wt't. o f Iluetuanou. the 1"\"('1115 seen in plasma
....i lh ~l'lltamkin are thoSl' ('''l)('(.1('(1 foll(l\\i ng a constant-rate infll...Ion for lIU)' d m ~ \\i th a
It.
low \"alll(' o f (Fig, 19--9 ),
Sigllific'llnt clink," imp lk'lltiolls ari se fro m the d istri lmtio ll killl'tics o f ~cnta mici u . !l.l ost
0!'Jtauisllls agai nst whkh gt' llta midn i... IISl--d. rt'side in tilt' r.tp idl)' t"tluilihr..ting t'xtnl<'t·llular
sp<K.'('. ami so fn 'f1l1{'ut lld lllillistmtion is m'todl"ll to maintain an !KII"tlmd t' lIntimknlhial
t'()Iwt.'ntmtioll. Unfortullah 'ly. ototoxici ty aud !U'phmlnxici ty. ll-..soc'iatN I ....i th th.. ll('('u mu·
latio n nf d m g llt slnwly ("(luilih nlt ing sitt·s \\i tbin tht.' ears lIml kidneys. ca n 1"\'t'Uhllllly Ol'('ur ,
AC,,('\lIllulatinll Cl.lllllnt he a\'()id<"ll if an e fTt't1 in' pla...ml1 COllet'ntrntioll i... to lx, maintaim'<.!.
T n minim ize the pmhlelll. a pmd elll pml1ice i... to limit till' tntlll du rAtion of ~l'ntlllnki n
atl minist mtinll wh(,Ill'\l'r possihle. M ()nitorill ~ th e plll-..ma l'()Ill't'utmtioll also m;IY Ilt'lp . of
til(' m(,<I-~ un"S in pla.~ma, the trough value is ti le IIlOSt se m itivl' iurnmtor of the ri...illg IUIl-
(.'('ntr..!ioll in ti ll' slowly equ ilibmti n~ tis."lIes , ," tho liRh a~ illustrAted in Fi~. 19--11. ("\"('U
this mea."lIrelll t'ut is not Ihal sensiti\"('. Sonethdess. JIlonitorill~ of trou~h t'OIKX'lltrlltiuns
is of \'a1 ue , p<uticu la rl)! if thl' c'OIlI"l'ntratio ll co n tinue s to ri...... indicu.ting il grelltt'r -tha n.
e xpt't11't1ri"'t' in tlJ(' sluwly t"tluilihmtillg pool "ith a t,(lrrt""pt lndi ng illcrea.\ e in tI... poh'ntial
for toxicity,
A C'( )IIII11I'nt nt't"(1s to hI' mad e abo ut th e applic'lltion of \'Olu mt" tl'mlS to multiplt· IktshlR
wllt'lI distrihution kiul't ie5 p n ....ails . 10e pu rpose o f a \'o lume tenn is to relatt." pLI-..ma
COIlI"l' ntr..tiou to amou nt in tlw hody. To app n't;ale the issut'S ill\ul\ro. co nside r the 1"\'t'1l1s
at stt·.ltly state , FolI(J"ing a co nstan l- rate infusion . \ '. is the appropriate \'Ohllne tl'nli tn
relate pla...rna C'()f)('('ntr..tioll to amou nt in the hoc:ly, With multiple (losing a tnll" stl·,tdy
.5 ... :-:
~~ :;.
,"",1· - "i."'-· ­
:;.~;.:- ":: .....
~,-. :....
O iL =. "'~ ~
= ;1 "
w :;_ i:: 'f=- ..:l:: .~
5" - '"
= !!. -' E
, .
~~~ a 3~~;';-i.f~
,. "'- '" ~. .... - f
... . "'_x l!l
::' "

;a ~<c ~r ~f~H'i H ~n ~~
i~~;:l
[ "' = '''':f .:0'
~ 3l. ;' ~ ·~ ~- S
:;;..:;:

¥i ~ =- 3 " !:, .:., a~ i", ~

':'" :-:: .: J: 'iii AmounVConcenlration, L Concentration. mgll
!" 2 i!.;r
l :' f.,. . "~ "'-: ~'! ":; i-
~ i. .
<: :: ' ,;7 o
!' o o ~ l5 <!; o
,.
~_ 5 ~-:-
:-, +:;; :1.
i- = ,:t'i til
_ " ... _. ", ~ .. r:. - _ J- '"
-" if ,, , , .. '" -,

~. ..;. t' ,1~ ~" "'_a ~_ ~" ';: :r~ "'; t~i "~ -., ... '-

'. ....
'
• i:! :::": '! " ii" :"' =- ='" '::''' ,
_._J~ ;.,,_;:/,"n
:: :' _ " <1;
,

~n-. .>-", J - ~.~/l1- .. 11.

:::. .. ..:
"
.... _ :l ~ ~
,
,

~ ~::'
" . :: =' e !1 .5 _ Ai .. !:Jl, ;l :: ,,
,,
, f= ~
7 ]0; ;: i:!.!:>
",, "[=I
:L.. ,.... :- :, ..
. .. _ ..... ::1. 2 = . ,, , ,,
~
~
- 5 '! if i ' - :'·:l = :r - !: ,, , , ,
;- ,... : : I =-
,,: ':0- ::- -= 3 ::;' .5 ii. ,, ,,
x_ -"
,, ~ ~ _ i ;"~" -!~"t.'='" -. = ."" '"
o~ '"
o~ ,
,
= ! :: ~ s, '; ;; ~ !:, t' =,~.=-.,., ~
•• ~
,
,

~ri i :;t != ·<~r~i-

riJ!!~ "
:- - t. ::: - ;;- i'" ;;I ;! '"
.."..
•
" ,,
,, ,, ~
;r ~ _i rt" a
,
; ~ __ = ~,..:i~
T ..l. · · : : .... ... i:!
,, ,
~ ,,1!1ji.·! .. ~e;.::< · = ",: ,,
... ~ ;~ =< =.!! .! .. :~y;, '" '" ,,
~~ e-iii !!~_ !!i! !L3 ~=·~ =~ r~ i~;
': s- ~J; ;. :; :: a
",: , ,,
,,
ir a !!,e :,' = ,~ ~-:. ~ i'-i- ,-
'- _ .:
"
=.',: ,,
,
,.:; "' > it l ~ " ll"j!! ~:; ,
r; - = -", .. J :;' '" '"
~1.=_ _: if il"' ·~ ..'f" r:.= .::~ -5 l=S,,
i - ~'5 -e
§:~ J=r -~~ -~ '"':~
...';! :: -
! !~=: e,i~- '!?-s-
.. '5 "" ! ~ ,, " II' '5 f
'" ,<

!. . ;.;:roTEl
S" =u
~2. = ~=, L- ::' = ~-'J4i- a
ji ... "
...

~
~.i" ,:::. :.. _ ,,-:z -
!~::o i ; = ?l
~
;= ; ~ t
~ i r- t ~r ~ ~•
, 1'1 ... .. - ... ""'"
a,:i! i"
_~ I,= ! ~K
$-
j-
=- ! i :l
~:: ,;fE'I-'
. " ._ = ! - ., =.:l. ~
="~ ::... :! ="
_ =1
~ '? -c
C HAI'TU tc OISr~ KNTlCS

state does nul apply th n m glKJllt a dos ing inlt-rval: th(" plasma concentratio n Huctuates
around a steady-state value . cwating a co ncentration W"cKlit'nt ht"l\.1o~"n p la...ma ami tissllt"'.
1I0\.\'t'\"t'f, a-" Illustrated in r ig. 19-13. as long as the fluct uatio n in plasma concentn mon is
smal l. tbe con d itio n is sufficiently dOS(· to till' t rue stead y state that V.. om still "'t· applit-d
to es tuuate amount in till' hud~·. n ils cond ition exists when input into the IkIl;l,. is s1l:",',
n-lanve to dispnsition ldne tscs . or when the dO!iin~ inte rval is short ("{'!atn't' to tilt· thllI' tn
aeh it"'l.· d istrihu tion equilthrtum, A-.. cne moves a\-\~el~" from this condnson. ei tlK'r wu h list'
of mo w rapid inp ut (t'l tn- lIl(" lwing an Lv. bolus) ur I,,· \-\idt'n in~ tlK- tlosin g Interval , tht·
dt...i atio n fnllll til(' tnlt· stt"a<~' sta te increases so that \ '.. has less app lica tion. ITKL.'I.,(I, if tilt'
dosing Interval is klllg t·nough so that di stri bution equilihrtnm is OM:hK",'tod. the n \ ' ht'C.u llJt'S
the appropriatr \"o lurn(" te rm to list' bu t. c1earl)', only tluring the te rm inal pllll.....·. n it'
problem is t~·ra h'l.l wh e n dist rihu tion equ shbnum is nol lIChit...«J wttl nn titf-· tlt:~ing
late rval, a.s is tht· C"dM" with gl'n tamK'in (Fi g. 19-12). Then tlK'" reltin of amount in but!)" to
plasma concennauon is conttnualk- chan~ng. and neither volune- te rm . \ ' o r \ .... is ' 1;'1)'
lIst' ful. F n..-Illt·nt !).·. IKJ\-\"{'\'t'r. tlistrilm tion is sllfficit'n t ~- ra pid to a1krw olK"-(.'Ompartlllt·nt
dispositio n l'harolll1 t'ri"tics to appl~' on multiple tlo!iing at stt"dd)" state . nM -n, \ ' am i \'.. an'
al mos t t'1lna!. and roi tht"r can lit' used to gain a reasonable estimate of amount in tlH' bot!)" .

AtTII!D CUARANe!
\ \ 1"-"n discwsi ll~ th t· use of gt"lltalllicin in patteuts \\.i th re nal ins uf'llcit-ncy (C hap. IS.
p . 3(6), 11"-' te rm inal pha.w is igrs orcd in adju.stin~ tJos i n~ n -gin k-n5 to ac bit'\'t' th",ra pt'utk:
concentratsons . nil' reasonableness of this approach is illustrated in Fi ~. 1 9-1 ~ . Dnly tilt'
initial hal f· lift' ts aht'rt"ll alUolIF; patit'nts " i th varying t!t-gn"t'" o f renal in sllffici t"I1(:)'; tilt'
terminal half-lift' is virtuallv uuaffec t ed. The observation mav lM' reltionali7....d in titf-· follllw.
ing manner. \\1It'n renal fUlKt ioli is u nimpai red, gt'll tamicln in th e rdpitll~' t'1luilihmting
pool is mostly t'!im ina h'(l hefolt' dist ribution equilthrium is either lICh it...«J aftt'r ;k lminis-
trerion of a holm. d OSt' ( Fig. 19-1 5 ) o r re-es tablished on stopp ing ill.tml nistrdtioll aflt 'r
chronic dos h l~ ( Fi ~. 19-1·1). Under th t'St' ci rcu m..ranee s elmnnation lila)' be viewed :L\

tl~. 19-1... S.·lI1il"~lll1t hm ic pauli of II In~" ... in II...

10
... n "n " " .......U"Ii..n ,,( K"'1"mldn tn r r pooIlt'Tlh...' 11>
.li ff nl ,101C'''''" flf ........l rmllot~ _ .... 1 II) .,.....
atini d " OITlU>l? CL,... afT"r tt' '1 '1''OK It",tllrnkin ;MI·
111Ini..t ,.",j..n S Ol ..... 11"'1 rn>aI ru nctinn Impounlln.1 p "';.
m..,..;I)' afT....ot' tI... h.oJr·lif.. or ll... Ant pha · lIlld ,I..· .101"1,
or II 1o·t"1uw In t"'...... ntnlolkon h.·r'll? 11 1.."ol...,] pIu.....
i... n- -I.....I (I "'WI. - 1.Ii",MI. {Kro.I....."tl rnll n Sd,,·nl..~
JJ.. IlL, kll. WJ . PLauT. \ I.E.• Cumhu. TJ. \'1U1l.... J W ,.
;md Ah ru l}"tl. E.: nn.... J""nhtrtk... of K" nlllmlnn in
n"'n , J.-\\ I.-\. 2.J.'l',327 12'Y. 1m . ("""","~I 1~';"7. A.. ... r_
ic'>on \1 .~ UoU '"'-u..ciA d
•
o

107
•
0.D1
o 2 4 6 8 10 12 14
Time Since last Dose (Days)
334 D1STfI1BUT1ON KN E1ll: S CHAPTU lQ

UC.,('1.lrrill ~ (mill vnlu nn- \ \ \\;111 a ch-aruno-, CI.. B ell et' th e rat e constaut for dL't ;linc.· ill tilt'
mpitlly ('fluililmitilll-: 1)('01 ( i lld l1t1i ll ~ p loLslll a ) approaches CU \ ',. wilh 11 l,(IITt'Spn lld iJl~ half-
life.' IIf o .r~J.:l · \ ' ./CI•. Hcduct ton in d t'liralll't' is thr-n rt'flt'(1('(! by an almost p mportional
incn-ase ill half· lift, of tht' first pilot"'-, In contrast . duri ll~ tlu- terminal ph a.\t,. loss o f d m g
From plasmu (;U1d tilt" mpid ly t'( llIi l ihm l i ll~ poo l) is cont rolled hy return fmlll till' slowl)'
l'f i ll i l i h mt i ll~ liSSllt'S and lIul hy its cleanmce from plasma. :\l'('onlill ~I)'. tilt' te rm inal half-
life.' is IlI lt· hall ~I "l,1. 11 0"', ("" ''', \\ith a reduction in clearance. di slri h ul io ll {'(Illilihriu m lake..,;
somewhat !oll/.tt'r to b.. ('st ablislll'd an d. IIt'l',lIIS(-' II's5 d m~ is c linunan-d Ity then, ti lt' ron-
cenrrauon o f ~t' llta llliti ll in plas rua is h i ~l l(' r comp ared .... i th tl mt ill a patien t with unim-
pairt'(l n-ual funt't ioll (J··i~s . 19- 1.J and 19--15 ). U!ti mall 'ly. if renal fullt.1 ion is 5llffidt·n tly
low , tln- h 'n uillal llil!f-Iifl' is M'usilin' 10 renal fUlldio n . T heu tilt' first pha.'>t" prillla ri l~'
n ·lIt"t:b di ~l rillU liuu . a.~ ..hewn in Fi g. 19--15 . Tn ap pre-ciat.. tht" last point, t'lmsidt'r ad m in -
isiraliull o f a bolus do'\(' of dn'g 10 a p atient wi lll 110 rena l fu ndioll. Dmg ill plasmn wo u ld
..till tit -clim- init tallv ....-ith ;l Illllf·lif(· dt'!t·flllillt... 1 so ld ,,' bv distnbutton. Be twe-en this extreme-
aud unimpam... 1n :lla! flllld iu ll i... a I"lmgt' (l\l'f whid l tin' n-rm tnal h:uf-Iift' d l,mgt"S nonce-
ahl)' ....i t" rena l Iuuct kru. For gt'nta mitin , C<lk' u lalio ll shows tl.i s 10 oc cur wheu renal Iuuc -
tkrn is It'ss than 7% tlf normal. Then. ,11I)(' it s lowl~' for ~t:"ll tallli dn, di st ribution is l\(:h it'",d
IM'fon' 1I11l1'1l dmg is ehminatc-d, tilt' t'lllltliliou lhal ncnnelly prt>" ails for mos t d rugs. :-.;'ow,
In ret urn 10 a point mittIt, p n '\ io llsly alMIIII \ ' and \'... As n-nal fUIlt1 io n diminishes. so dot'S
lilt' value of \ ', Thi s is a result o f less dmg ht,jug d im illatt... l lx-fon - di sl ribu tinu t"llui lih rilllll
is adlit' " ...1. III cont rast. lilt' va hre o f V.. rt'IIl1UIlS 1I Ild lall ~t"t1.
" 'il h ~t' li fa lll it'i IJ , couceru exi sts for t'Xt'l'ssin' accumulatkm in tilt, slow ly t"till ili h r,llill ~
ttssucs duri n~ chronic dos i ll ~. particularly in pa tients \\ilh n-nul Insuffici e ncy . 1I0" 1.'\ l' r.
p n l\i dt ... l rhat dusin~ m it' ha s IIt'('1I ,l(ljm lNllo t'llllljX'm alt· for d im illisht"tl renal function,
tilt ' risk o f lo\ k ity in I,.Itit'Uh .... t th n-ual insuffi dt'lIt, · should !It' no W('a lt'r than in tllt N '
\\i l h Ullilllpi un... 1 n-nal fU lld ioll . This t'\JIId us inn is l,.lSl,'t1 011 consideranon o f events a t
pl att'a u . Tilt" amount in thr- '0111\\,1)' (>t!1lilihmling Iis'O \It's at 'O tt·a d), slillt' is tilt' di fft' rt'lIt't'
1It,tv.'t't' n tlU' amollnl ill ti lt' I M N: I~' (\ '.. ' C .,) alltl Ihal in tht' mpid l)" ("tluilih nllinK pt N: ll
(\'1 ' e..). Tlml is,

. " 11:' 19-1:5. St·m l "~l h lTlio.· [' IUb nf lb.· Rena l Function
. illl" I;t"..l ,....·h,lt· in ,Ilt, " L' -'lI1;t (~M " " nt r;ttinu (Percent of normal)
..r"'r i .\ '. I• .t" , ..<Ill1 ini.<tr;tlitMI . of;t doll/. wid, 10
,11' 1" .. ih' M' d ...mt1,·ri>tit, .imil..r ,,, ~,·n l ;tll1 i · o
<'ill. fur .IotT.·.. ·nl ,t."W''OM of ....,u1 f' '''dieM!
fr"llI n In IIM l'I- .. f Ilnm,..\. :'\O" t k o' llul .. ..".I
r""tiie,,, "rin...rily :UT...i. th.· hllIr_lir.. or Iht- ~
o 3
1i"'1 1'1",-... ;tntl Ih.' ,t.'f'lh or . t..l"1i.... ill ('(MI-
,·.· " l r" li ,, " h.. f"ro· tl,,· t" r/nin,,! 1'1,,,... i. ~
E
r.."d.... !. "nli l " '11,,1 fllndi" n i ·0' I..w . 1l
\ \1lt,,, rt, ...1 fUllt i ie," i. wry I ti M: inilLal :5 0.1
, t. "~; llt·
;0 .t.i n llllu,..1 rri n...ril~· I~' oli'tri h.,· <.> 10
tin... ;t1,, 11 1... i"'l';t ir m""1 is rt·lI...·,,·,I I,y' o
d,an~ .,. in lilt· " ' m ,;"..1hllIf·hft·.
"
o
E0.01
~
33
100
0.001
o 125 250 375 500
Hours
Ct-WTE9 rc ClST918UT1ON KINETICS

~ffiO\If1 1 of drug in slowly equilibrating = IV _ V) .C

23
msoes at steady stole u I ss

From thls I.Lst n-lunon ship il is S("('II that , p rmi dt"ll dosi ll~ r ate is adj usted to maintain a
~in·tl sh '"dy-stalt' p l,Lsmil o uux-ntratiou. tilt" amount in Iht" sluwly t'(lllil ib rati ll~ IiSSUI'S is
unaltered. a.sIXII II \ \ and \ '" an' pu rt,ly dislrilml ioll terms that, at Il'asl for ~t' l\t a m il'i Il , an '
IlIIalk n 'tl h~' n 'llal iIlSlIllidt'lIt·y .

Changes in (olKentration and HaK-rlfe

A ('t md ll di ll~ (, mlllll'llt is m-cdedhen- about (:h an~,'S ill plasmu concent ration am i half-
lift'. cOllsidl' r tilt' follm\i ll~ tlln"(' questions. \\1Ial is tilt' Iillll' llt't"(lt"(l for tln- plasma t''OII-
reutrutton III t ill by olll'-half followin~ all l.v. bolus do st,? How lon~ tlot's it take 10 reach
.5()'k (If plate-au folllJ\\ing a constant rail:' in fusion? \\1ml is the dosillV; Intervalneede d to
en sure th'll the- maxumnn ;U1d minimum pl,Lsmil concentratfous OIl plateau differ twofold
foll()\\i n~ a lixl'lI-t1oSl.· nmltipk- Lv. bolus rt'¢lllt'n? \\11('11 dislxKitinl\ kineti cs is character-
il.l'l! by a 11I1l'-t'J l1lpa rtllll'nl model. rlu- lUlSW(' ~ 10 all thre'e• question s ure simpl(' allli the
sanlt': lilt' k limination) half-lift,. It should lit· appan'llt, however. From what I.'LS IX"l'11
dis('usst'd ill this chapter. thai tilt' an swers cannot be dirt't.'lly inft'rrt"ll from tilt' terminul
llalf-lif(' \\"11t'1i d istrillllliflll kinetics is evi dent . 111 (On, termtnul h,Jf-lift" or illtlt"l"ll any half-
lift" ('l',L'it'S10 han> simplt, applil'lliioll. 11.1' lUlSW(' ~ 110 IOIII-":t'r lit, just in 11.1' half-lift' \'lilue
of lUI t"IXlllt'lIlialll'nll hilt mlllt'r ill lllJ the p;lI'anlt'te~ thai dl' lilU' tilt' entin- phunuac o-
kiuctk- mo del (t·.I-":., C ], j _I ' C 2, j -2)' KIl( )\\ill ~ these p;mUlll'lt'n , rlu- lillll' 10 adlit,V(, any
couwut ratiou r-an lx' calculated dll rill~ and foll( )\\ill ~ d m~ admiuistrution .

STUDY PROBlEMS

lAnswers to Study Prob lems ore in Appendix II .)

I. I>dim' Ill(' fllllo\\il\~ tenus: inilial d ilution volume, \u llllll(, of distribution dtlrill~ IN-
mina l ph,L\t' , and \'OIU lIlt, of dislrihut ioll at sleady state.
2. Comment UII lilt' f(JlI()\\i n~ statements.
a , All d m ~s an' (', pt,t:It"l1 to t'xh ihil t1isl rihutioll kim-tics .
h. Fur IIIOSt d m ~s it is r easonable to n 'pn'S(' 1l1 the d ispositi on kim-tics by a comp art-
mental model. wi th dim ination cccu rn ng ('xdllsin ·ly fm ill the ('(onlral COII\Il<trtlllt'lll.
c. Fo lI(J\\in~ all is . IXIllIs do S(' flf dru g. t'sst' ntia ll)' all d rug is l'liminall,1Irmn rln- Ixxly
by 5 termiua] plasma half-lm-s.
3. Aspirill l"MlSs('SSI.'SlmuIW'sil', ann-intlanunatory, and anlip lah'!l'l activi ty. To l'1laml1('ri7.l'
lilt, d isptlsiliOll kim-tics o f this dmg. Rowland and Hil'gt'l man inlrawlluusly admmt s-
1('( "11a fi'50-rn~ IXllns doS(' of aspirin, as its ;\:-IIll'lhylghll'ilmilll' salt. 10 subjects. Ta hk -
HJ--2 lists til(' plasma concentration-ttme dat a obtained ill one Tl'I)J'!-'S('ntal iw subjt"l.'1 .

'."'.19-2.-
TIME lmlnl I 2 4 8 12 15 20 30 45 00 70
Pb!>tT'IQ hpl,," 98 22 17 12 75 37 18 12
COOCe<lI1"OI,on fmg/lt'
o ~ ~ _ ," f ~ /vi ,..j ~~
82

5
" 33

Pto-mcx:oIo .....-o <J<IC ~ ot.d ontl ""'=v"c <ICodd'te< ..--..,... ~ ..

...,.,J"-"
X. ~71313-IJIQ 1%8
'0>0 "'9/1 • ~ " ,.M

u. Prepare <t SI.·ll1i l(J,.~a ri t ll1n i{' pint of tilt'S('da ta. Usin,l!; the- IIWtll(X! o f n-skluals. estimatr-

lilt' vahlt's of tilt' pumnu-ters o f till;' hit>"I"MlIlt'utial equation that fi t these d ata (C l,
j 'I ' C2• J' 2) and tlx' initial and tt' nnillullmlf-li\1.·s.
 CHAPTER 19

b. From tilt' (Xln Ulll'h ' f val ues ill MaM, c- aIclllal(' C L , V \ , and v,
c . Frum tln- btexponeunal equation , predict the plasm a ccncentranous at 10, 50, and
7.5 mill a nN tilt' holli s dose.
<I. I la<l a not he-r 6.'50 -mg bolus dusc of aspi rin ht,t 'n ati minis!t'n'(l3U min afte-r lli(' first.
wha t "~J11 ld tilt' plasma concent ratio n 1)(' 30 mill latN ?
4. Hamilto n ('I al. (rt'f('n ' lIl,(' in Table 19-3) RN'S ~ '(I the effect of al'(·tylator p llt'llOl)l)('
O il tll(· d is!)()Sitiun kine tics of amnuone, a posit in ' Inotropic agcut wu h vasodilatory
properties. TII(· acetylator sta tus wa s deternnm-d for tilt' su bjects with iso niazid . Eadl
subject t hen n-celved a 'j'5 - Ul ~ bol us dose intra veno usly (infuS('(! O\l' f to mill). Table
19-3 list s th e plasm a couccutranon- ttnu- d ata ill 0 11( ' slow alit! O lil' foL'it iK·t'tylalor. The
d m ~ is lIwt aboliz('(1 (p mha bly in the Ii\l' f ) and is cscn-ted uuchauged. Both su bjt'<.'!s
wt' igh('(1 lilt' sa me-, and till' duS('s were WH'U inslant allt,(lUsly.

r.~I. 19-3 .-
~ ~ CONC~N1R"o,IIONLmsflt
SlOW ACHVl....IQl1 fAST""ClT'fL,t.IOIl

010 1.30 1.20

0 25 1.03 0 ,9 3
033 0 89 0.7 6
05 0 72 0 .54
007 0 64 0,41
I 0 .59 0 ,31
2 0 _51 0 ,19
3 0 47 0 .13
4 0 42 N O'
8 027 N .D'
12 0.17 NO.'
15 0 11 N D.'
~"*-~ """'doo:> ,,,""""""', ~'" ~y , Sf .W,"if' £M e- p ~. op ~. ~M ondE'-"' , J fllod<i
~"""""""'01' '''''''''''''''~01."""",, a...
l'I-o>nocol Ihoo 40( 1)-.O lQ 1980
"One "'QIl M :, 3 ....
'N 0 8ooIo:M dooo<"""' ol.......

a. Prepare S( ' mi lo~ari t h m i(' p ints of bot h set s o f dat a and. usi ll ~ ti lt' method o f residuals,
den-rmuu- the va lues uf ti lt' paralllt'!(' rs of tilt' biexl)(lO('n tial equation s that fi t r-nch
sd of da la: C .' ;' 1' C 2 , ami ~ ,
h. F Wl1I l hl' values in MaR, eol.k' ll:tll' C I.. V. ' and v. \\11ie h of tln-se- pamnwl ers show(s)
majo r di fft' n 'l\l't'S between the s1nw and Iast act' tyla tof plwl1ol)pt.'s?
c. Is Illl' assu m ption tlmt the live-r am i kidn (')'S an- part o f till' initi al d ilut ion volume
f('it-'illllaille?
d . Had data o nly bt'('n avetlable from I hr onward. so that ouly th e terminal phase is
(,\; t!eu t, what values for \ ' ami Cl , would he e'ol.ll'u latL'tI? Compare th ese values for
ti ll ' slow ami fa.'it ace tylators wi th IhoS(' ob tatued in part Mh .-
e. \\l mt Fract ion u f tilt' doS(' t'l iminatt'li is it-~S(X'i att'<1 with tilt' te n ntuul ('xl)(lllt'n tial
term for ('a(' h sllhjt'<.'!?
f. Is it n-as onahh- to ('(md ml(', for b oth subjects. thai th(' tt'rm ina l half·lif(' will prin-
d pall)' den-nuhu- ti ll' t illlt' to reach pla teau in plas ma following 1I constan t-rate
in fusion?
5 . In Fi~ , 2 1-9 ( ~ It'l aI M ll i te Kim-tics . p . ~ I ) rln- plimlla conccntr anons o f til(' la-n zodi-
il:l.t:pi n(' halol:l.l:·pmn an ' show n durtng um] follo\\;ng an oml dos,a ~l' nW "lt'1l o f -Hl mg
o f lilt' dnlg ( '\'( '1')' H IIr for 1-1 d ays.
a. \\lly is tilt' plasma roncent rutiou o f hlllll:l.l:'lliU Ii lI11('tllatillg mar kl'l1ly ( '\'( '11 al steedy
sta tt'?
h. C all li lt' terminal half-lifl' nf lIal:l:I.I:'l)<1I1I lx.' dl'l ('nni lll'(l d uring ad mini stmnon of til('
(h lSa~l ' flW llw n ?
CI-W'TH' 10 :137

6. A IIlUdt'rdtd y polar dm g is di milmletl t'lI lin 'I~' by n -u aI exert-non. FolltJ\\i ng a SH.. lIlg
t.v. holm dose 10 a (i..")..J,;g he;alt hy su hjt'(:t . th e pl<L\llIa tlmg 1"l1llt'l'lIlrdtioll \\~L\ "},'>('I"( '(I
10 dl'l')iTw hi t'xp' lIlt' nlia ll~~ C (mWL) = 2.711' - " 11M + 1I .(~l4t, - u , ,,,,,,, . wln-n- t is ill
!JOIlr... 1111' Iracnon of tilt· dn lg ill pLL~ lIIa unbound is 0.37 a nd is ind l'!"N'lIdt '1I1 of dm g
UJIll"l'l1tmtio ll lJn'r Ilw " m gl' '>('(' 11 ill plasma.
a . Gi \'e n thai l'Iimi llatioll 1I('(·Ilr.. onlv Irom ti ll' init i<11 di luti o n \l,lu llll' (o -nt ral U IIII'
part nn-nt }, e.l.k ' llah· lhl' folltJ\\illg ·phann.u."l,kindk parame-ters : \ '1' C/. . (l... . lip ' v
tioual] .
h. COllllllt' ut 1111 ti lt' IIIt'(:h ani slIIllf n-nal excn-tiou of IIIl' d m g und ti ll' a p pmpri a h'llt"ss
of till' assump tion t ha i eliminati on occurs o uly [mm the- o -ntral compartment.
(-. OpliOlI'II: {"l lllIIlWllt lin till' d iS('n'Il<IIII'y bd Wt'('1J \' ami \ '.. .
d. c " It'ula tt' tl.(· f md iom o f tIlt' doS(' eliminated that an' ,lw ){'ia tt't ) with t'ae h (·:\po ..
IlI'lltial term, 'l!ltll"l JIIllllt' nt (III ti lt' (1IIt'st i(l!l, R\\ 11at is IIu- Imlf· lift· I)f IIII' dm g?""
e. 111(' dmg is ~\l'll by a constant ..rat e infusion.
I. Using all i!t' rdtin ' procedan-. l',lkllia tt" how lou g it t'lkt·s fur the- p la.\ lIIa {"lIll("l'U"
tratlon to n -ach SO'l an d ~ )'l n f rlu- stendv.. stan- \'a ltn'. CUIllIlIt'III 011 lilt' sta ll"
meu t. ~ It lak('s I half.. lift· to n-ach ,')( )t",f of platt ',ul an d 3 .3 half. lin 's to n-ach
plateau."
2. COIIIIllI'III U II wilY a p nmollll t't '(1 hit'xpom'lIlia l l' lrn ' is St'('n ill II...• tit-d im ' 1)f
plasma conccnt r anou pustinfll\io n "fiN slt'ad y sta tl' h,l~ 11('('11 n ·lK·I]('(1.
3. \\'o lllt! ~UII (' xpt'l11 0 have dd t'(1t"t1 a bi" xPOllt'lIti al l' U\ l ' 0 11 slu pp ing lilt' infus io n
at stt·ady stall' had lilt' di spo sition kluetrcs (If Illl' dnl g foll(l\\ill g a 5()"111 ~ ho lm
tluSt" Ilt'1;'11 t1.,fillt '1;! by lilt' equation C(t ) = O,Sf'll' _ 0 11M + O. I.k - o ,nYll, l1 MI is,
tjn- snnn- t··'lx lllt'lI lia l l"ll(·ffidt'llh, hut di fT(' n'llt t"l l("ffid t'lIts compan-d wit h lilt'
i.v. II(IIIIS tloSt·,
I . 111(> [ractions o f tlnag IHlnn'llly excre-ted IIl\d litn~t '(l aftN i.v. ad lllillbt rati tlll of hoth
lilt' ur-uromuscnlur h1( ){'~i ll g <lJ.::,·nh t!.. tubocuramn- a nd paucurmmuu a n ' sim ila r <II
appl"ln illlatt'l y CI.n'}. Ye-t, lL~ S('('II in Fi ~. 19-1 fi , lilt, ('fTt'(1 of t"lllllp rnlllist'd renal fUlld iu ll
u n til(' tlispusiliou kinet ics of th t'S(" dna ~s i'i difh-n-nt. For p ancuruuuuu Ihl' teruunal
Imlf·lift" is p rnloll J.::l'tJ. whe reas for d.tub ocurartm- the- lenn ina l ha lf..lif(' ts III1t"h,mgt'(l.
Hrit·R, · discuss tilt" n-ason for til(" d ifTl'n·lIl'l." ill tln- t'fTI'(1 o f n-ual d \'s flllldioll 011 these-
two tfm,",,,,, '

~E .-•-e t' K. 19- 16. n ..· ' b'l .....'llUt' lind ...... "f t!·lul..

~~
60
500 '.. ~'ran',.. 10. • 1 ",...1 p.o,...~ I,.. ..'inm (Q . ' Ii...
40 a I',at....'h ....illo 1 10 ..u nnal (t ..lo ll"'n ) and ion..
~ 300 li
\ '"
1""",, 1n -r,al f" , "", (---). I ft I..-" fn.." \1,1·
s '. 'tl . .... o.

~....pa~u~oni~m
... Q.
~ ..
IN . 11.1>.: 1'I 1I ~"'i 1X.. ,,( """.-\0, " .6....""
3g•
20 " 200
~-
.;ij a. .. " .0 . ....... ",..I t1"oir "",..l,."'" 1.. 1'h.om ~.l.",,1M ... of ., ,,•

~
• E 10 '\"~-.·
''' 0-.".0 " " · '<' · ,o 100 ~ ~ .
,,,,,I,,...i.&. t:':l lt.,II ~ C 1'":"·.H"I h a'KI C (:. IIIll(
( h.fn..d . ftI.. 1\...11 St... ... ""'· I'lIhli<-.llic"'. I.i,," h..1.
, - 7 70 n
0 1!J"r4. r . 2.').,.)
':" u-Jubocuranne - -_ . ~
-e S SO ~

e• 3 30 S
,
is
I!. 0 30 60 90 120 150 180 210
Minutes

8. In T ab le 1~ a fe lish'() ti lt' tlisp(lsil io Tl kim'tk pman wlt·!'"S of Ihl"l,(' ix . Olllt'si hel il' t l m~s ,
a lft' nt llllil, (t'llt an y!. a nd suf..nl anil. ~ (Jli{'l.' t'ad l n" plin"(l th t' SIIIIl tlf 11m ...' t·>;ptllll·ntial
Ipnns to at!,"« (..al l'l)" d l'S(·rillt· tilt' killt'til"'!i aflt 'r si nJ.::lt, ix , IMIIIl.\ dost"S.
 CHAPTU IQ

,
D •
,...... DllapeSltI_ ..I ..... ~_.eten ..".,.. I",-w...... Aae.tItetI.

AlffNT....... HNTANVl 5IJ'ENTANI,

c;. 0830 090 084
.i. d m,n · ' I 103 0 _b7 0"
c; 0.120 0.080 015
~min - IJ 0 _052 0.037 0030
0050 0020 0010
.i. J]m,n - 'J 0 ,0062 00015 00012
Te<m,nal hoJf.jife
[mm] III 461 577

Om" of rlu- critical factors in tlu- liS(' of lilt"S(· d m w; is tilt" tum- taken for tilt' plasma
couccutratiou to fall O TI s lopp i n~ aduuuistra tton. Gt'Ilt"r-.J ly. the sho rtt'r tilt" tune, the
q uicker the p;ltit'llt n -covvrs. a desimhlt' chamct eri stic.
TIlt' t'(llIations la-low descrtb- tht" plasmn (Ulll,"" tra!ioll ut rln- t'mlof an infusion of
dunation r. C(t ). and tilt' fraction of that concentration at tilllt' t,~", aftt>r st(JJlp i ll~ Ill('
infusion.

Froction of q r) Ol 'pc»I "" ['1 (1 - ,, - )." ) " - ).,,,- + ,2(1 - 6 - ).1') ,, - ).1'-'
+ ' 311 - ,,- l..J') ,,- l..J'-'j/ q r)

wln-n-

C;.C~ ami C; a rt" de lhll'(! in footllott' II of Table 19.5. These equatlons a rt' expansions
of thost" Wn"U in the I~('nd to Fi ~. I ~. whidl app l~' wlu-n tilt" di.spositioll killt'tit.'!i
art" dt"st:rilN,'(I II)' a hit'JI[X'IIt'lltial equation.
a. Cak'ilutt' the values of f .,Il' ami hem, ' / 1 for alft'ntallil, ft 'lll illl~'1 alit! sufennuul.
h. Cak'ulatt' lil{, fr.lt.1ioll of 11.1' fili al t.'lIIl,"ulnttion for t"ad l t1 m ~ ill II." follo\\ill~ Iililt'S
afh-r stopp i ll~ an infusion of l -lrr duration (t = nOmill).
Alf{'ntanil t,~ = 24.5 min
Ft"nlanyl t,~ = 15.6 min
Suft'ulanil t,~ = 14.8 mill
c. Gi\'t'll that tlw palit'nt a\\".lk('IlS wlu-u the pla.sma (llll{" lllmliou falls by 5( )ll llflt'r
stupping the l -hr infusion , II)' refe rence to ~ullr iUl!>'\\l 'r to -h-. {~ lI ll llwn l un tilt'
Il lil il~' uf Ilw It'rminal half-life (Tahlt· 19--4) ill pn."{l il1in~ durunon of action of the
th ree is . am-stln-tic drugs.
 33.

d. \\'ould tlu- mllkill~ l)t<;my di fTt' n~lll if tilt' ph slll;l {'1J1l{'("nlmlio ll had 10 fall hy .')()il
a fh-r sl oppi ll ~ all ill fm io ll at sl('ad y st all - le-fon- Iht' patit'lIl ;lwakt' m ? O l in l: I II
amiWt'rilll!: thi s ' llIt'st illll ~nu IM'I'(l lu dd t·rm ilu'. by itt-ratio" . rln- \111U(· (If ,,..... ill
(',tdl of lilt' abon· ('(Illatio ns thai W\l... a fraction o f Ilw slt·ad~'.s l ;lh" ronce-n t runon
of us).
e. COll\lllt'1I1 011 tln- impild of the- duration of infusion \\'111'11 ;\11I'lIIpli lll: to rom" tilt'
durano n of ar t ion of t hl'~' three t1mW' O il st(Jppi ll~ itl.lmi nistm linll.
9 . 111l' d islxl"iilioll ktnoncs of \;,lil' lie add fnll(I\\; II~ a .'500-1111: hol ns ,10'01." is t'!la r.K"kri /.l't!
by ,Itt' ('(Iuatitlll C(IIIW!.) =< 37,·-0 ••• + 57 ,, - ° '''17' , wln-n- t is il l mill.
a. U si ll~ tilt" appr opr iate ('(Illalioll in Tllbl(' 19-1 . caknlate th t' \ '.. for this d m~.
b. 11w dal'l can also ht · dt ·s(:riht ...1hy <l h \lH'olll ll<u1mt' llt modr-l . U si ll~ Iht ' ap pmp ri:llt·
t"fillival t'ut r...l:llioll sh ips. ('lllt'lIlah ' 111l' \'llhws \ ', a nd till' mit'ms(upi<: mit- ('(", stanh
k12• k:u . and k.,,. ( I l int: USt.· the t'tllli\"0l1l' 1l1 relatio m hip fo r C j 10 t':11(1Ibh' .1;2" ami
Ihat for 1.., ~ 10 caknla tr- k,o')
c. Coufi nn tlMI Iht· \";lllIt· of \ •••• calculan... 1fn lln \ ', ami tilt' lIlit'm 'ot-'(lpit' r an- t,(lm ta llls.
a~n't"!i ~'(lll r
R
with answa-r lu - a.
d. U l i li /j n~ tilt' appmpri:III' values for tilt' m it'n lSl'('pie rdlt· eoustuuts, (-:11<11Ia ll' Iht"
r ll.pt'(1t"(I Il<lmllll'lt·r \"alm'S of Iht' blt" I"lt llwntia l ("flll:llio ll for "" Iit,- lic "dtl \\111'11 II...
dt'anlll(,(" o f th is d m~ h 0."(1,,('("(1 hy .'50% . :\11 di st rihlllinn:II Il<rnu lI t'tt·n remain un-
dI;Ul~t... 1.
 PHARMACOLOGIC RESPONSE

OBJlCTIVES
The reader will be able 10:
1. Describe. wirh el(()mples, the telatiomhipgenerally expected between a graded 'e~S6
and ccoceoectco or the site of action.
2 . Show graphically how one con readily deect when response is deIoyed co-cored to
plasma drug concenlfolion alief a single dose. and give alleosl I'WO expianoTtOnS for the
delay
3. Descnbe !he parameters 01 the model rhol ofren cbcrcoedze the relol~ip between re-
sponse and pIosmo concentrOlion ,
.d, Exploin why durotion of respcese is oken Pfoporfional to !he Iogo'irhm 01 on Intravenously
administered dose, and when il 1$, calculate both !he minimum eHecllve ccee and The
eHective half-life.
5 . Describe the inAuence 01 distribution kinetics on the relatiOnship beweeo durotlOn 01 IE!"
sooese and Iogollrhm 01 the dose loIbwing single i.v . bckees.
6. Show glophiColly howdurolJoo and inleMity or resporu.echonge on leper"".-edosing when
each dose is given [ust os the response and concentration 101110 pedesemired levels for
drugs showing o-e- or IWO-Comportmenl diSlributoon dlOlocteriSlics.
7. snow why response 01 fElVefSibly ading dlugs declines linearly With rime when response is
ptoportiooollO the Ioganthm of the cceceoecnce andcooceonoeco declines 8}:;pooenloolly

Til t, h;l-~k p rtuci ples SIl IT{)lII ll l i ll~ the l'stablisllllJ('1l1 o f an up prnpriate d OS:IW' rt-'~mt'lJ an -
p resented in Cha p. 5. TI ll'S(' principles rt-osI IW<l\i ly 01 1 tln-n- being a fUlll1iullai n-lationslnp.
albeit s ometiuu-s complex . betweeu coucentrauon o f tim !,!: at si h'(s ) of ,l{1io n nnd r('sl){lIISt'
p r oduced. So llie t...i dt' ut'(' sup porting t his view ts pn-senn-d in Chap. ,S. h ~t't1lt'r with shu rt
commcntan es Oil such atlditil)lml l'u nsidt'mtiuus ;IS dt,lays ill dmg n 'li!){)I\St' , m it' of at.1i\"t'
metabolues. a nd tole rance. III thts chupter StJII U' of tilt'S(' 'L\flt'l.1 S an' l1ll1sidt' n'tl in gn'al('(
ck-pth an d tht' temporal rl'l iltiull lihip )It'tWt'{'1I tluS(' (o r l't}l\t'(' nt ra !ioll) and rt'SI){lIIM' is ('X-
plon-d. TIlt' ch apte r h('~ IlS wit h an exauunutmu of Ihl' concent ranou-n-sponv- n '!illioll ship
andconohnh-s wi t]i a tliSl'1ISliinn of hp tt' n 'sis in a plot nf n 'lil){lIlSt' \"t' NIlS couceutranon.

CONCENTRATION AND RESPONSE

Bt't'llll."l' sltes of ac t km lit, mostlv ollisitll' tilt' vasculature, tlda\"li Ont'll t'"ist ht'lwt '{'n plat't'-
nu-nt of tlmg inlo b!tltltl a m) n~I){lnM' p roduo -d. Sill'll tlda)~ can uhst;lIn ' 1I1l(It'rl)ill~ re-
lanouships Iwh vt'{'n l'Ullt'('lltmtlnn a nd n "I){UlSt', Ollt'!){ llt'ntial sol11tinn is 10 IIIt'lL\ lIn ' cnu-
centranou at the site uf action. A lthlJll ~h this lIlay he possible ill an isolated urgilll system.
il is ran-lya practical solutinll in lnnnaus. Apart fm lll ('Ihil'll! a nt l lt,d lllil'lli issu es Ihal ariSt',
 341

many rt' SPOI\Sl."S ohst, l'\"("(! i/l l'iw repre sent an integration of muhipk- effects at numerous
silt's. Another approach is to develo p a model that inl'O'l)omlt's the time -cou rse of dru g
mownn-ut I W.' t W I "t' 1i plasma and sitl" of action , the reby predrcttn g "e ffect o r site" couceu -
lrations thut can then I)C.· n ·1;III'(1 10 respo nse. Yet a nother approach is to relate plasma
concent ranon 10 n.'S p O Il'i(' unde-r steady-slatl' co nditions , which uhviates conslderanon of
distribution kim-tics . \ \1mh'\l'r the approach adopted , the resulting conce ntration- response
rt·!<atiollsllips for mo..t dOi gs have features in conuncn. Response incre ases with conceu-
tration Oil low e uux-ntratious and tends 10 approach a maximum at high values. R("('"d11fmm
C hap . 5 that this was n hSl,"I"\'('(1 for the hnmchotlilating t'fTt"l1: o f te rbutaline. Such all t' fTt'l1:
is also seen for tilt' ane sthetic ketanune, as Illustrated in Fig. 20- 1. H( - )-kt't am irw and
5( + f-ketauutu- an' optical isom ers which. as till' race mate. cons titute th e com mercially
a\..Lilahlt, intravenous [i.v.] aru-srln-nc a~ellt, ketami ne. Although bot h compou nds have an
allt'sll wlk effect . rln-v ck-arlv tlifTt'r [nun l'ac h other. ~ut cul v is the maximum e fTt"{.1: (E.....~ )
wit h H( - )-kt't amillt: l('ss than thai with S( + ).kctam ine , iml the plasma co nceut ratkm
T('q uirt'(! to pmc:lll{.'(' 5()~ of E,,_ , referred 10 as the F.C~1 value is also grt'l ltt'T (l ,S mglL
vers us O. i IllWL ). vt on over. the Tl'sponSl.' CIH\"l' for H( - l-ke tamiu e appears shal lowt' r than
thai for S( + ).lw tamillt' . Alth oll !!:h the n-ason for the differences an' unclear. the-se ohser-
vathuis stn-ss ti lt' Importance thai Sh' T('(Il·lw lllistry can have in dmg T('SPOIlS('.

General Equation
A ~l' Ilt' ml cqu.uion to d" SI,.'rillt' lilt' t)pt'S o f observations see n ill Fi!!:-". 5-1 and 20-1 is

E . C'
Intensity of EHe<:! - ECfo" + 0

wln-n- 1:".... and EC">l' art' as defined a bov e anti 1 is Ihe ~'llo1J(' fonor that accommodates the
shapt' of thl' curve. Till' illh-llsily of T('SPOIISt' is us ually a dJaIl!!:l' in a measurement fro m its
basal value expressed a.s dlher an absolute d iffe rence , o r a JX'rt:e nl cha nge. Examples an' an
Incr ease in blood pn.'ssun' ami a de-crease in pen.'t' nl o f ne uromuscul ar blockade.
Altll(Ju~h e m pirical. Eq. 1 has found wide e pplicatiou. Certainly, il has th e right pmp-
erties. Fi ~ . 20-2:\ shows Ille influe nce of 1 011 th e sha pe of the ccucentratlon-respouse
n-lutionslup. TIle la~t'r tilt' vahu- of 1 , the greater is lilt' change in res ponSt' with concen-

S(+ )-Ketamine . ·IK. 20- 1. Ch ..n!:.., in rhe electroence phelo-

!(nf>hil' lian frn l'........-y ........ foll, { to ' I"",n-
tify 1110' "' Iho-tic t"ff....1 of R( - ). k "''''i..... >l'MI
s ( + )· Lt"la mint" in a . " hjt"O:f who r("('t" i\·t"r1 ",n
inf kMl of !10M(' No.., ''I''JooU ioorTW'n on ~..I..
Ec", "tI is !Ill' I"f"n~'nt n"(!,x1io n in I.....

,-
Ol"(."' i<Ml'. s lM
c
c
0
50 I R(- [-Ketamine f
" Ii.." f"""'l, ..• ~ pLum.. <~ .... '·llll'llh" n .
Ahl,o"gh <'hu;u;1..rhl ic s .•h"'Il,..J, or .igmo.d",I,
<'U I'"I, " lU"E' """'n with hnlh UM'nI""'IKU. tt...,· ,liff..r
n
~ • ill Idol'. maximum l."fT."(1 . tlio>\,-d. #-:_ . ;mtl ('OIl -
~ <..-nlrati<.n '<"(Io.-d 10 l'T'udu,'t" 5O'l ..f E._ , Ih.·
~
a:
25 E_ #-:C..... Tho L.li<ltlJhip' lruI.~' hrronsi,lr n-d di R"ct
01"''' a' ron oljl;It'IiO:llnt tiflM'oIrL.y ........ fOlm.t lwtwo...n
""
~

~
c,
WSjk Ml' " and OO<lt.T1llr.dkltl (l mWi. - 4.2 ", "'I ).
(R,...)rll...m from s,t..unlrr, J., St...cl<..I. II., s,t..wMI.
1 2 3 4 5 .In. , II ., ;mtl 1..a'J\WI, P.M.: 1I)'P"' ~ k Jnl~ . In
Plasma Concentration (mgIL) Quanhlatlon , " ....1.·1'''1: lUMl ....m lrnl ill an;."t1M~ .
Edit", ~. II , SIO("('Lt"1. S!l,It~ . ( ~Th ;,- .....
\'l."~ 1lPi.'i. !'P. 196-210 .)
34'
tration anmnd the EC,.,., \<4111(', Fo r example. if., "" I then. hy appmpriah' suhstitution into
F'<I' I, til e t,llll'l' n imiiom l'lJlTt:'spcmdin,g 10 20'l ami f)( )'l, of lIl;t\ illl a! n·spollSl.' art" 0.25
alltl -I tunes fX:....... n~I )(·l:tiwl)", a 16-fol<l nUl~(· . \\11t"rt·as. if "( = 2, the' ('(Iffi'sponding
concentrutions an' 0 .5 and 2 tunes EC••H• (J1l 1~' u fourfold nlllgt". Using till' pern' nl d{'tTC-'L\('
in hea rt r an- du ring: a standan l c'xc'rl'iSl:" as a mC'it-sun' of rt 'SllClIN" to pr opranolol. tilt"an 'ragc'
m lllt'llf y is close to I (F ig:. 20-3 ). ( ~·II{' ml1y. lht. val u(' of y lit,S bdWt't'1l I andS. Occe -

A Shape Factor B Shape Factor

5 5
100 100
2
~ ~
~
c
0
~
80 1 s 80
~

~
~
~
or 0.5 II
or
60 .. 60
•:;~ 40
~
••E
~

:; 40
0

''"" 20
~
~ "'~" 20
e, ~

0 o '"":::::....-""'--~---~
0 1 234 5 0.1 1 10
Concentral iOnlE~ COncenlrationlfc...a
tlR:. 20-2. 1,;" • •.., (Al '''MI " ·",ilc ~th ,,, i<.o (Ill .." ... ·" tTodio >l ,· n"'j. "'''' ,"" h. Im ..IiI1,..I ..,"nliul.! In E'I I. fur
tI'n.... 1,~ldh.i i<..,J .IAI!/;' t11;11 II;I'l' II......." 1£ 51' .<LI, 1>l,1 dilT"n'nl .<LI1I•., nf II,,· , hall.' f;>ti..... y. .\t Inw " IIl'
i,,'..
...·ulratit ",. tI..•..1T.'<.1 n ·..._ ..J1I",,1 1i,,,· I~· "il}, c.." ·" 1..."'.'" (:\). wlo,'" y _ I, "I'I,n••d'illl.! a ma\i mal .:aI,,,,
..I I,ij" " "In'"lr"' it"". n..· !t"••" ." th..· .·",Io",· ..f y. tI,.. .h ..·pt'.. i. li lt, d l.U1W in ......, . "'.... .n"""I II",· IX:,., "..II",·,
floriv, , 2f1 aJltl ¥l'l " f " ...,h"al ..fTt"(; (.....1,,1",.1 ,L.,I"..I Ii,,,,., l, ,I... nosl"""" . 1'1"'''''' In I. · 1'"," 'l1itll",ll I> tl,,·
It'lo!arilh,n nf tI... (l "... ·" I... "'i""
(81 fi,,, all •..J,It.. nf y. ( ;.>IIt. '''lr.ll it..'. ....' ....1... .... ...1..d ali'" I.. f:C" .

nit. 20-.1. 11."'1" "'.... n..• " n..ll -.;. tilt' pt'.",-nl 40
.It......•...... i" ·n i h" I" t1 I;Ot~'~~"I I" Im l-
r""'ItJol iflt-'ft ""'" i ll, ,I",.. ""1"",,,,1 , '1'1....· •
tit", " f lilt, ,IAlt.: in I.r....",a, n ".. ,L..", r" ln" Tt' l-
fMoI",,1 lilt· ..." " " .." " "fl,'" .i"J,:It.. ,,' ItI 1ll"lt,plt..
(,laily) or..! .It of !\O.. ~tIll1: 1",lol.i . "f Prv-
8
•
. ~
1' ....u"'... 01 I.e) 'Il" '" Ifill-mit .".I.,j,It..I-•..!.......' ' •..q>- •
•,,1.. (0) in an i....li..it.lu,1! 'lI h,.'<.1. n".. C'l"'m..lli,...
i. tI.., lil nf ~:CI ' 1 h . ,l it.. J.o,,, . n ".. "..,.."'.... ;tIl-
pt'an 10 folk_ tI.... f;_ " ....Io..J ...; Ih;t y ,,( I.. an
f:_ of 4ll'l- , ......I ;t" f;C.,., <Jl 5.31<~1~ (1I.... lr"",,
f".." 1.;olc1t.. 1t·. Rl_.. sl ,b. It.J., Pit,..·
r, J.A.,
Botto.ff. \ l.B... ""Id \ Ii ; •. 1),\1.: 1'" '1 ,....,It.lcoi
,,1o,....n; I;.,..."'I<· lI u lt ..1i"lt ".inlt ""I....I1ItI ...,d
' ''I ..l ' ''''', ntr ..lio". in "....lthy ....lun lt,,"r,. J.
11"'"1laII....ldIMi . Rit'l.lllann., 15 :9'olh~'l2.. 1 ~'l7 .l
o ~_~~_~_~ _ _
o 5 10 15 20 25
Unbound Concentration, 1Jg/l
C ~PfH 20

siollally, it is much Wl'a tl·r. ill wh ich l'a'\(' till" d Tt'l,t appt'a~ ahnos t as an all-nr-noue re-
spo nsc. lx-cause the r.Ul~t' (If coucent rutions lL"....)(1ah '(! with min imal am i maximal re-
SP O II<;(>S lx-corm-s .... 1 narrow.

Patients di fTer \\i dl' ly in their values of f:C.,," 11lld y fnr II gin 'n dm ~. Part of th(' \.uiahi lity
in f;C50 may hI.' diu- In difTt'n'II{'-'s in ptL"1II11 protein h ill(!i n~ , a" ft'Spo nst.' depends on
unbound <!m~ at till' sitl' o f acnon. E "(' II wln-n lxecd ou unbound concentrutiou. iL.. is tilt'
l~.L~· in Fig . 20-3, IIIl" EC.,\o m ille Illay still va ry, im!icilting di fTt'n'n ('(-'s in st'ns ili,ilr to IIIC'
d n l~ ,lInon~ patients. \'ariah ility lIlay also exi st in E"l<U Stl that lilt' maximal ft'SptlllSl' p m -
duced in mil" Indfvtdnal djfTt, ~ fm lll tllat in another.
A counuou form of n'pf{'Sl'lItill~ conceut rut ion- respousc d ata is a 1'101 of till' ill!t'nsity
o f ft'sfMlIIst' agains t tlit' lo~mith lll llf coucentratton. Fi ~ Irt, 20 -2 11 shows thi s tran sfo rmat ton
o f tilt, cu rves in Fi ~. 20-2A. Th is tran sfonnanon is popu la r IM'{'a ll.'\(' it expand s Iht· init ial
part (If tilt' curve, where n's ptJllSI' is dl iUl~II ~ lIIarl.:(111)· with a sm all d m n~l' ill conccutru-
tion, an d cont r acts tilt" latt er pa rt. wlu-n- a ]a ~l' dl al\~e in concentra tion p r oduces on ly iI
s li~h l d lan gl' ill n· spo llSt'. It also shows that lx-twt-eu appmximah' I)' 2Q'l. and 1')41~ of
maximum. n 'SJXlIlM' apl't.'ill"S to ht· pmporttonal II) ti lt' 11I~~a ri t h lll of eoncentrutton. This
rclanouslup 1 )(1,.'1J ~ with propruuolol withi n rlu- nlll~t ' IIf un bound couce nt rutions o f I unrl
10 J.1 w'L. us SIIlI\\11 ill Fi ~. 20...... afte r trunsformahon o f ti lt' d ala ill Fig. 20....3. The g n'ilh's t
n 'slMlIlst' that may hI' produce-d i,. !"in l fur souu- dnt~s is less thau tht' max imum. Fo r
example, lilt' l'Uti rt' cardiovascular sph' lIl may dt·kri umh' . an d til(' pltli(-,Ilt Illay d lt· Inll ~
befon- till' h{'art rate approaches its maxunuru value. O tlll' r tu 'tid til'S of th e I l m~ o r me-
tal MJlitd sl mav furt her [i mil t!lt' maxi mallv tolerated concenr ratfon ill d n J.
AIlIIIl' prt~'t'(!illg exnmpb-s an- ~nt( I('(I ·rt·SIM lIlM·S. Eq . I h;LS also lx-en found to tlt'M'rihe
conceut mtion-res pouse curves innlh1u)!: a lillauta l I't'SIMlIIM' in whic h lilt' n 'siMIlIM' is e-x-
pn-sv -d as till' inddt'l\n ' o r pmIJahil ily of IX1,....I ITt· II( "(· . In sudl {~I,\('S , till' f.C~1 f('f(,fS 10 Il.t'
concentration th at produces a 50 % probabthr y llf n 'slMlllst" and y detcr mmes the sha lM' C)f
tilt' cumulatm- p m bah ility-l.,,(lIll1·n tm lioll l·U " ·t' . Fi ~urt· 2Ch5 shows not on ly tlu- applic nttou
o f Ell . I to deM'riIM' pmlMhility dat a aris i ll~ fm lll a stu dy "itl. tilt' op ioill 3I1illg('sic alfe-nnuu l
hu t alStI that till' concentration 1It'('(II'(1 10 pnMlul'l.' an (·fT('(1 lila)' val)' with tlU' spl'(oj fic
app hcatiou . AsS('sS('(1 was Ih e fn'-'Im'Ill" of patit 'llts w ho reo-lvcd alfe ntarul to SUPpl('1I1l'1l1

40 Fl!\:. 2~ . TI... n",,""'''' ,Lit.. in

Fil:. 2lh 1 ..... "-pIt,n...1 ,.\ lh.·
'''J',,"thm of Ih .. ""h..u 11,100, t"..
~ ., ,, .., ·,,t rollifN ' _ a ."m""", "pTMt"n.
lali l'" or Iht·l'mt..."lr..lic..l _ I'"U,, ·
" 30 n -blio,,"";!', TI,,' l" I" n, llt
ill is 11K'

."" 20
lOtU ,,' _ 11.... i n Fig. 2tl--J. "a n ,,·I~',

1110· 1> , fit "f 1-::'1 ' I lol l.. · , I..t". S ,lt.·
,,,It
j
thai tI.., n",pc"''I(' ,It. os I..·... N . W·
;IJ''r'n ''(;.. lolt· until a ("(wK.1" d roilioN, ,>I'
ah..tl i 115 ~Wl , b l'n... ·1I1 ......111,..1..

-
~ 10
limitill!t o~ ....".· is ;q'l",0",11 ..l",.•.
..l....d I ~ ~WL (• • ho " "iI l--tt1J' I..h-
It-Isof 1'" '1>Tu l"l" t 0 - '>1'" lfiI)·m!:
8: , ,,\ loti,,,..I·"'It....... c....1.." ....1
•
o .l--'o'--f---_--~
0.1 10 100
Unbound Concentration, ~ gIL
 CHAPl1' Il20

lIitrnus m:id t· aJlt's tll('sia a mi wbu did uot t'xhih il il se ries u f clin ical e ndpoint s Indica tive of
Il'ss than cpti tnul iUlt's thetil' t:o ntm l d ll rill ~ surgl'l)'. III Fi~ . 20-5 th t· mean pl'ft.'('lIt prol...
a hi lity of attain i ll~ Sllti.~ fal-tl)rf control is p lotted a~aillst tilt' mean a rterial alfeutaml cou-
ce-nt runon for ~n lllps o f pa tients u mlt' '"Kl)in ~ breast. lowe r abdominal. ur uppe r abdominal
Sllrgl'I)" III l'UIlHI1011 wir h other opioill~ , lilt' co ncentration- r espo nse curve is u'ry shot' p in
all tlm"t· ~n J1lps . In additio n . tilt' mean EC."o values for tilt' tli rt"t' slIrgi lMotl p r oce-dures we re
ill ti ll' ordr-r, IIp pN a"do mi na! > lowN abdominal > bn'il-~t , ll1ld all wert' KIt'a tt'( than the
,.: C~ , vahn- n-qui n-d fo r S<ltisfad OlJ spo nta nt"tJUs ventilation ut till' t'nd o f SlIrgt' f)', Colh-c....
t i \'(' I~" ti ll'S( ' datu indicate t ha t d iffNt'nt 01'H.·nd ivt' l'(lllt!ilions re-quire di m 'n'nl dnJ~ con-
centrutious . Th, '~' alStI show that alfellta nil admi nist ratiou must be finely adjusted tu th e
illtli\i d ual's m-cd ill onk-r to maiutain ad t"tlll<ltt· aUl'stlll'tk control. yt-t, by mlnimiziug
res piratory p m hlt' lIls, 1'H.·l'Init rapid rt-'l'(I\'(OI)' aft ('( SUrgl'ry,
nme Effects
So fa r. ti ll' t' \ ilm ples l'(lIIsidt ,(("t1art' Ollt·S in w hich rt' sl)(lIlst· is sllslailll"tl us lo ng as ('(II\('(·n·
trattou at III(' site of act ion is ma tntafned. A lth()\I~h t his is fn "tllll'nily the- case, oc c asion ally
it is nol. Tolerance can develop. w ll('n'h)" til(' n ·sj)(lIlst· is di min ished wn h ti mt' for a gi\l ' n
l,(lll('(' nt ratic)fI (C ha p, 5 ), T Il(' tiuw (,(IIl N(' of tok-runce can \"af)' From min ute s to weelcs.
T he nu-chaniam fo r tole ranl'(' also car tes. It lIlay in\"ol\"e de pl e tion o f ei tlrer a n e ndogl'IlOll'l
transnutn-r Il l' till' receptors 10 whic h d m~ must bind to in itiat e a resl)(lIlse , Tole rance Inily
also 1)(· m ust'l l by •• homeostatic mechanism wln-reby. I h roll~h ft·("tlba e k co ntrol, th e mea-
surc nw nt n-turus toward tl l(' p rt"tlnl ~ value.
/\ n t'xa mplt· (If toleran o- is that a.,o;lxi;th"tl wit h tilt-' n -oeated administration of nico tine
( Fi~. 20-6), \\ 'lu-n nicotine is reudmmfste n-d .... i t hin I hr. til(' d r ug accu mulates extt'llsivl'i)',
but tll(· peak ('a rdioa('l't·lt' r.di n~ rt'Sp(lllSt' appt'ars to d im in ish . If tilt" d OSf ' S are se parated
by 3,5 hr . accumulation is less, hut tilt' peak It·sl)(lIlSt· is now Increased . These res ults
ind k a tl' a rapid development of tole r ance to tln- cardroacceler atmg t'fTl't1 of nicotine , t he
TIIt"t,hallism of till' W II' n Ul (,(' is unkno w n.
\\11('11 ac ute tolerance exis ts, the rote a t wll idl th e concentratio n is dlilll,gi ll~ may he a'l
impo rtant ilo; rlu- (,(lIl('('nt mtilln itsd f. TIl(' t·!Ted of nifcdi pine o n hemod ynamics Illu strates
this last sta h-nn-nt . I"' ifl.J.ipi ne , a cak- nun channel hll l('ki ll ~ a~(·llt. !)(lth Increases hea rt ra te
(tad lyl:a n lia ) andlowers diastolic blood pre ssllrt' whe n j.,ri\"en to patie nt s as a rapidly di s-
i ll t t1-:rat ill~ (~dpsn lt' , Fi,g. 20..7 shows the dlan~t·s in IWllrt ratt' and h lllllli pn-ssu rt' , tf~l·t1 lt'r
" i tl l tilt' ph'ma ('(lIll'('llt m tio llS of lIifl"tlipi lle . fo llo....i llg ,,",11 Sd lt-dllies o f i.\', ad ministr.ltio n
to a ~n )lJ p nf no rmote nsi\"e su!ljt"t'ts. \\1wll it rt.>girnt·n is t'm p lo,)1"t1 t ha t pmmptly attains

t 'iK, 20-3, \ 1" ,,,, ;art" ri;J <-'' ''...' .... I.'' li.. II- .. ••
' 1>1" '''' .. ·I"Ii/"" hi!" ohl.u"...1 fur .Jf.' 11I.."il. ,
!! 100
"pi/Ji,1 ..n;dlo:< " il', d"rin!/: lhe- illlnl<JPI'r-... tr.,. P"n 1 lower
in ,,;01.... ..r tim..' ' ' J"I/:i<.,.] Kn",." "f 1'''1;.,,,1$ ,I"nnl/; Abdominal
nil.. "" cniolt' "n." lhl"'a. nM' Ii",., a... II"""" l'n- Surgery
cli'1,..1fnom 1<:'1' I, ,,~i"K rl W a " foe "" an.1., ,1llu,.,
tlt'k .." ""..I I ~' ,,' , ' ral:i"!/:II,.. ..,Ii",al,'" of i,,,Il\'iol,
,...J j",li.. " h , nM' .....I" ..1i,,. Ill" '''l , .,.Ju,., uf EC""
",,,I 'f fur II", Ilm '(' ''' ~.,.] pm,,,I,,..,,, ......: h"'<I.' 1
50
Breast _
-
- Upper Abdominal
Surgery
(0,:27 mwl ~ 21), ]""",. "I>I""'w'I' ( 0,31 ",)',11.. 21), Surgery
."wl "1'1"" "I"]"", ,,,,, (0.31 m)',l1.. 21) (U41 "'Wl ~
II), n ..· h..n""",I'" li'II'" III so'• ..re II... Sh" llL...1 O +---.-'-'-L-~--~~
[....."Iitli<"~' " f tI.., ....1....1;"'. EC!ot, •...JUI., (I "'WI _ o 0.2 0.4 0.6
.. 2.0 10'\ 1). ( 1I" Ir",,~, fm lll A,,",,'m., \I ,E" ""11:, Arterial Plasma AI1entanil
C C .. \ 1..." .1<1. Oil., ",III Hum ,. " .G.I. : l'la, ,,,,, Concentration (mgll)
" "I1''1 ,Ir-" ti".....r ..Jf,-nlanil " "I"i.. '(1 In ~IlPl'''''
" ' 1 ",I"" .. ' ''I' k-a..... lhMoi'' fur ~" ...r-..J ' !lllt" I)'·
A' I IK.,io..u~·. M,3fi2...J73, I ~. 11'1' " ... 1,11" 11,,,
I,,'nni..il.lf l .. r J.H. 1.i1'l."'"Ild l )
CHAPlER 20 34'

50 80
40
..
1\ 75
30
20
.....,. I . -,
• i __
I \
'\
•
70

65 A
10 I ' "'---. 60
55 -1--~-~-_~
o 100 200 300 400 o 100 200 300 400

~ 50 80
75

70

65 B
60
55 -1--- _~-_~
o 100 200 300 400 o 100 200 300 400
50 80
40 75

30 70
20 65 c
10 60
o +---~-_~-- 55-1--- _ _- _ ~
o 100 200 300 400 o 100 200 300 400
Minutes Minutes
F ig . 20-6. ~Iean blood C'OTlC'ffi lralion of niootine (k>ft panels. hue in color) alKI the eorrespcndmg mean Ik"art
rail" (righ t rands) in t"ight subjt'ds art...r two 3O-min i.... i"fusKH's of Z~ ~glminl1<g separated be 1 hr (.-\). 2 hr (BI.
and 3.5 hr le). The sOOrt bars al Ilk" lop of e3f'h graph inc:licate tile po;-riolk during which nicolilk""~ infu..-d.
11lt" Ion~ the.- separation between tbe doses. tbe smalk>r is the irlC."n"tif' in II.... plasma ~Iralkln. but lhe
grt'llt..r the maximum n>spon... folloo.\;ng the S«OOd dose. Tht- efft"ct on heart rat... is cll"a~. diminished \\n...n
thO' doses qnickly folki'\..· ~ oeber. a phel1OTlk"TlOll called tolm:n«. (;\ daptt'd and f{'(ITlI\'Tl from Porcbee. H .C..
Beno<.itz. X.t.. . and Shei.llt"r. 1...8.: ~namk modt-I of tolerance: ;\pplkalkln to nicol ine . J. PharmacoI.
Exp. Ther.. 244:231-236. 19,>.'). n... :\ rl'IC'rkan Socit:t:o-for Pharmacology and Expt'ri nW'ntaiTherapeuncs.J
am i then maintain s a corwant p lasma concontranon (n -glIll" l1 I). a ~ mt<li l1t, ! i1wn'il\!' ill
heart rate h ilt 110 fall in dhl\ tu )ic blood Prt'S~lIrt' is observed. In l' lIItr.t.\!. a fall ill diastolic
blood prtossu n ' hut 110 t adl~'l~l.rtlia ( )('(·U N when a constant- rate Infusion ls e lilploy('() alone.
IIl'sp itl' u com para ble- steady-state couceutration o f nift-tlipillf'. ~ i ft'pidi ,ll' "s pri m,lI)' action
is arteriolar vasodtlation . l1lis causes a n-ductiou in pt.· riphl'ml n 'sbtillll'\ ' and blll(xi p res-
sure, fnU(M·t't1 hy all tucn-ase ill eanliac out put ami lu-art mh ' I h nlll ~h ill1 ivalillil of tilt'
bar orec e ptor reflex. Apparently. if drug inp ut is slow t.· nou~h, the mla pli n ' control sys tem
has suffid f'nl lilll(' In n-spond and .so maint ain Ih.. basal lu-art rail' . Further t'\idelil"
SUPlx)rti n~ thi s hypotillosis is Iht.' incre ase in heart rate prod ocod whe n a smal l sllpp ll'lIlt'll -
turv bolus d USt , is mllllillbll·n., 1at ti ll' end of tilt' l1111slalll· ra tl'.alolle scln-duh-, which mo-
IIll:lltarily mi st's the plas ma lIifc'tlip irll' l'J1ll" utr,ll inn ahll\1,' an alrt';I( I~' hi~h ~1t·"t1y.~latt.'
concentration. 111l' Iatlun- to O!JS('I"\'l' 11 lowt'ri ll ~ of blood pn.·ssun ' with tln- constant- r ate-
,,)mlt' rq; nlt' li is at variance \\ilh Ihe conststeut IU\\l'rill~ ild lit'\ ("ll in pa!it·nh . 111t·S(· n-s uh s

~~ A

j!i:G::
80
. •

0 2 4
,
6 8
2"
10

~~
B
20
' ~i_ 10
lf ~
tH£ 0
I
2 B

.v ~
0 4 6
Hours
10
" C
oE 0

o.
~§.

.~
-5
- 10
If,,, - 15
g~ I
m 0 2 4 6 B 10
H...rs "
. ·iJt. 2U...7. 11,,· r..t.·..( d"",,( .. ,,£pl"m.. (,("K~ 'fllr..ti"" I"''' I..· .. " u j<'" ,1.1,·nll;""'" " f " ...1'.." ...... ;(., '''·III..,,'l r.d,~ 1
IN'"' i th tl... 1"'nn!:-llOOlIli(' <'Il,'(1' pn"hltl'(1 ~. nif•• lil""O·' t:. d , " f .il \ ul'jt"(1' "'wi",,1 nif,..lipill" in ,1l.•till'1
" '):in ", u" t>o-1, ,IifT,·r..." t ............0 " • . R''l'im,'" I-_ hy ""...... of .. f,( "" p'JI,' r-n .ntrnllt..1 i ll r"'~M I ''' '' ''I'. lh,· r..t ..
....... ,..ljUl,lrd til illl 'nt'(ll;lh~' all;&i Q ;lI,,1 II...., mai lltain .. " ·Iatn..l,.· .. ,,,,t..n t pl... m" "M It... " lr.. r;otl fur iL"i hr .
Rt~m,,,, 11 ..."ulant·...l" inf,,';'It] .. f 1 ~1 "'''''If fur lu hr ..1 1,;1:1, lim .. II,,· illfll.io" rat,· "'.... iIK'tl·........1 10-
{"Id. lo 13 llI ~r fur III min (ti lt' ' rintl.lM"oI...I I", 11 ).. -\. tilt· pl om.. ' lll>t-l· lllr.din ll (, l .ln n .. \ lill'· ) in III It' " ,1'J''t:1
.......,,;..,..<1 ",1lh ~ "It·t1. J (. ' ltl ll (0). H illltl C. tilt' tUIl'M!""" ll1l( III" ''''' ~lt l l' d ... ,,~ ... i n I,,·..rt ,..11,- ;II1t1
cli..." "lk hl..>lI I'A"'l"A·. A"I ."l11'o1·~" n.....1<"". "'PI'" ""'''' ,,,
1.t.1'~"" ...,.. ,.;"'1< .. 1" ill, n"):i""''' II ,..., .....1.. fodl ill
,!i....,,,Iit.· h1tu I I'A"'' ''", ""I ,•• t~~ '~"·"Au... ""I"·A·'" "ill , A'j1;illlt·" t. tilt· ...>Uno....· """'" ,,1"..<i.It..I. F",lI,,·,. \1'1"
I'''rti n~ ,,,, . ;mjWN1..'It'f' or ,...... ,~", ....I.'I>II...... i . II..• .1""'1' rl ...· in ..." .....Il l r .. li.. 1> .. ,.. II,, ·art ,...1,· ""I..·" tI", i" f",i""
r .. t.. ....... In<"fl''..... -d ..t...rpty .,,,1nlt>fl"·flt..ri~· .., tI,,· ,·,..1 "f "";" ..·u I. ",.(,,,,. " t ,id. ,1,,- pL.."...... "... ·ul r.. li..".
1"'"1,,,,,,1hyII,,· "... """",,·n. "1'", IInllilrolhlt·. n nlt't:I",ni.m fur tI,jl A1Q1I1t·n I'11r1" lt·'ll'lLff,·A·rK. · JI".I,,,. ..I
I." nif...lipi'... i. 01:111 'Kot rul~' 1Il"!..",, I I..,t "",~·I ",,, ,,""10'11 with ,h. · I> I>\(' , ft.,
10..1 lI\(·I",rnn"l"'p' '''' n·ll."\
tl> .....1..,,1,,, ,, dlal'R" ill ......·,.,....... ,_. bLdil... "" .I"......1,,~, I>if. .. bpirlt· (1 "'WI. - :l.!I IlMf. (Fn"" " It~ n hl. .",· rn .
<:' 11.. \'lI n Iln llnnlt·I.'TI. D.• 1>..,,1,..1'. M.• Fa"" ". II.. Unl"llaTt . J. ...ltl Bn ·illlN . U D.: H.." , "I' ;,It.,.,· '" ill ,I..,
,,1"""1<1 ,utlt..-lllmti" " ..f " if,..bpir" "win,. ,1.'l,·n ni"alll "fi l. I,,'uul:o,...mit: dT... 1' i"I,,,,,,,,,,•.cn., 11 n".... >I.
Tber.. -IJ:2t}...."}tI. 1 ~7. ",",m""k~ ..I ;tI ' llt·n ni"it,.. til' C.\'. \ 1..J~·.1
umlt' rlim' tilt" 1It't't 1 to complement ba seluu- ~ 11lt li t,S ill lI("alth~· ~ lI hjt't1 ~ \\; tll ~t ll<ljl'~ ill
p;llit'nls. :\'OIlt"thdt'ss, the OhW f\"dlio ns dt,~(-ribed ill Fi~. 2U-7 may hOI\{' .1 pradi("dl appli-
catlou. 111t' pri mary U ~' n f nift'tli pillt· is 10 IC"o\'(' r hlood PIl.'S~urt' : I "dl~l..·;mlia is a ll UII(lt·-
strable sitlt' d Tet.1. 111t' data s u~t'sl t ha i tilt' latter I'lTt"(1 can lie' n'tlllt"t"ti by ~ lt J\\i ll~ ah-
so rption.
:\nnt lll'r tilll!' l' fTl"(1 that ("tlluplit"lltt-S till" ("tlllt"t'u t ral io ll-n'sptJllM' 1l.,Iatiomhip is t ha i of
im",, 'nih ll' hi ndin ~ til th l' ad i\ (' silt' . :\ lIolahlt, t'xm lll' lt, is till" illhihit iu n of at"t'ly k hnl in-
t'stl'nt.w hy diiMIJlOJpylflllnri dalt·, an n~allop"ospI IOltt' Iuhihitor. 111is t"t,mpo llllt l hilld s t"t...
\' llt' lItly· In till' ell~llw. He-tur nu f ,It''t'lyld llllilll,,,le nl.\(' ;It1h i ty is. in la~t· 1l;lrt . t1t'Ill.' ndt ·1l1
011 sylllht",is of IIt"'\' t'1l01llt'. 11 1is compound show,; W hit alltl run" ad ioll . i.c., IIIl" ptL,ma
eouceutration lilt' ra lly' \.mislws, \\ Ililt, tht, ;lt1i\i ly ppl""iiSh . ( ;It';lrly·. till' tUl\("t'lltr.l tion-Il.' ·
Spt lll~' rt'laliomhip t'\lm's~'tl hy' E'I. 1 dot'" nnl apply 11t'1l.'.

RAPID DISTRIBUTION
111t· 1111.\( '1, duranon, inlt'lIsily', and h lllt' course o f " 'spou se an' n-lun-d 10 tln l~ di sIMI'o iliou .
Fi rst t'o nsidt 'r drugs \\i I1l 1IIJ('-<.'oml);artlllt'nt d la r.Il1t'rh ti(:s. For tlll'~' d m ~s . di st rilmtinn
10 Iht, silt' of .It1inll is so raptd n'lat in ' lll other killt' tic t'n'lIts Ihat. t·fTt"(1 iH·ly, a const ant
pll.lpllrtiona lily, alwOly"li I'xisls 11e't\w'("n unbound dm )!: in pI.L~ Ill " ,1Ild ;.t l ilt' silt' u f action,

OnHI, Duralioa, and blltllsity

(;i\l 'n til(' llIan y t"t ullp lt'xitit'S dl"l t'rlll illill ~ tilt' temporal pallt"nt of n "!oopOIIW, ("t lllt"t'p IS that
Imn' un iyt'l"i<Il app liedtlclll tin nol t'xist. 111t' suIN'l llll' nt t1i S('lI\ \ iun is n ",tril1t'll to tlm)!:s
that :K1 n"'l' nihly ami d in"(1ly' al till' sitt' of ;K1iu n to produo - a n"'lltlll'it' iL~ d t·st.-rille'll hy
El l. l. Furtln-nnore-, IIwta llt,lih ... all.' ('tlllsid t'n:"(1 to lie' r-itln-r inad in ' or nol 10 n 'ad. ;l
su ffidt' nll)' hi ~t. ("tlllt't'ulml io ll to l't mi rilllllt' 10 n -spoll 'it".
Befon- pn lt."t"('t lil1 ~. il is impo rtan t to n 'aI17'(' thai rlu- amount of tlnI~ hl\llln'(l III pm-
dudll~ a n'Sptlll ~' is usually nnly a minult· Iraction of the- rotul alllnlllli in tlu- lle ltly" Cnn-
M't jlll'ntly, t1n1 ~ M) inn,lln'tl 1Id.\ lIO t'fTt"(1 ou its 0\ \11 ph'mU al"t lkillt'l it -s. An t'Xl't'p l lon is a
t1m ~. likt, propranolol. Illal reduces IIt)tll {. m Ullt· oUIJllI1 a nd IIl'f'ill il' hleltMllIow and ha \ a
hi ~1t t.t'Il;lti{· t'.\Ir.K1iuII rat io.
O u",d of E fft-rl. An t' lTt"('1 t lt."(1ln wln-ntln - t"tJli("t'llt mt ioll at tlu- \i tt' of at1ioll n-acln-s
a ('rilit~ll \1llm' . 111t, l imt' of (IIIM't o f pO't"(1 is ~cl\'(' mt'( l hy' mall y' fat1on: n "lt'a \(' mit' of
dm~ [rmu its dm:l~t' Iorin, route- of ad lllinbt mtio n. di st rih ulioll to l a ~I 't sin-, ;mel o lllt'1'
tim e ddap , a \ c1 i S(:t1S~'t1 prt...i o llsly in l!lis dlaph' r ane! t'ist 'wllt' rt, ill lilt' llelok. Addition al
fac.1on alTt "(1 ill~ Ii li lt' of Oll~"t ,Ill.' tlo<,(' a lltl ti l(' ('tIltl't'lIl mtio ll-n'\ IItIllSt' n 'la tioll ship .
(I K' n':L\ i n~ ti lt' do<,(' shortt"lI\ t ht' o nsl"l of t·lT('(1 lIy dlll rtl·ll in~ 111I' tilllt' rt'tl uin'tl 10
adlit'H ' Ill(' {·ri lit~.ll l' IIl ("t'll l ml ion 011 tilt' sitt· of 'K1lnn . Fur tlw S;llIlt' dt N ', l ilt' li m\' uf 011<,('1
of d TI"(1 is alsn slln rtt'Ilt't1 in 'Ill ilitli\id lJa l \\illl ot 1,1\\ ' EX:.,., \·a1I1t,. 11e,(1IIIM' It'ss timt' is
Ilt'l'tlt't l to n "K·II lilt' ("tlllt"t·nlr.i1ioll pnlti lld n~ tl w t·lTI"l1.
()u nalinll , An ('fTl't1 la \1s iL\ IOIl~ iL\ Iht' mi nim ullI t' lTt"(1in' t'tlllt"t'llt r.ltioU al tilt' silt' o f
<lt1iOll i\ t'xt'("('tlt'll. 11w tlu mtiull of t'fTt'(.1 is. Ilwn,fo ll.'. <I fUlld ioll of Iltllh t1n~" allt l m it- n f
t1 m~ n 'l1Im 'll frum III(' silt' uf ;lt1iuli. Ht'!Iltl\. \1 (-.m n '\ ult fn llll t'itl ll" r l'1imina lion or n'tlis-
lrihulion fmm lite silt' 10 moll.' slowly t"luilibr.ltill ~ tiSSllt.... a \i lllalio ll sll b~'t lll t'll l ly d is-
l'usst'tl IImlt' r Slel\\' I>i\trihulioll . \\111"11 <I c1m~ t1islrihuh' \ mpitlty It> a ll liSSllt"s. i1K' IIlt Ii Il~
lilt' silt' (If 'lt1inn. ;tnd n 'S[III11M' im mt'l liatl'ly n 'l1t"(1s tht , t''Unt''t'lltmtiou u f t1 m~ otl till' silt,
o f ,K1 ioll, IIII' rt'lali on sllip 1Ie'I\\1"('n du rat ion <lml killt'lit... is rt'ad ily t"t lllt't'in 'ti folltl\\ill ~
siu~lt·I It,1 1lS c1o'it,\ a mi fllll",\in ~ dost's n '(wa ll'l l t...·I·l'y Iimt ' till' n 'slltlll\(' falls 10 a min imum
\~tlllt, .
Sill1{'~ Holu . f)olfr , (;omitlt'l' a tlm~ Ih,lt t1i\lrihult-s inl o a \1lllllllt' \"" is di minah'll hy
fi"t -onlt'l' lilll'l it.... am i is dL<lmt1t'ri 7.t't1 hy ralt ' UlIlSI;UlI k. Aflt"r ;t Iltllll\ e1tN', lIlt' ph' lIIOi
t"t JII{'('llt m litm falls t·\ p'"lt'nlially. i,t".,
34. CHAPTEt 20

Eventual jy, a lime is reached. the duration of efTt'<.1 (t d ) , when tilt" pl a.~IIl;1 concentrutio n
falls It) a value (C ...." ), !)t>jow which the n'spelnS(' is les s tha n th at minimally destn-d ( Fi/ot.
20...8 ). n il' relanouship between C..,;.. ami t tl is gwe n by app r op riately !;uhsli l llti n ~ into tln-
pn-ccdmg equation. thu s.

Dose e - ~' Id
Cm... =v· 3

Upo n rea rra nge me nt and taking logarithms. an expression for t tl is obtaine-d.

whe re e...... . " is the minimum amount needed in the body, A .." ... Al1:o n ling to Ell. -I a
plot of du ration of effect ~.ti nst In do se should yield a straightlim- with a slope of lJk and
all Intercept. at zero dnranon of efft'1.1, of In A ...... (Fig. 20 -8 , Inset ). For cxamplt', the
duration o f e ffl"t.1 o f m all)' local anesthetics is p roportion al to the logaril lull of the injt't.'tl"(l
dOS('. 11l(" 1II11scl(· relaxant ('fT("l't of succinylcholine co nforms to t l.i~ last equatiou . Figure

16
Duration
(half-lives)
4

:iF
~ 4
8
3
2
1
/
lSi?
.-.SE=
~
0 +
-0""
0
::i:~ 0.5 1 2 4 8 16
~ 2
Dose/A....
:38
Ci~ (Log Scale)
:28
~ ~
::i:fi
~

==
w

0.2 +--~-~--~-~
o 246 8
Time (half.liveS)
. 1Jt. :!O ~. U" natio n of .... po"'... ill • I,:,' ,.. Il' 1...1(·1;(.. wil l, ..•••d , . ~ " ,ltlltl~ o ( II,,· .10",· ..., \ ~-t.·no" "."I I,:,' tI...
ilK·A • ill Ii" ,.. A"I"iA,,1fur ,I..• c..'K -ut twlll lo ,,"'(·Iint' lu C_ (p>q>h ,.., ~·fl j. Dur.d i<.., i , ;</,. . 1'"'1"1Iti<1l1.OOl
10 t1..· lu~..,;t1un of .10...• {W.oph un ri!{lll ).
 ,..
l U---H ,huw\ till' lillII''' til III iT ln), C)l ) ( T.~, ). ami !.ll ~ (1',. ,) rt'( " )\,'~ of lIlu'>(·I" twill'll (;.
un-aom- of III 'UnJIIIlN'ubr " ItIII aft " T ,tilllllbt illll of a lIP"" ) fllll,)\,ill ~ i.v . i ll jl"i 1ioll\ IIf
n..'" , I · , 2-. .1I1<) 1 "II~1.: h..111\ tI..,, ", IIf \ll l'(;lI\kh.. luu-. .\ .. '·')Jol ,(·!c"il. till' , I"j"" III., j ..
ind'lll 'IIl I"1l1 tlf Ilw l"uciplllinl dln~·II . Wllidl only 'inllllt'!K1 "; lilt, \';,Iu" IIf . \~,, ~ , 11..... ;llIlO' flf
k , ,... !i IIMIt ,! [rutu till" ,I,,!,,,, j\ ().2 ruin " ' : 111(' half·lif,· i.. 3.5 nun.
To fllrtlll' r ;lppn 1.;;I!l· IIIl" 1.'\1 "I,,,,liun . tllu"j.k·r tilt' f"Il, >"illi: ..I ;I!l-lI wnl : ~ 1 )u r 'lhulI «f
t·fT'"(1 uan..,......·\ I~ IIIU·!ldlf·lif,· willi l"aI:h ,Ioubliug of 111""-,- n Ih 11111\1 b. ' true-. Tn pn",-
Ih .tI II i ... 1..-, ;j ~\"t'1I d ,,-,..,· O u Jlmdllu· a dur.ltiu/I of (·fT,·d. t J • \ \111"11 :2 ' /Ju i\ \0 \1'11 , IIIl"
alllCltllll ill till" "u.. l~ fall, I ~ o IH·-lliUf ill filii' !Ialf-lift·. Ihat is. til lJo : 1111' dllratlull u f ,·0'..(1
11l;'1IIHI nllt · h a lf-Iiff' 11l1I,t III' I J . 1111 ' tu !;U dllmtioll of 1·0"'(1 rrlll l llt~"( I I ,:, tI... 1.1rt:l'r . 1.1'01'
h . Ih,·n ·furl ·. ' I '! + t J . 'nil" ill('n ·.lw ill 1111" duranon of ,' 0'1"(1 1'. Iht'wfurl·. ",II' !I••lf-Iifl·,
For ,·ulllpl••. .I.' ll ..'i 1I1~ ~ ••f " I( 1.ill~ 1.1."lm.· n ...lilt s in a T ill of 4I lJ ln "III I.tlt' I~ , .,'j 11111I . II..·
c111r.lliull of .· 0'."(1 fj,lIn\\ill~ I m~l\;~ i, ., min l F i\l:, ;20-9 l. 1111' ill.n·.....• ill IIII' 11I1II' I"
rt1.U\l'r. :l .,'j min . h IIIl' h.M·lif, · u f ,,"('(i n~ khohlH' 011 tht· sito· flf ,..1I11n , B~ ill'I ...1.1 ill\l: 1·... ·1.
" fll ... T I,.. T ...... 11I.1 T.. , ( 1 1"" '" in Fi\l:. ;20-9, il i, app,(n'lIl tl ",1 1111· "'.. ,,, . ' ,1 h .. " I.lill.... 1U II
IIOllhlill~ Iili' lit"",·.
.\llIlt il'lr Holu. IJtnlr •. E\lo'IHlilll: II... I l tl r.d ~ 1Il uf 1·0'(1.1 I ~ illt'n',I,illl: 11 10' litl'ol' r.lpi l! [~
n "'lIlt .. ill a .~ 'llI l l t ioll of dumni..hilll: n -turn.., I ... pt '(iall~' (or a tlmt: \\ill, d , IHII1 h.M-lif,· .mt!
d n;lm l\\ Ihl 'rd l'll 'IIIit: iJHL.·\ . Fur 1·\.;lIupl.·. \\11l '1I dllmlM>II of dT,... 1 i, " \1o' 1I( 1,, 1 1~ t m l hOllf·

Ii".... IIII' '11l.I(IOIplt'tl 11.1'01' n-quin-d " I.I~ prue.lll(1· too t:n ·.11 "II initi .J rl...!'IIIII...· ..r 1II .1~
sul )',t,,"h;tll~ illn' ·.I...· IllI' dl.lllu · of t01,K,~ . \l llh ipil' \ 11I<t1l" r tl......... m· ,1"'11 (·all,...1 fo r
Im h ·;,,1 u f fi\in~ Illl' t1,,"C.•1IIt!II....i ll ~ Iute-rval. " ~tfl'r apl'nOd(·h i\ I.. L,'h ,' tilt' "'IIIH' lit,....
1',Io('!' tillli ' lilt' t·fTI,1 n ·'ldw.. a prt"( ld.'nnillt,1 vahn-, I·.t:.• jm l wln-n t h.· .·fTI"(·t \\t',lrIo o fT
l "'i~, 2u_IUl. \\ '.11a filiI. .lpp n l,ld •. all iIK·n·.N · ill c1.. ral iu n 'IlKI. if 11M' ro-\J!0Il"C' i.. I:r'tol,,,I. an
innt';l\l ' ill iuh-n..il~ i, 1'\1)1'11'(1 \\it" till' "C'~lIId t L. N ·. 11,.· n ·;L\l'1J i\ ro-;u lil~ ;tllJMrl·111.
h nrll,, !I'lh·l\ af ttT L,'i\lllt: tl.......'(,llltl (~ ...... 1111' allll"lIIt in till ' buh i, nol til<' II'N', 10111
D,....• + ., \ ~,,,. How lIIudl inh' n, ity or t11lr.llMOIl o( (·lTl1.1 ill('n·'I"C·\ . t lw n ·fon·. d"I'II'lId , Oil
tin' rt'bt i\ ,' II(;1L,'1li h ,(II' of tit....• and .. \ ",,~ . If :\ ...... i.. \11I,1.1 1rt·l.lliH' 10 IItN'. \ 1'1) 111111' r, 'IIMIII\
(Rim th l' lirlol .I'N· wlu-u IIII.' "C"('tllld mu- i~ ¢n·n . a lltl littl .· jlll'n 'a\! '; 11 n ·\I'IIIII...·. or d ur al lllU
of t·O'I'l.1 . i, " '1'11 '1.'1<"(1. 111 ('tmtr'l't. 1.111:" illt·n ·.l....... ill IIlJlI. rt·'II'm.... .tIlt! t1ll rali"l1 aft' 1' \ -
1'II'l.1t,1 wlll'1l tin' n '~I'IIl!I"'" fmlll tilt' li.... 1 dIN' w('aN olT III ·fo n · II1I1l·if . I m ~ b I,)',!.
:'\0 flll1lll'r iun.·a ' ill i lllt 'n \il ~' Ilr d ur.t!illll IIf 1·0'.'1.1 i.. <llIli. ·II);(Io'l 1 will. t" ird or \lIh-
"C'Iltll'1I1 dn ·!>. I" , ·a · th t' '1111011111 in IIII.' 1IIIIIy alway!> Tl'l lIm, It. till' ,"11m' \ 'alll ' ·' . \ ~'w
I,,·fun· tl... I ,t do... · i, ~i\t ' lI , ~ lal, 'tl t1 ilT. ·rt·nl h'. frum IllI' ..."" ..101,.... · , Illw a n i. dll rill~ 1''1,·1,
t111\ iul: iIlIN " al . IIIl' ,1111011111 lo,t 1''1l1a'~ till' "I;...• J.:iH·II.

20 H e . 21t-lot, n~· ' m w ,,, ....... ,.• I.. ~" .. ~.",,~ ·I~,
;;- 1m.. p.<•.&h.." " """ • ..,,,,,,,,.].,, 1I ~ . ~'I:o&nll"" ,"·11,,·
!
~
15 ,,,..... m''''1,,,,1 l ~~ T.......,,1TI"I.... IM' '_I. ~,Il, ... ,,1
II I'l ..... "'·n· ,,( ""..,'1.' " ..h-l, (.. " ~,",. "I ,I..·
E '''''''''' ,of .. "I"m , ,( "" ,1.., h" M' '' ''I ) -/\••1._,.
;: 10 f.. ,," II... n(',n ' I,;, I ~ (; I.""." ," I ""..
~
~
>
..01.""",,,,,,,",, .. 1" ..11ml.-I.... ""· Ul ," , J 11 ,,,,
Q
U
5 'Wi 'ih ] h'o7_1 , I' ll>';' 11..· ..n('".oJ ,l.oI ,, '
~
(,um \\'.oJ". l. ,,,l l hl~,,, J K ( :1"' 11'".] ..,,,I,,...

'" 0 "r "I<" 'lh~ld,,,llI'"

2~:l7Z_r.Ii . I'#>7
..1,1",,,1.· ' r"·.. ' I.... It,I,,~
0.1 0 5 10 50 10 0
Dos. (mon<ol
'50 CHAPIfR 20

CL'.="'~
.2 "iii
7;; • • • • • l::
;:; .!! •••••
C1 •
.

2 46 2 46
Number Number
of Doses of Doses

.2 6
i8 4
C

~
o
E
~
Time (arbitrary scare)
.'111:- 20- 10 . Iiotl, ,I.., ,I,mdio" .u .. l tl..· in t"mi l)' of" "";011... .1 n...' '' ..' · ill. n ·.......· "itl. tI... ... ~.."t1. 1",1 , MIt ...i ll.
," I""~ I 'It'''1I....... ,It ~ "~IC·n ... -11 ,1<.... i, ~in·" . itl. lic:ah..I I,:\' an ..m -,ill II.., l in..' till' c·lT,..1 (ur n " K't'1,l r" Ii..,, )
R·....~ ...... pn..1t1.·m 'ir 11t'\1·L

COMentration, Intensity, and TIme

All ('!Tc'(.1 subs ides when conceutration at thl" sill' o f action falls. lI uw tltt' intr-us itv u f
rt'SI)(JIlSl.' va ries \\i tl. tiuu- tln-refon - depends. llS does tilt' d urat iu ll of c·fTc "(.1 . UII dose ';Iml
rate of n-moval Frum t ill' sill' of ac t ion. It also dl'pt'mls Oil till' rt'¢on of the conceutratton-
n "powi(' CUI" ,' cown-d dllrill~ tilt" d.'c.-lillt', 11 1'1"(', di <;.('1 lssl u n h !illlilt'(l to tilt' sih liltiull in
which tilt' couceutrati on-rcspouse rt'la liouship is maintaillt'(l <II alliinit's and drug d islrih..
IiIt· S ill a si ll~l(' ("Illllilitrt lll('ni Irmu whit-I. it is t'li lllillillt'ti b~' first-order ktm-ncs .
I nt ra\"(' mm s Ro lu'i Dosc.' . To appn-ciah- til(' rt'lalionsh ips ilIllnll~ tluSt ·. inll 'usit)" o f
n·spelllst'. and lillll'. ('(JI\side r till' t...'ent s. dt'pk lt '(l in Fi ~. 2U- I I . that follow tilt, i.v. adnuu-
istratton o f a 1O- lIlg IMIllIs dusl' o f 11 d n lg with a half-lift, of I hr. :\ plot o f inle llsity Ilf
n 'sponS(' agilillsl lll).~ali lill n of tln- p lasma eoucentratjou is sho\\11 in tln- Inset .
A n llnplt'!{, dt'S('riptioll of tilt' {'nlin ' time-course u f n 'SI'MlIlst' cau 1M' ~a i llt't l hy suhsli-
tu ting the- equation tlt'fining till' n ·!atiu m llip IM'tW('t'n ('tIll('t'lItmtiu ll am l filiI(' into Ell' I.
lI uwt"" l'r, for didactk- pu rpoS('s il is l'tlnn 'nit'lIl 10 di\i dt· the pillt tutu Ih n 't· n -giun s. In
n'~il'" I , up lo :2!)ll maximal n 'sl'M IIIst·. inft'llsily of n 'sptlllst' is di n '(1ly pml'M lrt iona l lo tilt'
plasma concent rutiou. ill n 'giml 2 , t'U\l-'ri n~ 20 to SU% u f ruaxunal rt's!'MllI.\('. inlell sity is
prop ortiona l to lilt' It ~a ri l illn o f t'tlllt'('ntmtion; am i in n 'J!,io " 3 , n 'sl'M llI'W slowly approaches
tilt' llI.ninml \~ll l) t· dt'spi ft'la ~l' dla ll~{,s in concenrratton. As lilt' i uitialcence-nt rut km lu-s
in rl'J.,rion 3, de spitt' a mp id fall in (,(IlI('elltmtioli ill tilt, first hour, i ll h'mit~· o f n 'sl'M lllw
remains ulmusl con stant andmaxlmal. O nly aftl' r 2 1If, when concentration falls hd uw 3
u nits and n -spoII.\(' falls IM·low HU% of tilt' IlHn imal ,,11m'. dl M'~ n 'SIMllI\(' I M '~i ll 10 t1t'(,lim'
IlIOT(' mpidly. 111t'lI, for the ucxt 2",) hr. on !lil'>Si ll ~ th nlll~h n'~iuu 2, n '~ I'M lllSl. · d ' 'l'IiIU's ill
an almost constan t mit ' of :2211/h r. Tln- n ,.L\(lII for this cou stunt <1,'(,lil1l' in n' sl'M IIIst', ",Ilil,·
lilt' pLL'illla coue entmt jon dl'(·!int'S ('xpelllt'litially, is appan'nt [rmu III(' iu\('lof Fi ~. 20- 11.
I M ,(~l llst· in n w un :2
CHAPTU 20 3Sl

Intensity .. m' In C + b 5

wlll'n' //I ami iJ an' tilt' slop,,' and tnten...·pt of till' n ·laliumhip.
Sllhslilut ill ~ C(o ) ' (. -ll for C ill EIJ..5, wlll'rl:" C (o ) is 111e concent ration UpOIl t'l1tt 'rill ~
n 'W01I 2 from n'W01I 3 , 1I11t1 (~)Il( '(1 i n~ tenus t1w n ·fon · )i eltls:

Intensity . 1m · In qol + bl - m ·/r: · t 6

l .. ·tti ll ~ 1(0 ) IN.· IIll.' illlt 'nsi l)' o f n 'spo n"",' wil('li 11ll' (UIlt....-ntrution is C (o ) IQ't·s

Inlensity • ~ol - m ' /r: • , 7

Thus. tilt' i lltl"~fjty ofeffi'rl faJL~ lillmrlYldll. tim" ill n ",oll 2. ~olt · thnt tln- mh' o f decliru-,
III . k. dept.·lId s on !Iolh slopt.· of tilt." illll'lIs;t)"-ln l'l.1Il('l,·nl mlioll ('I.,I'"\l· ami half-lift· n f tilt.'
{ I m~. In this in staue-, for example, III "" 3 1 (ill n woll 2 til(' illlt.'nsil)c· of n ·spoust· dl;U1~t.·S
by 3 1% of lilt' ma.\ imal n osptlll""" fur ;I I-In t.:han.t:,,· in C ). alld a.s J.: "" 0.; hr- I. u t.~ms l'Ul I
rat e o f 22 %11" in lilt." de(·lille of ,1l1ivit)" is lIutidjMtt."t.1.
Bt.')und 5 hr. when tht· concent rution h,Ls fallen llot·low 0 .3 unn ami "'nlt -n-,,! n WolI I.
Ihe fall in n ospoll 'it.' paralh-Is Ihal of d rug. III 1I.t.'II)·, tilt.' half-lift' ('lUI lx- t1dt ·fJllilJ("t.l Imm
iutensity of n ospollst'-lilllt' ILltil ill t1lis n -ginll: lu-re. half-lift· is II,,· finn- fur iUIl'II"il)" 10 fall
b)"OIw·half. In prdl1k...-, l lot 'ill ~ dlls(' III a n uiahlt.· haselim-, 1Ilt.·,LSIIIl·lllt·1I1s in th is n "¢1ll1an'
ofh-n Ion illlpn"t.;st· to permit accu run - ;lSS('S" UW ll t o f tlu- half·lif(·. TI I(' fon~lli,,~ t.'il"il liulls

II
10 2. 11)0
~

~ 80
E
B E 60
~ 40 ReQion
"5 1 2 3

oo.".1==--:oc
.3-'--,3,----~10:­
Plasma Drug Concentration

2
Region 3
.Region 1
Region 2
o
o 2 3 4 5 6 7
Hours
..
. 1jt. :W... I I . n", .fo·d"... itt II..· il1lrll,ily tlr r' rn..... *~· tf."'1 "" Ill tin ..·. r"IIo""1ul/.;o ..,,1/.... t..r.:<••1....·. I...,
th...... 11ot,... . u .....""\.. "" I;ul/. 1.. 11... .. ~ >n' "f II "".·nlnlti" n ·n....p''''..·•.,,,.. liu.. 'f l. I nill ",lIy. '" n"jtit'" .1. Ih..
""'i""'''' n'I1"''''' ",I"..oot """s,,,,i1 .10",,\,,'.. ;0 ~'l- f",ll iul"" U""""' r",tiu ,,n,,·n.,.f,,"r. ..' 10",1/. ii' II,,· ·nl n.' '' ..'
i. "'1110;" ""I:l''''2. jnlt·".. I~' "f rt"'t!" Io·d " .. ~ "I'I'" nim"h-~·lin.'''~ ",,11, Ii"..·. ( h' ~' ",i ..·., u" ' l nali< ..' f..tl.
In' n "1ti''', I .\<".. ,....·li l... III ""I" """ l nJIo.ll..... tI{ .1"'1/.111 tl ..· !""",. nIt·(.".....l1lr.d" >n-....I""" ·1..,,,. ,.1111'
·Ii,,,..
i . ... I I>;', E'I' I. "" 110 H :"" - 1 ...,,1"'1 _ 1
 . 52 CHAPTER20

art' exp n 'sSt"t1 ill terms of conceutrutto n. 111(' <-llm'sp()lld i n~ e-qu at ion s using doSt, ad min-
Isn-n -dand amount in hody are olitaim-d 1Iy llmltiplyi ll ~ ('It(' t. rt'Sllldiw co ncentr auou term
hy \ Ulllllll' of distri bution. Th e nume r ical val ue o f h also t:hallJ!:l's .
111{" (,(lIIl"l'p h dewlop-d i11)()\'l' an' now illustrated with d(~rt'(' of muscle p aralysis pm-
dUl1:"t1 by Slll'(111)'ld IOlillt' . Cl m ll~es in dt>glft> o f muscle p;.t ral)'sis with ti me, follo\\ing a n.5
lllWlg IMIIlIs duSt· of s ll(.'d ll~-I(.'h(Jli llt' to it palit'nt. art" shown in Fig. 20- 12. TIl(' I -m in tlday
IX'fo n ' OIlSt·t of (·ITt"<.1: i .. probahly accounted for by tlu- !IUll" required for hloll() to d R:lilah'
(mill inject ion silt- 10 IIII1S<.'1 (· and . in part . by tilt" li llie for SUl"l1llylcholinc to d ilTlIQ.· int o
til(' m-umm uscular junction . 011(,' (' at till..' silt', however, full rt'SpOIlM' ensues p romptly. tile
turu- IId "'I'1'1I CIIIst't and lol al pa mlp is is less tban I m in . Total pa ralp is is th en maint ained
fo r a full 2 m ill despi te th e contin ual rapk! illac.1i\'alioll o f thts aJ'elil. Subsequently, tile
d TI"(1 subsides. As pn- dtcted. !M;'tWt"('u 2( )'l. an d M>% of maximal n 'spm lst', th e dTN1 d e-
d im 's at a l111lstanl rate: ill l!Iis inst an ce, 22 V lllin. At h i~l lt' r doses . the duratio n of e fT("(:t
is IlIn ~1'r ( F i~. 2U- 13 ). b ut OUt" SO% of maxim al n >sponS(' is reached , Iht' amo u nt in tile
hllcl)' shoukl 1M;' lilt" same andthe sulecque nt m it' of del 'lim' (slope) in int ensity shou ld he
constuu t. 1111s is im ll"t'(1 so , K ll ll"i n~ !M;llit th t' rete of dl·t:lilw (m . k ) am i k [fmm the
d\l mtioll -l l ~ dClS(' 1"11 11 , Fi ~ . 20-9), tilt" vahu- fur m , lilt"slope.' uf lilt' Intensity o f ti le n'spcmse -
I ( ~ (ilIllo liul ill hudy ) ('1I 1"\·t', ea n ht' t'lllt'lIlah '(l; for sU<."(i nylt:bolillt' , III - lOR It is th e sho rt
half.lift, (3 ..5 min ) and tilt· slt"t-·p resp onse-dose cu rve that mak e s llc'ci n~kh()l i nt' such a
llM'flll a~I 'll t d illic,;l1ly. Ch all~('S ill mu scle panJp is ca n he produced wtthlu a [ew minutes
of d m nlQ n ~ all iu fusioll r ate. whic h allows fiul.' and con tinuous cont ro l o f n"Spolls(~. Also ,
OIll't' IllI' infu sion is stoppe d. 1!It" pati ent promptly rec ovr-rs.
Oth"' r '-ItMll's o f Adminidnllio n , COllu'ntra tiou- in!t'ns ity- ti mt' n ,latio llSh ips after a
sillglt" i.v. holliS doS(' an' ('1I:))("('1:1't1 10 hc' d ifT(' n 'nl Ircm tlloS(' St "( ' U follcl\\ing olhe r modes

C
1 2 3 4 5 6
I II
....-.-.--.• • • ' . I I I
0
"in
~

5.. 100
•
'.
~
j
~
~
•
u
"~
80 • -,
~ •
~.,.,
~
~
c 60
0
~
~
40 •
'"E
j • •,
E •~
"~
~

'""
~
20

0
•' .•
~
c,
0 2 3 4 5 6 7 8 9 10 11 12
Minutes
. '\1(. 20- 12. C h....,\:.... in I h., d.ltn... of ",...dc' p"'• ..:Jp;' (a., ...........d ... tI....uptm ...u..n n f '" f\<.'ild . p md 'M'l't1 tIl
" "'I. 'Il\(" In IIlu",. ''''1'\'''
, h ", ,, Lthnll ) f..I ~ ...inl( ill . I. "oili. d, t\t" fJf 0.5 mJV\K1lK"linyldl<>Iitl<' 10 II. ,,1'1 '1:1. I. TIm..
of 1"1'1:1.. ..., 2. ' m..... " f tv.1Id . " 'I'1.........k.n : 3. I.""p t"1 td • •"W,...... k"n: -I, S. .....1 fI , n'l:" " 'r,' 0( ho11d, tn 10'lt
,noW"""" rwtld.l.. i~ l . n... IInoiK'" lillM 1'1....... . tI.., rr,cio:lIlS of n....d m um
(T 'n l, ;'jll'f. IT -5<' )' .. JIll YO'~ {T .,.) ,, ( 1111'
n.. 1""'''· \11I.ri...."I...:I ..,1..,...1 line) .....1 ,",'11\'''' tI... ~JI '''' ' -Ii..... {I. "",...... -1 ..,.. I 6) nU.oIly Ii.......ty wt,h
h llll' (,I.·d in;,,!.: 1'1 .1".... 1 li' II' ). { ~ ".Iif"'l:1 f.." m ,,""",•. L. t' "d l)il"lIl . J- B.: Clinical .tn. I 011 ,uITi n~ldlOli ll"
d ... >Iit..·. l u lI.. d .."' it* IK\. 21j:3 7W 76. 1Yfi7.1
of adllliu i~lralitlll . A n'C..'lIfn ll~ llllto"Stiuu for dr ugs of sho rt half,lift" is wlu.1her ti lt')' an' l a-st
,ulrninisfto n 'tl ;L~ mult iple-dose n~lIlt' ns o r as constant-ra te in fmiolls . There is no ~l"nt" ral
,I1lSWt' r, hut it h Iikd,' t ha I tilt" IIUl(11lllt Omav ht' di!Tt"n"nt . ("'\"\"11 fo r th t· Silmt· total t!.aih ·
dost·. s ud. a t1i lTton'Il~" is Illustratr-d ill Fig. 2o--J.Iwith lilt" diu n-tjc fun)S('mid t> ( ha lf. lift·
is .lbOIlI ~)( llI1 i n ) , T Ilt' saUlt' 40'JI1~ doS(' is " t1 ministt n ..1 a.'> a si ll~l t· i.v. ho hls and folll J\\ill~
o

an S-Ilr (1)1\sta lll ran- nf infusion (4 mWllT) aftt' r a loil(lin~ hollIS of S 1l1 ~. 11 lt" nnt u n -tk-
l·tTI"(1 is dtOarly ~n'a lt'r a fh-r tilt' illfllSion as is tilt' diu n-tjc t·ff("(1 (S.H ,"S . 4 .6 L of uri ne in
~ hr ). C II·ar ly. concentrauou- respousc-ume n-larionshtps ca n hI" mo rt:' complex folll J\\i ll~

100 . ' • . 2~ 1 3. Im "'l" "l'tiw of I...• " f .....'("j"'I.

d ....i' ", lnoini.t t' n ..J, u,...... 911'l of m i" uJ l"'r.J -
)~ i5 ho...I, lI... nol .. of .I."-~i,,.· ill O1 '... .-1e- p" r.J -
p is i5 t'Olnt..,,1 ;al 22'lJmin. (1\,..Jr"",n fm lll tI,,·
fiWlTI' h)' I A"'Y' G.: Kir,,-1it...,cof pl,~ n,,_~ *~ _in'-
i l ~' o f lt1<.'Cl " yld",hlrf' in ", ,,n . J. Pha rm. Sd.,
.5I'i 1&i7_ 1fW>. 1l*i7. n... ''"J:I"a1 ,Ltl" fm'"
Walt•. t·.• lU"l l hl lul" J H.: e ll" " ,,] oI,,,lit n ~I "'''
n,,~ld",",i nt'
chl. >ri<.... A".. otl" ..... * ,!o"" 2'1:37z..J76.
100 7.)

"0
~
~ 20
Dose
(mglkg): 0.5 1.0 2.0 4.0

o 5 to 15 20
Minutes

500 . ' 1" . 20- 14. \I ."", ,~ "" "Ltl iw "n·

1Lit' )' C'U'n 'fit'" "i ...1", ,,, ,I"n nll: I'" "-
lor pt·rit.1 aflt'T ;a .l" lI:lr -'41''''11: 1...1,,,
400 .1. (I,Lot·.. Iii,,' ) ;a,,,1 ;afl,·r II......."...
;a" m l lti n "'-~ lU ' ~"'II: I."", JIlat L" 1I:
°0
~
,g
~

E
300
E
,I. f,..k 1 hy llIl .Ii.hr i" f,,' I"" of "'
"'WI,r "f f"mo. 'mit.I., (co l" ,."l lir...) ill
~ .,; d !4'1 "'....' ","" ",I " 'n , AII I....,!4, II..·
ss
~

~=>
... " ..' "" " "lIll .....""' lti\1·" ,tl,,' r"'., uf ,I.,.
t"..'), Ilf f" o N 'mlcl., i. d, ·..ri)· a ,I.",·r-
> .S
:::: 200 "' i"" "1 "i ih .~m",LtIi\.. ""l " ""it' ,i-
~ f."i . (1\' 1Ir""" , fn "" ,".u, "I .~.-I. J J M,.
-s E Soni" , I' ., R",...I, "' (; . ,,1., G.·rI;al!:.
e
~~
=
'-'~ 100 1' (; G.• T;an. l .• ;01,,1<:,,;1"''' <1, .· W-J.:
1), " ll' lk .·fT Ir"t:-·oi f,,"...·"'itl.· ,j"r_
inR .."'tim ",lml" i' lrAlit", ' '"''''''
I...." . i"ydioo ill 1....a1II,~· ...I" nh...n ,
0 e li" . l'6n"'..... n it..... .SJ,+I4l-1 44.
0 2 4 6 8 I ~l. )

Hours
 C><Am '20

Illu [tip lt·.t!ow n ,.,'illll"ns am i s ill~lt· extravascular du·w s than those wen fnll(J\\; Il~ si n~I(· is.
ho lus (11)S('1'.

SLOW DISTRIBUTION
Til t· onse-t , dura tion . am i inte-nsity rdatiollShips art- 110 '\'" l1l1lsid" rt"tl for thoS(' d Ol~s th ai
slow ly d ist rih ute intn tissues. A tw o -('ompart llll'n i model (C hap . 10) is j·lIlp h ilSi :tA."t1.

Onset, Duration, and Intensity

11 11' im p'let Hf d istribution kim-tics 011 du ration allli illk nsity of dTt "t.1: dl'pt: nds 011 twu
[ill·lors: sp('('tl of ('(Illilihmtillli of dm~ at sitt' o f action and si...a- o f tilt' duS(',
S i n~II' HolU'; Dose. COllsidt'r first the sttua tlon in which rlu- sill' of ucnon ts i n a nlpid l~'
t'1lu ilihraliuj,t. am i lu-uce « ell-perfused. tissue. The peak l' fTed is M'(' 11 almost illll llt't iialdy
afh-r an is. holus d o'it" il llll t llt'rt'lI fh'r tlu- (' !Tt'<.1 is di n '(1ly n ,11I""I;1 In tln- pl ;l~ lJl <l ('On('('I1 -
trutton. Typical ph~ lIl a e uuvnr ration- nuu- cu rves oh ""' n 'l"l;) aftt' r various bolus t!ust'S ure
~hll\\1 1 in Fi~, 2n-15A; li lt' ('u n l:'S only 111.'('(1111(' line-ar 011 t h i.~ St ·m iln,,~ari t hllli(." pInt wln-n
di st rihu tion t'l illiliini lllll is adli{"\"t't) ill all tissues . If doSt· is small (he n , ll'ss than HI tlIlits ),
rl a.~ lIl a t"ll!ll"l'n lratiou f'lll.s 10 ti lt" nuntmum effecnvc value. am ] f'('SpOIls(' wears n fT, du rin g;
thl ' d istrib ut ion p hilW, In Ih al vase. 0 11 i ll("n'a.s i n~ do....-. d urat kru of l'fTl '(1 increases di s-
pmlx lrtiunall~' wi th tln- lug:a rillutl o f d o S(' ( Fig:. 2U-15 H). It takes disproportionallv lo ng:I'r
tn rl'ach tilt' muumum I,ITt'di \"t' l"lllll't'nirulinn dm- 10 a sliMing: in till' declim- Ilf pl;l~lIla
(111l("I'nl m tioll \\i th lime. Onl), whe n tlu- t,ITt'1.1 \\'t'urs ofT wl' ll into ti ll' terminal pha.\.(· is
duru tiou of (,ITI'('1 pmporttonal to tilt' log:a rith m of dOSt·.
S nplxl rt illg: lIlt'S(' t'xflt'('latiolls an' tln- tinu-s o f n '('m 't'I) III IO'! (T ItJ). SOt,{ (T ..,.) , and
H( )l} (T I• I ) tlf norma l 1Il 11s<:11' twitch afh-r i.v. injec t ion o f Ix)lus di N 'S {lx-twee-n 4 to 16 mg
pt'r IIl z) of ti lt' ru-unuuuscular hlol:king ag:t'nl d-tubocururuu- ( F ig. 20- 16:\ 1, Ti lt' p lilsllla
l"l llll't 'lll ralion-ti ult' p mfi ll' d isplays p nmoulll'('t1d istrih ulio ll ~i lll'lil'S ; it takr-s a ll hu ur III.·fo n ·
lilt, p b slli a l'tllll't'ntra lillll n -aches tilt' h'rm inal ('xpt lllt' lltiul plne...• ( Fig:. 20--16 B ), HI'lalin'

A 8
100 10% 50%
c 10
Effect (%
~ of maximum) -c- 8
Eo
" 10 90%
'""
~
u ~
c 6
0
'-' 50% ~

0 '0
2 10% c 4
0 0
~
E 10 30 100 ~
0 2
~
~ Dose (arbitrary units) 0
a: .1
0
0 2 4 6 8 10 10 100 1000
Hours Dose (mgl
"·il/:. 20.. 1 ~, D " r.. lio ~1 o f .·ff,...1 i, "..",... li''' 'arl:_ ...-jl lt II..· It'l:otril lnn. of.iI",,' ''''J:......I.. ·ll t h.· '·ff....1 ......"" " If "''t.1I
i" t" II,,· " ·nni" ..II"''''''· "f a <lm lt f I'id , tI... ~ l.· (If ...-tit", i. i " it raroitll~' ' ~ I " i li"r..li lll/:Ii ,..·. \\1..,,, II... ..ffrt1
....·af\ .. IT, 1"ri"l!: II..· ,1"tol.. ,Tj, ,,, 1""'''''. 1"...-.."",· ,.;11..·, II..· ,!t.... h ."",11 .., , ,,I,,tanhal o ""{ "",· . till ...i, h aid...
r..~ It·It· n ""M ...1.·",II..';nl . ,I" mlit,,, "r .'ff' 't1 i'''·..·..'''.. I li' I'" >t" .rti" " "lIy f" r " " ..II i' '' ill .It"",. SI" ..." an"
" ·"'ilt.,;:..ntl "" it· I,It ~ , .. f .i" " ,I.." ...I I.I...." .. (' Jl". -" lraIMN'-Ii "'I' I'" ,filt... f" r .lifT,·n"'11.\ ', 1• .1 ". ,iI"" "f it .Inll( II""
,I" plal' pn"..""..... 1", ,,hi'''I,,,,,,·nli.J ,1" 1" ..il it'" li 'l("tit.. (,ll. .11,,1 tiM' "'m"p" n.1inlt,lnr..li",, "f 0 1.."'.. ··"·,.01. ·
!t~ ,,,"". I,!tll:' f.., pn"'''·!t'rmi,,,...I .·,,,II''>illh t" rn"'I">I"hnl(In .lifT,·n""1''' ')(n.... ..f ,,,..d ,,,..! n...I..>I • (HI .
CHAPTE R20 3 55

til this lime fr.ullt" d m ~ l'i luilibrollt'5 Illlilt' mp id ly lx-twe-cn pt.L~ lIIa a nd ucun nuuscular
jllnl1io ll, tile stn- o f a<.1 ioll . The R 't"(l\"t·ry." tilllt' incn-a,.... 'S pmpo r1iunally' with tlw le ~ilritlll n
of tilt' dost, when tl. t' l lu ralio ll o f (' O'("(:t is well ill l'Xl't"SS uf I 1Ir. 111ls l"Illldi tioJl is IIIt'I onlv
a l the hi~h('st dost's of d-tuboc urarine a nd wllt'll a small response, T»I,' is dllN ' n ;L~ 111;·
e ndpomt. At 100we r doS('s a nd when a wr-a lt' ( (t'SPOIIS(', T ill' is {'hoS('II. tilt' d urati oll of t,IT("(1
is M'i'll to ill{,rt"l'it' d ispmportioll"lIy' with tilt' II ~aritl llll (If d oS('.
\I ulti p t(, Do\ i n~ . Fi~. 20- 1. illusrrutes tilt' {·'1'JI.'l1 1"( 1 n -sults wlWII tilt· sanu- Si7.t· d IN '
is adm inislt·(("(I I"K:h tinn - (('SpOil S(' fa lls tn a pn-detcrmuu-d value, or when tilt' rt'SpOl I <;( '
h'L~ jusl woru nIT. 111l' s('l"lmll d ust' p md ul,,(os a l.i1-:h{·r l"lJIII"(' nt mt ioll in pl;L\ lIIa a nd a ll liss Ulos
of tilt' IMMly a nd a {"Ilm's!'M lI1llinv;ly mon- in!t'lI<;t' (('SI'Ml!I'\(' than th .t! ad.it·wI I a fte f t he' first
d ns(·. AISl), sillt"l' Iht· !t'mlt'u l'y for dm~ to n-t um from IIII' tisslll's is aIso incn-ascd . tln-
du rutiuu of (·ITt'l1 is g n 'a h 'f t han afn-r till' first dOM' . Up In IIIis point tilt' n-sult is tilt' smllt ·
'L~ expect ed for a dm g c1ispl a:"iug flI1(, -I"(IIllpart Ull'nt (·hara<.1(·rist il-,; ( F ig. 2U--9 ), h UI di lle'f -
(·lIl't·S do (·II\(·fJtt · on ad minislt'rillJt the third and sllt'('t'ssiv(' dIN 'S. O il n·I'JI.·ati ll~ ndmuus-
tmnon a mi as d m~ in till' sluw ly t'i l ll ili hm! i ll~ tiSSU('S r ises. lIlt' I('nelt'nl, ' to t1 istri lmlt· 0 111
[rmu "100(1 a nd othe f mp id ly t 'i lll ili" r.tl ill~ tiSSIl('S diuuuisln-s.. \l,("II nli ll ~I} . tilt' du rut km (If
efT('l1 beco mes p n~n"Ss i\"(·ly 1 01l~t'f un til, within a d()!\ill ~ interval . till' amount t'1im ina h'l l
fm lll tltt' hod y equa ls till' dost· i.d lllinistt' I'l't1. O llly' rlu-n an' tl,(, ("I)ll('(' nt mtio lls uf d m~ ill
a ny ttssru- tilt' ~1II 1l' at till' 1){'Wllllill ~ a nd (' nd o f tilt' t1nsi ll ~ inlt'f\ ul. III("( llJl rust In durution.

160 A 8
8
T~
~
§. 4
c
? 120 .~
§. T~

il '"
~
u
c
2
~
""0 80
0
<.>
~
c T. c
'0
0
O! 0.8
~
0
0
:,:
0
40 .,.
D

~
0

0.4
~
E
~

o '"
e,
0.2
2 5 10 20 0 2 3
Dose (mg/m2) Hours
. 1!t. 20-16. ,\. " ""<l i"o_,I,ip 1.. 't'Al,,·1l tI..• n....:)i«n ,)ur.di..u IIr rM, ·"".. I " l, · ..r 11..· 1..>1". ,I..... iI.'ll; ...,.Id ..r
,1·t"I........flU'ir..• !ti'..." j.\' I.. a I:n ..,p ..f ." I';...·h , TIAP T,,~ ""..I T '" ;".b l' · !oIl1. .'50. .....1 It'" n '(":M'''' "r "m..·I0·
""ild' (11 n "" · ,/ II..· .,,1:..... IIr "1 ,,m "f mu.. -J.. r"",-1i",,). 8. S.·",iIoI(ViIIKIIW;·I'I.. I.,r ....h r".. h..:I"......, pl...."""
d _I" I ,flU'ir ·. ."I....lio..'.li"... I'..,lil.· r.>l1o"'1nl: " O..5- ,,,w\:.~ t \'. 1..>1". ,10....,,( .In'l: I.. a 11:.. .. '1',,( 10 .,,1'1'(1<"
(...., R I " rn NII L1... lili(ull' I~ Gil..J.b. \ 1.. I..... ~·. G.. .......III ;t~1 ..n . W.: Ki".1it"1 "( l"I"nil""I;'''1 a' .. I ,.....,r<.." " .."lar
hlt...-I<iOli: riT....1 II( .1·lu l..." ram... in Inan. Ar..-.l J.... io*'l{'·. 36 :213-2 11;. W;Z. ",.. mili(in.ol eLota r",111 W,uh . I ~ t· .
an,l l>illo"'. l fl.: 1>" ....1;.'" "r at1i",n "f ,1·t"I".....'nuir..· . ,,,I Ii("'I Ia"' i..... A,..-.tI....ic.I"K'·. Z9 "~ l-l , 19M. ". ,.....
.I"t"I..:1 with "'·nIli..;"" of p i. UI'I""c"lI. H: R' ' I I.."",' n [roru Ih.· IUla ,,( SI..';I\O·f . I. " .. Stan .~;' D,H. \" rn·h. S..
Mille-r. It l ).. ,,-,..I II","n. J.; s; ","h..,........ n.." Io·I;"I( ' / l>lwm_~oI.i "' 1"'''' ,,-,..I I.t...n"at'<ll ~ .....""in , AI'I>l K...I"'" tn
,j·tlll...:unuillt' . Clm. I'twml"",~ >I . n "·f.. 2.5:.1';.'1--3':" 1. 11r.9. R'l ," ",I",..:..:1"illl ",·n" i..iono 1/ CX \1". ,,:,·.)
356 """"""01= ~f 5f'ONSl: CHAPTE R20

ts
~ 6 B
'" ~c
w • • •
...- '"
0
~
4 •
~ ~
-
100 A
-
~
~
E:i5
-
'"
2

~ Tissues ~
~
0- 0
S 1 2 3 4
c
C DoseNumber
~ 10 2.0
c •
'"<;" e
1l 1.5
c
0 w
~
•
Plasma
'"<>2 ,, --- --- ------ --- --. -- ~ 1.0
--- ------
c
Q

E
~
, < , .,
--- --- --- --- --- .;;" S 0

0.5
~
Q
~
•
'" 0.1
- .~.
0- •
0
0 2 3 4 1 2 3 4
Hours Dose Number

.-II(_ 20-17. A. \\ l l<on tl.. , ... ..... d. ....• oi/l.' " lmill;,,, ," ..1 "1"';01...11)' "ad. Ii"..• tI ..· .....1.......• ..... ....,. lilT", ..I ,h.·
n~)"fl'" l••iLn.......!)· .......1...11" 11"'1.1.,,,... n ..Il " lr..li.... . tI.., .I"';oh[", lOr ""'"''1'' ' (lim" .dM"'· ;o pn ......'·nn i'....1
.-.dn,' r..I"""inF: ('ad , m('(TS-.n~ lI ) itllTt'.l- fur;o tlml(,1 ; ,,1: ,li.triIH ltiull ki" t-1 i<..... n ..· ;"....·a"· in ,I" rati""
j. ~fll'(II')' eccrual of ,Imlil. ill tI , 11,1, .....1.1<'1" ,I..· 1,· k·'K' - fur r.... ''''''''I1 IC''''
{"'IIn 1'I;o",TU int" Ii..,,,'
aud . k""... fill' ,I.·d ill(' " f pL..'1l1ll ( n1I( nlr.lliClIl Oil n'f"-t1I" kNU)!; (" ,s,m, l llII'·)' :\ 1..0 d .......Tl i\ tI..· ,I1:.1.<n...
'''''C'f' nlratl" " "' P',<1...J1-11 ' "k 1< "''' h...·" ";"'" ( I. II. ' ,JoI,' II"" I I"' I" '''~ i"1'''''i1y ..r .. ~" ", .
i~ C"lq"'lil.. 1In in..""'".... .• nnly' "ilh ,ho· " ltl , C . Thi~ i, in ...",' r..,110 ,I" r..li.." ,or.·rr,
i , :O': "I it..... I.' >'\-' ,I" mli""
i lK"R"" _ t1na'IlIIti<'alIy' "1",,, tI,,· ti" ,,· ,I,,· ,or
n ~ ", ""an "If n ",,~ inh, II... Io·nn in..IIII, · II..· ,~ " "~·n t r."i",,-
Un,,' """I"W (W"III, A).

10 .·11(. 20- Ill. K"d, pl.., n", ...",n ·nl"' I"'" ,J II'i"I" " "
Ial lei a,,,1 ' I""i r..l ...11...• (,..~, ..I ,.. 1.." ..1 lin"'. "n
•· 1""·'".." II.l..'l/;r"lll,it.· " "'",,,,,' . ,( ",,,-st1"1if;- .·r·
r, i . ,,~ n ' n..",il"....1in .. ,,,101'1 " "" .....'"'''''1tI,n..·
c 40 "" ,;0.,. ,1", rI-I.·.." i .v. inru' ion, ..ft h,,,,,.·nt..l. 11,,·
I1l 30
It.,,, ,,,), r", U '''':' '" Ir" ti" " 10 ran in 1''''''''''' ",w.l in
r"l'iJJy.' '''!lli lihr''Ii''~ Ii""".. ,,"'h .... tI,,· hni" dimin-
s i, I" ... a,,,1
Ihi"I ........"
I.."'...· i<. 1'"* "'1:1."1. lI" tI..· ......."..1a'ltl
,.. ";;,,,..1"ill, tl... ri .. • "r .Iml!: ..'11.......' ·
'" 20
30
I",li"" i ll ''''''''Iy' '''!IIi1il,r..Ill1K Un , T" mio",..i ", ·
II,,· in.... •...... in ", imal .. lT,..1. a1 ~ ,1"'1 1'".10 "....1
" i ll, tl,,· 1i"I (Jt;, 4 rn~ltl . tl "',. .. uf tl... No"
_ Infusion ~U( ... ... i' " "n' n..It" ....1 if" S.~ m~K). 11,,·
• "" li,l li,,,' ..-10 to II,,· pLa. rna u" ....·ntr.at:i,," ' ,.)' ''''1 i,
o I ~ l'....ki 1(u".·"I..." h"" afk , filii"!!: ,, "it"I"""""
o 10 20 30 40 50 60 70 ILl! ,h. p'" i' it'' ' n".It·1 ,.. tI,,· I'la.", n "...~ "l na' it ..,.
Minutes Ii",.· 01:"... Ko'Cll"'" tl,i..I'.'flI..l I"'.It "1 a .li",i" lIlit'n
'" ,h. · ' p"dr..l ...1".., Ih.. , ,"" i n! 1Jo:t -..It. i. in·
wrte..1for ("Luit',' I I 1l1W1.• 4.11.1 \1 1. 1", lruwn frotn
11 ,1<1,,,,,. H J.: SI"",l l. 1>1\ .• slIi.I",,,,,. I.,J.. "" ,I
\ 1<...,,,.,• •:.; A n""It·1ror ' ''Illyinlt llt,JlI, of "~ Il('~i"
",,,I "" ,10' t.>I.·r.......· t" tl'it'l"' lllal, A'''''t1 it,..'K)-'.
S9,.3I11 ..,JO". 1!h5. 1I'11rtK1,u 'tl ..." h IK·.." i" itll' of
J K. LiP'I'i 'Kd t.)
CHAPIEI1 20

inh'lIsit)"o f n 'spo lIS(' tlOl'S 1101 ill(."rl':L\I·IM.",u lI(l tin- sec ond dose. beca use-th e concentrat ion
at tln- silt' of actio n jus t befon- t ilt' IIt'Xt t!c)St' is alw ays tilt' same.
Tln- evr-uts sllll\\1l ill F ig. 20- 1S with thiopental are illllst mlivt' o f d os in g to a minimum
d Tt'l1 . FolIl l\\ill ~ n 'I)(·t itiw· i.v. tlc lSill ~, tilt' plasma couceutranou dt'dint'S mort' slow l), and
lilt' t·lTI>(:1 lasts 101l1-:I' r a ftN Il.t, Sot'l1Jml and thtrd doses, t'\'('11 th o llgh tl l t·st~ dUSl'S Wt·n.'
smaller than th t' first to pH'w' nt 100 g n'at a n:spIJllSt'. The da ta wi th thiopental also ind i("a !t'
Ihal tilt, hnuu is a rapidly 1''111 ilihratillg site . with a minimal t ll,LlY in wspo nse. In ad d it ion.
tlu-se- l Llt,\ tin nul Sllp po l"1 a com mon stlg,gt'slio n that tolerance to the h)lllloti{· t·lTl'(.1 o f
thiopental fM."{1U·S a("lIlI'ly, If lull'r.uwt· had IJ{,,{11ITt'l1. tilt' se nsitivi ty to thiopental " l lUld
haw decn-used. it wo uld haveleeu exp ressed a.s <I h igh e r ECYI val ue . No such Increase in
f:C~} vuhu- with tinu- is u hst ·r. ·t'l l, 1I0w('\1:r.
\I ajor d ifTt'H'1l1"{'S hdw l't'll m pid l)' and slow ly t'filli lib rati ng sites o f action are apparent
nil ;lt l lll i ll is t t'ri Tl ~ a d m~ nil a nXl'(I-{lost·. fixcd-lnn-rval ft'WlIlt·n . a s illustrun-d in F ig, 20- 19,
\rh t'lI dnlg at till' l'fTl'{1u r sill' ('l:luilih r.ttt'5 rapidly. rcspo llSt' follows tilt' plesma conccu-
tratiou wi th mtnnnal tll,lay, \\111'11. ho wever, equilibrat ion is sIO'\\". it lIIay take several dose-s
1M.·fnrt > ti ll' tuaxit ua] n 's po ll"l' is seen, even Ihnll ~h t he plasm a concentration is at virt ua l
stt·ady state. I II ad di t io n, Upoll Slo p ping administration. rt'5POIl.W wears off sl(I\\'ly a nd ilia)'
re main IIfJt i{'t':thl~' loTl ~ a fter tilt' ptLsn m concentration falls below detec t ion . In the a h M'lIl't'
of sud . i ns;~h t , then- lIIay Iw: a tempta tion to mist akt'lIly dassi (v tlU' d m~ a s om- wi th h it -
and-run characteri stics .
A IOI ' ~ simila r lint's. bi llt ljll~ o f tl m ~ a t 11ll' site o f act ion ca n <.'tlll{'l'i\~olh ly 1)(' M) light th at
its n-ruuval, allll SllhSt'IIIlt'ut de-cline ill e ffect , is slowe r t ha n the n\"(' r-dll declme of dmg. in
the ho(ly. Au l·xitT tlp lt· is t hut tlf tm-thot rt-xate , a ll ant icancer dnt!-"( tltal lunds a\i <lly to t ilt'
silt, of act ion. na me ly. tt'l rah yd mfo lak rt"{III{1a <iC. UIIlIl'r such ccuditions, plasma {'(Jm '('I1-
tratioll t'Ufn-'a lt·s poor l)"wtt h t ilt' temporal pattern o f t1mg t·lTt'c..1 . e ll'arl)'. a Iatlun- to t l<'lt'(1
d m ~ in pl:i...rna do( 's no t mean it i... abst'nl fnJlII till' site o f artio n.

10

~JJJ\f-rn01\1\1\t\---1Effect Site
1 Minimum Detectable Concentration - Minimum -
~ ',, Effective
e
'- , Concentration
~c -, Plasma
<3 0.1 Duration 01 Effect "
,,
,
---
o 2 468 10 12
Time(arbitrary units)
tI ll:. 20-1Y. \\1..--" . Ii_t n t" ltio ,,, In ;ultl r" lt" <I h,,, ..· .... h. ,rt' lhe- In'l( <1(1' i, '~M 1'1"1..1i..... 1<> .·Iiminotl;' ,.. ..In'l: ill
II..• Ii ..c,..' at,~ ..""Lh.. ,\.:.....~' "" ",,, hip\':, .Ic"'inl(. Thi. ,1t·Lo,"l lht. "m.1 of (·ff.'t1. ....,'" whna I.... . Irul( i, I(i\''" i.v,
,...rIN t1i '<:~.nh tlllitl~ dn l ~ ..l"'ini' t rati.." . Ih.· pl , ,,,a COtK'<'1lI....tkltl...-y '11IiN-J:.' ral] I..,k tI..· ,1c1.'(1ahl.. h",il . htlt
II..• .~ n ......'C r~I ....' <II II..• " I.· or <1(1...., m<lYp'· i'l for " m... Ii",,' . Tht· tL....hNl li'... n,.. nl~ Ihr lin..' .,.",rw or
Iiu' pla."" a '~""-~'Il l rdlit ", I. ·k...., cl..• <1.1."",;,.., l im il . ( M ,.. bftrd rrum (; It...kb. ~l. , I.....,.. G.• aI..1 W.·l"I ...."1>. II.,
Dr"1llo: ,li, lnl," litln <1,..1 rt '<ln ' lat"k ~' .·1T.",,1•. Chll, 11"' n ll....~ .., Tht·,.. 12:734 -741. 1!:l7 1.
",,_,k," ..r c.v. \lc "I ~" )
K."".. h""t,, ,1"'11. 1"" -
 CHAPlH 20

(oncentration., Intensity, and fame

T ime Delay-s, Dm~ rt'sponM' oftl'lI lags behind p];L\Ill11 eoncentrat jon. A st ri ki n~ ex-
ample o f sud l a tlday is till" rise in l(,ft vent ricula r ejection tum- index, a measure lakt'li
from an t'!('l1ml~lrt li u~r,lIn , whilt' IIIl" pl'L'IIIOl coneentranon fall.. du ring IIIl' first -I hr afh-r
an i.v . ho llis dOM' of digo xin ( Fig. 20-20). Certainly. tilt'S{· data tlo not 1II1'.tIl that h-ss dnlg
is Ilt't'tlt'tllo produce a gn'ale r respo usc . Rat lll'r. di slrihutioll of di guxin tutu l'lIrt!i"c tisSllt,
is slow . Tln-refon-, to lise plasma couceutraticn .t,
a ~lI idl' to digo xin IIlt' rap y, Olll' shuuld
wlIil llUtil distrihutlon l"t"lllilih rilllll with cardiac tissue is n-ached. wh id l is alMIIII f hr alter
" dose o f d igoxill. On rd atill~ n 'sIMIIlst" 10 l'tJlll't'ntmtiou lM.'fo rt, 6 hr. a ll ab sunl n'lati omhip
is oh M'nlt't l (Fig. 2()...21). 111l' n'SpO!lM' is nil when till' l'tll\('t'ntml iull is highest ami till'
(1 )flV( 'r.;t' . " 'l' n ' till' n'SjXIIl'>t' lu 1M' follO''''("t"1 \\;Ih lim e , il would ("\,'nillall)' (tl tys) t1t'l·IiIll'
tow ard ze-ro, ;L' apprndlllatt'ti by til(' dashedlnn- in Fig. 20-21 .
Following an i.v. in fus ion or an extravascula r dost" p lasma t1 m g conccutratiou riM'S ant!
fall s. 111is llIay lead 10 Ily,derrsb in th e concentratton- n-sponw n-lanonsht p. 11 us eful di -
agnos tic o f the temporal featu res of drug n 'SjXlllSt'. An l'.x:u npll' of such a cu rve is shown

FIJt. !~20. n...pml' lI1!:"linn in tl... Ie·fl w n· 8

I rk~ ,Lcr .,...1;.... lin..' j,,,Ic"$ (OJ. a " " ';/.." 'rt ' u(
..fT.'O['f . i'I('ft"lI....-s a'i lhe· IJIa" CllI .Ii~ni h '''Il1k..,,,·
I ....tic", (cule,rt..J hn..) .1c'l1i,,,-s (.. r 4 lor arter ;_".
", 1r"ini'(l>llic.. of .. I · n~ .10 · or t1i~JXin . A",r•
• •141.. (nlln <i1 ,,,>mud . nll;. 1'1 (I mltfl• • 1.3
",M l. (1~ ... b "'1\ fn ll" .1..1.. o f SII>l("i'U. W ., ~ .....
al,ara. K., and Taulll·rt . K.: R..I..li ",,, hi p H(
Iw...."'.. ,Ii!tilll'<i h ..,,,Idi~.. i" In ...Inl ;., ""I""""
("IIe""in Jt ;" lr...TT1C" " J;Jtilal;,...liu" in ma u. Ctr -
(; ,!aI....,. "2 , 1t~ 1 072.. 1U7lJ. H'1' n .. I ' K~'t1 10:-'
I'('n" ;,,icll' ,,( tI..· A"" 'rk"n lI ....rt .\ ' ''Ki lll ic..,. 2 3 4
Inc .) Hours

H Jt. 2~2 1 . \\ l " 'n tl..· n",p' ''~'''' ,Let.. i n 40

F'iJt. 20- 211an' Il'lah..ll.. II..· Iw...."' ,.
('(·nlroiliclll of Ji~lin . II.. • rt."po..,.. · ;'1 '1,
1,, 1.., hid .... ' .., II..· 1e" 1 ('t" I('('nl l>llic" ,
..ne! tI... ("I .. " , .,...' (('(.I ..J Ii,..-I, n ... t"$ '
1","p, oL!li" CI 10 11.(· " I:*,I is 1."'.....1 .·....tic·r
Ii nl('S "'he· tI... ('l"""·nl r-. ti,, CI is h j~, . At ,, ,
, ,"'"".
1111.... lin pn"...tl~' ",;my ,L.~"'i L.t..r a'i
Ih .. " ..lr· M.. ;. ..h."" 4 4 I,r. n ·'llClrl..• , ,,
,
,,
"huClkl rt'fllm 10 ",,' m (.La. h....1 h,... on
WIl ,.
,
,,, •
, .....•
I

o
o 2 4 6 8 10
Plasma Digoxin
Concentration, jlgIL
""""20 '"
in "'i~. 20-22 fnll(Mill~ tht· i.v. infusio ll o f alfe nta ml. an upinill ;U1;J~I~k . ShtMlI in Fi ~.
20-22:\ a n ' tlw plasm a (''UIK.'t· n lrd.linn~ and 1h.' reduction IIf spectrul ('( I~l " ;11I (,I.'(:I Rx' n-
('l1lha]''''ra phi<.· IIWa.\ UR" of rt"!iPlllI~. in a \ lI bjt"(1 (ill ri n~ all(] aON a 5- lIIill illfu\ iUII n f 11K'
dnlK. Ahl.ulI~11 then- is a stl~('St ioll of a time la~ ht'h\l "t'U pLt'III;1 ('"K't'nfr.ltinn anti
"-spon..\(· (mill flJis graph. the tlt·lay is much IlK)r\" appa n-ut when n-<illl lll'W' i, p) nl:h't l
(Ln"(1 1~' a~ mt Iht· l .. )m"l;pnn( li n~ plasma l'lJlK'(' n trdt ioli ( F iJ.:. 2H- :22B), ~it·k1 i ll~ a dlardl"
te n stie h)~I t'n"Sis hIP. lmually, dunng lilt, infusion. (·(f("(.1 ~s ht>llllllltht· n '\(' o ( al fl·lIla.1II1
in pk.\ma. SulKt"l:lllt'lIt !>', "...hilt- tht' plas ma ('01K"t" n lrdtic K I falls r.tpi d l)". Iht'n ' i'\ lill lt· d"lII~('
in (·fTt'C:t . On ly aftt'f 10 min do,,'S rt"SponSt" fol k~' ti M" fall ill p la.\ma ('u'K't'nlrahofl . :'\otK't·
lhat d M' dlRmok~ ~" I IU'IK'\' of th,,' paired cUI}('t"ntrat ion·rt"Src m~' OI"l'J'\-aU' Ml-' lUI"'''' in
a l·o llllll·n.-lnl·l." i ....• "lirrt1iu ll. Witt. a1fl·lllan iJ. as wnh man~' otl w r d m!:s, Ihis l't)llllh·n ·k,d l;·
~i~' h\'!>h'n"Su is most lil.d,' can ..J b\' ddan..J d istri bu tion to Ih,,' silt' of ac:1ion. Othe r
loxpla,':"Uom fur (L.'Ia~ 1....1 n~pnn • ind; ldt, d~· fomwlion of an ....1 in · IIM1al. ,lih', ....1IK·1.
t;di;n till"" to n ·"",11 all alL."JIWh· ('tHK...·ntratic:HI (Sl't" Chap. 21. \l d at-ulitl' Killl1K-S); 11.,,·
sltuabon ill ....IIM:h th.. ohw J'\l...1 n...pull ....• is an i1Klin'C:t nM·a.\lIR.· of tiM' true dT""'1 (st...•
Chap. 23. Tu mo"N C..orK..-pbl: and the rondition in ",hidl t1K· ('t'IKl 'lIlr"tMIII of an (·IMS.,:..
MMMIS IlwlrriaJ is rrtlIK't"CI,IMlt onlvw IM·n I)"" ('U'l"'t"ntr.dltMI falls 1 .·S. ~· a l.,;til..J ,..Jilt· t11.'S
a n·ar.1klll Iha l pm"llIl't"S Ih,,' oh ....·;."l:"'l! n-spon\(' h.....'OIlW rale.limiting,.
!\ I an~' dn l~ an· lip,..bilil- anti equilibrate rapi(~' OK,"J\S ~,·II.I'.·rfu ..."(1t i\\lI~ . e .!:., lK~.u1
and brain. w hK-1i an' orh-n taf'l:d o~.ms. For t"'~· ti \\II('\. bec au....• 11.,,· p"'riod of ul~'r-

"c. 20-11. .,\, T,n....m unr or I........... tIt.. in

1.5 ,...."f1""<1n/ ...~ l "" rIn1n .......~'lU.."..K' .......
•
i~
.. .re- "I rff"" .... II.. I...."n/ nrn."~ ~~rml "",I
I &I1..n.1 pI.o.-n.. . 1 '",' 11 (~ ......'I nol...' •• ' ii,
" •. 1.0 '" hjn1 dunn( "'oJ f" U. , lI( '" 1..5 ~'mln inf,,·
~i .... ..I -'fn ,b,nil f". 5 n,in h ..lill h.r l. 8 . t'r n.... n1
....loJrtl<-. ll 'l'"1n1 ~ '""" U1rri.td rota' IN .aI.
"-
2. € 0.5 rrfll....11 n ....-nl l01 ... .__n...." ..." >C "1....•

H
do..hi.,. ~
L.:-....I d..t nil"til.. .,( dn 'll: In''' ' '_n
Io:..,\, l"'tI..I oIy ( I I~· ,__.
n... 1I.m "'~
indK..... d .. 1m.. .. ~ I'IrTK ... III II " h ... n ...h . .... ( I
10 15 25 m1(l1. - 2.0 ", M ). IFn ll1l !lcun . J C .. I""~
KX 1 ~lol/ .. 1d. ilK : t:t:C:.." IoI/. ltl odlO lI. "r , .
A Minutes (uh e ..IT 1 : n ... (~ "" IWflII k" I~"," I_n f:.u.. n,iI l
f.. n' ",n,I d ",1f" " I. '" 1. ..,..·. d .... i<>l.<~ . 1i2.Z,'l-4-
80
2-4 1. IW>. ltoT'n. I"...... II~ 11O·n" i..iI .., "I J Ii U r-
•• I'i'.'>cl,)

•
05 1.0 1.5
ArtenaJ Plasma Altentatlll
B Cooc<nt~"' lmgIt)
 OWT!'"
vanon ill dillil'lIl pml1il'c.· is ofh-n hours if nol clays . all~' time delay iUt·fTl't1 is Hied)' to IN.'
minimal ;lIul dOl ~ in plasma ( P,Ul he com-l an-d dt rcct ly with (·IT(·(.1. Thls was the case ill th e
study frum wh idl tilt" pm pr'U1lllul data in FiJ:. 20--1 WN t' obtained. Propranolol was ¢W."ll
nmll)" in s i ll ~l(· .111(1 Illuhip ll' dust·s, and measurements ....'ere mad e OVt>f several hou rs.
pa rticularly a(tt'r tilt" pl ·uk plasma U lII l'\'lltr.ttioll hat! lx-en reached. n il' statem en ts uho,,("
apply ('\ '(' 11 if dist ribu tion I h ",lI~h()lIt the hody hao; n ol been ;leh it,\,('( 1; all thai is requm-d
is thai t1islrihulio ll ('qui)ih riu m I lt·~'t"t·1l p lasm a am i la rge" org an ht· reached .
E nwrgt'!ll''Y admissions alltl Sur~kll] proce-dures a n.' sl"('(1<1.1 ~·tl i n g.<; d uring whic h re -
SpOIlW S art' frt"< plt'li lly mt' ,L'IUreti in mi nutes rat he r than hou rs. He re . delays III res pOIls('
afh'r d n lJ.: arhnmtstration arc ah no!>t al\\'a}'S lIulit'l'l1. E"t'll t holl~h plasma concen tration
mon il o rili~ is un!i1w!y 10 IIC-' {'Ill plo,"l:'l l in tlwse circumstance s, it is still llllpo rtan i 10 dehn-
('aft' tilt' de-tenni nants u f the tune-course of res!)(IIlst.' to im p rn\'{' gen e ral IIl1de rsl alltlill~
and 10 o plim ize treatment procedures and dnl~ use.
EfTN.,t Com part men t. A delay in ;l{'!Ji('\i ll~ a n 'sponse. as slllJ\\'tl by hysteresis. ca n 1)('
Illuddt'l l ;L' a de lay ill n'aeh i ll ~ an film N m IIHI11 " U' 1It or in tri ~e ri llg a numbe r of events

nil:' 20-2:1. n ...fl. · ' (win if.It·~Ji ff,·n".'f" (m..· A

n":1.~ 1 fur I'l... ~.ht , 1' 1 ill .. ' '''11 1.,] 1l••1to1 " f
..n.oI".... it: pain I...f fUII(11t.. , ..f tilt· llul1tlt.lIltl
1',4 .",.. ('t .. .. ~ .. ' t l it'" of 'IO<f'n,...·" . ful l",,1 n j("" "not 43
7 6 5
.'jI Kl- m ll:lit ",,· . A . " >till ·h" f l·It¥..rIy .I h~...' ..n ..i •.
in 110.., .Lff' ·"'·" 1 ""'I a....aM"' " t . l l' lt· C\au'"
" "1........1 1' 1.... ,,... "'" nlratit..' . B . \\1...n ..n .. If......
lUfIIl).& r1 " ,,·n' 10 U'lC."I1. ,Ilt· n ..."'h- n.-lt..:l.wi :w' h~"h'f- 8 2
... i. i' n·" n...
1. 1...'..· ....41' "' ' I. · n ·1..'....1
ttl 1I ·fT' 1 . il<· nl l'llli..n . l ..Jllim n w till. ·
"f "pI;,,\( fn m' I In " lor is ,ItIl,..:1 "'-:\1 I" .....-h
1.';" 1 i" I,," I, I(ml'l.. . l l>l'lI" lI f"'"1.L lll ki", I~' pn..
•;, ....1 lor S~Tl I.·~. u.s.." I ",'.)

o 10 20 30 40 so
Unoound Naprcxen
corcentrauen. ~aIl
8
~ 1.25

~8 1.00 3 4
7
8 6 5
I.
~ 0.75 2

~
~ 0.50
i5

f
s
~
025

o --~-~--~-~
0102030 40
~ unbound Naproxen Concentration
in -ENect Compartment,· ~WL
C HAPIE ~ 20 36 1

Ih al han · a h llll" 1'(111,1;&111 ;Lv,,,d ah·t! ,\i l h Ill" dl ·Ia~ . To Ih h l 'Ut! ;l ph;tflllat~ KlyTMlllit· 1110 KI"I
with an c'ili 'd l~ m l l);lr1 Il1I' 1l1 lillkt'lliu llt c' p t L,ma l~ lIIn' lL tr.l tie lll ha , "t'l'1I 11M'll . T i,t' H·I,I-
lilll l'l lip IM'lwl'l '1I rc"pt lll'ol' iUllll'tllln'lll ralill il ill lill' 1·ITI'C.1 e nupartuu-nt (';11I 1111 '11 1M ' lIIIKI ·
d C'll ;L' ill Eq. I . T h i, pnll~·t!lln · hax " t 'C '1I applil'(1 10 lJap m wll. au alla l~t ·,k . ;Il1t ipy rl'lie.
und allll -illlla'tllI lah l ~' a~t ·lIl .
Fi ~ll n ' :20.....:2.1:\ sho,,"s hySlt'H'sis III ti lt' nwan pain illdl' \ ill ,I tI"1I1 al pain I1 I1K ld ,L' a
fllllliil JlJ o f tum- a fh' r a sing ll' .'it It )-1 IIg orul eh''ol' .,1' n,lp m \ t·ll. \ \11<'11 au I'ff, -ct (1111 '1);11'1 ,,11'111
is atlel,'ll. ti ll' n ·lati llllsh ip IM·IW('l'1l H'sp"m 'ol' ;1I 1t! (111lt't'I, lralil' I' iu til(' t·lli 'C.1 11'llIp.tt1 11lt·1l1

A n". 2u..2 1. nIl' "....", h''''I",•." " ,,·.I,I-

f,·.. ·"•• · \11""'1'\ ~, ...., " "' '' '' 10;0....·1" ..· '" .1."
3 180 ""~ ... Fill,n ·"I",!. I \ ' F - 1,lfe l .,',..• .,
240 120
..-- 0-
0
fi-mW1" ,I. "f ,10"1'".1,'" '" :'If, ,~"I, I ..·"
0
~
0
300/ ~
f... ", (, " ,' 1" tI... ,,,.:I, II ~ .·....... M~ a::. ' .\
~
u
c
~ · 360
0
0 90 ,Mt,·..·,....· ..,..I
" ..,
"I..,, ,.,
11,·1"""",1,,1' 1..·' " .·.·11 ,1,,· ..·"'1..· ' '' ,,·
,t",I"""' " 1( • • " .
, "II.' ,I...I..~· ,1.'10:'..·••1!" "'h'W'"
~ 2 I 1'' ' ·''1 '11..• I",.· "I " ""I,IIlll:" 11.1,, ·..10... 1
'"
05
420
",'\1 '" ,·.•d ' lw.", R. T""' I. ·".r",,· ,I,IT.'r-
,
<;"
0
,·,• •· .." ,1,,'..1"'" " f ,..,,,. (11•• 1,..... " h •.",
0
60 1.:..11.-:-'. \ 1T . Wal" .,. I' ll E,k,'. J II
:!:
E
0
I
480 I C... . "
.. ...lI w·I
1 \ 1' >fl" " " 'I1 , \ I~: 11 ~"" , ., -
11'10..,"'.•" ..1.11.. "'" ... "I ,I..,·
~
~ 0 1""f" 11 ,,,,,,,,.,, ..,,,I"'·I..,m,w1,lw·,, III f,t .·
c 40 .ol,· ..1"1,1 ,,·,, e l", 1'1,... ", ... ,,,1 TI,.·•..
~
~
/

--
.)2 ,I " I- I "·J. I'I't.U

"
0 0

0 10 20
- - 0
20

30
PlasmaConcentration, mgll
8
3
0 - 0
0
~
0
~ 0
u 0
C

~
05
2
/
0

e I 0
0

~
/
~
~ 0
E

-"
~ 0
~

~
~ I
0

0
0 120 240 360 480
Minutes
36' CHAPTH20

now shm', lUI d l'l)('Jl( Il"lI t "l' UII lill ll" (Fig:. 20-2.'38 ). Thh rd aliollsh ip ilia)' now he lIloc.ldt"tl
hy Ell_ I.
h th.·'l)rd illion 1)( II >-",Ie n-'si.. C u rves . Ih' sl)(ll\St-' is an all-t·m hmdng: n-rm app lied to
a \\il1,' , - arid y o f III t' ;LS1Irl'lIlt'llts. 111(' n-spmIM-' ilia)' he din -ct o r Indirect . It lila)' 1)1' all
1I1l\(' l'\"alloll th ai in lt' v:mlt·s (l,l'" (·fft'(1S . it" in ti lt' t:aw o f till" uature th- d Tt't.1: of f"nJWlllitle
( F ij,t. ::!U__ I-I). Two ilio n ' t'~lI n pll"l' follow , whk-h show rhat mn- m ust lit! careful in Inter-
po" i ug: t'( 11I( " ' 111fill itlII -rt ' Spt JllM' (·un·t·...
I n till' first examplc-, ibuprofen. a n a na lg:l'sic a m i an lip)Tl'li c ag:t' nl. is administl"rt'tl a... a
rucenmn- If) :3(i «hildn-n \\il l. n-ct al n-mperunuvs. rt'po rtt't l ill l! t 'grt·"l-'S Falm-uhelt !K 'f',Vt '( ' 1I
10 2 a lltl IO·HfF (;).I).S ;l1\(1-IO..'5°C. 6 months t!lmll~1J 3 \l"i1ni) ;lIId between 10 I and II n .9"F
(3.-"i.:l a nd 4ooC. 4 thmll~h II )l.'ilni ). The II W ;lII f:11I in t('Il II'll'mt u n' is noll'd i ll Fi~. 20-24A
n-lsnvc to till' (1J1l(1"lltmliu n o f dm ~.l1lt' rdat iollship im p lil's t h'ltl h(' dm ~ has lutk- (·fT(>(.1
al ('arly time-s \\"1l('11 tilt' concentrunou is hi ~iJ a ndmadmal ('fT("t.1 whe-n tlu- conceutrution
hax IImpp"...l to 1.5 lllWI.. ;\(1uaJly, th e ,,·IT,,"t.'! of l ilt' dmg is Rn'alt'st at earl)' tum-s ami has
P;lrti lilly \\lI m lilT hy tht' ti me ti lt' h'lll l)('mt u n ' is min imal ( Fi ~. 20-2.J 1l). Temp e rat ure is
all illh-gra h'l l f('sj1(mst' t hat measurt-s tilt' cumulative- ",fTt"t.·t of tilt' dm~. Usi n~ sJX'('ific Iwal
tn n ·latl' km pl'ratu re dMlI~t" drMt, to uet h(,,,t trall.sfl'r. Ilu-n

Specific en Role o f heal Role of

heal ' di .. prod uction - heal lou

E\'(' II ifllt'ilt p n ltludi()l l is ins talltl)' reduced. tim e is n-quin-d for Iltltly tellll"lt'J'dtll r'l' to fully
n -flect ttlt' n-duct ion. This pln-noun-non is further d iM.·usst'll ill C ha p. 23 , Turnover Con-
("(' ph. for tilt' al1til1 "I~ulall t f('SllllllSl.' t(l warfarin.
'111,,' hph'rt'sis in Fi~. 20-Z·M is there fore nol T\'a d ily Interpretable. Ck-arly, if tilt' data
wert- to lit· ('(ll1ap....'l 1 hy tilt' 11M' of all ('fT('(1 l'()1II1li.lrt lllt' llt, tilt ' n-sults \\1Iulti ht, 1l0 IlM'IlSl.' .
1111s is lli.u1it·II],lrly so if iI corrr-lat km ht'lWI'l'1I n ~p()l IM ' aTltI (, 1T1'(1 silt , ("(II1('l' lIl m lioli wt- rr-
tlu-n I n ht , ;llt"'lTljllt"ll.
'111t' M'(1111d exaurph- is tha i of tilt' dT{"l.1 pllltllll't'l! foll ll\\i n~ i.v. udministrutiou of {'T)1h .
mpoir-tin, all autiam-mic a~t'll t W \"{'11 to pa ti{'1l1s \\i l h {' Iltl. sl a~,,' re nal d iM';L'it~. Fi~Irt' 211-2S

35 ,,• .. • • ••
.... 1(. 2n ..2.~.
1"" "" 111
no<, h.·",. I'I<'I11 .n
IUMJ,'T):"in~ ,h..J:. u
•

r. "·
uremk-
;1./ ..1r'l'C'l'i>i nlt"l')d ,,,,,."1i" . ft I••
• .1pi~ 11,...'1' lilll'''' " Wl'l·1o:. IIM'n"1I- ...
• f"r 70 cLoys ;u..1 ll"'n 1.·",ls "rr. A .
,,' ",.. dml( In............... 1'I')1I, ......, tl' pro-
c 30 • ,
" • ,
.I... ti"" .,,1.., ""·,,,,,....";1 II..............
~
~
~ / I,,'("au,,' II..· ,It'\('I~ l,nlllo.."( ",1 "'1')110-
........t . ... <I" "..( <1,.. " I Il,i rh.. ~"!tt· .
.~ •f R. ~:l')d'""I..it1 1" m nlln -s j.. dl;"•

,. / niMh ' p....1"<.1 i< >ll "f " l')thn M:yl"",

'.Il'
•• ,tl
1I' ,"1'",r, ;trio'. w ad'ln j;: lift'-
E '1>;01'. , Lo~ '" ,.I')t hn ..) t ,1;, ' ;011 II..·
~
:I:
25
("m'II I 1'....1...1;<>" ra ;u"j • I.......·
, h.... ~ . I;al", I' n'"d"11. ( R...[rawu
A B
• rn"', U"'hlinj(" ' , I>E.. G"I It!, f .A.•
",>II s l..·j " .... 1. 8 .: .... pl"'m Iy.
'....m it· ,,,,,. I,A ..r .·1')1hn " ....1In 11. ·
al~ fur IIn'lnK' ;a',,·mill. e li" . PI,••·
20 11....,, ~ . Tlw... .~I :,6-IlD. 111I1'2.)
0 50 100 150 200
Days
CHAPI EP :?O

SllOWS tilt' results fro m a patient who n '("t"i\'t'(I ·IO()() unit s of t'f)thropo il'li n t1m 't" nun-s a
we-ek. T he lu-ruatocrit nws for ahollt 70 days and then levels o lT. O ne m ight he tt"mplt'(l
to conclude tha i Iht, e lTl'('1 of the d m~ takes time to develop. In fact . tilt' dmg lncrvaws
the mit' of production of n -d blood cells I h roll~holll the entire course of its ad mi nistration .
TIlt' o!l<;t"y alillll is tlu- accuruulatiou o f lIt'w l\' fo rmed (,d is un til tlw\' have n-ached Ilu-ir
lift'l ill lt" poteutml and hl'~llt() d ie . The rail'; of production and dt'ath of tl w cell s subse-
(1lIt' nt ly l "lllllt' intn a IIt'W sh';lIly sta ll"; tilt' IWlllatoc:rit !l OW f ll ll y l't'lIt'(1s the men-used
pr oduct ion of ("(,lis indlll't"{1 by tln- d r ug.

STUDY PROBUMS
(Answers 10 Stud y Problems ore in Appendix II.)
I. !mlie llt" wln-tlu-r III(' follO\\i ll~ sta te ments an " true (T) or false (F).
a . Fur a dnll-t sl l(l\ d ll~ first -u n lt' r d ispusilioll kirlt't k s and pn Ml ul"illl-t a ~mtlt"{ l n "SpOIlM',
tilt' duration of t"tTt'i..i Incr eases Hm-arlv ....t th dose.
h. ..\ Il~'SIl'n'sis loo p ill a l't'speJllst" \"(' I"!iU; plasma dnl~ coucentrutiou cu rve is not ex-
pc cted to hc" o hS('I'\"('t1 afh-r i.v. admtntstrution (If a bo lus dose
I', For a graded n'slx ltlst", th e EC!'A I is th e p lasma d nl g coucent rnnon at slt'ady stale
tha t p rodmes .5()% of till" maximum rt:'sIXlIIst'.
d . For n"spoTt!it"S le ss than 20% of th e maximum, tilt' response is direc tly p roportional
10 t1m~ concentration onl)' when y o f Eq. I equals one,
C'. Om' shou ld wuit for d istri bution t"(luilih rium Ix"twt"t: n drug in pla.\ lt1a am ] th at at
till' silt' o f aet iou to Ill;" t"stablishc"{l before atit"mpti ng to Ust" plasma mon itoring ;L~
a guidc" to lllt'mpy.
2. T he concent ration-response n-lat lons hip fo r ;1 d rug th at p roduce s a graded n 'slxlIISt"
is lhmtctt' ril".('t l by un F.G.....) of 10 mgfL am i a y of 2,.5. To bt, e lTl'i..1i\"t', tilt' rt'spOl\st'
tu tln- d nl l-t must 1)(' kept lx-rwccn 20 % an d 80% of t ilt' maximal value. Calculate tln-
r.ll1ge uf 11J!l1'('u lmtiu llS th at art" 1I1'('((l'(l to ac hte...'e th is cbjecnve. D m g at the silt' of
acti ou t"(ltlilih mlt"s rapid ly \\it1l dmg in plasm a,
3. Tlu- d.lta in Tubk - 20 -1 were obtained ill hu man s with AF ·DXII 6, a CilrtlioS(,I('i..1:in '
muscarinic agt'tlt. In p aralle-l ....-ith measun-ment of hea rt mit ', blood samples wert-
d r awn am ll'('ulri fuj.,'t'tl for measurement o f the plasma concentration of the d rug.

,.ltle 20-1 . 1 1. H_rt ......... PI. . . . Ce........._ ••11_1. . . 11",1.

40.•• 0-1 D._" Af·DX t t 6 -

o o
O.7ot' 1.00 X 10- 8
1.73 3.08 10- 8
X
40' 7Q7 x 10- 8
605 8 32 x 10- 8
6' Q8Q x 10- 8
,.
765
11.6
1,52 X
I .Q8 X
10- 7
10- 7
206 X 10- 7
15 8 3.17 X 10- 7
17,8 317 xlO - 7
211 4 69 X 10- 7
' 47 1.71 x 10- 0
2Q Ib 1.00 x re-s
30" 1.00 X 10- 4
°Mopoodlooro~ e V~r Z""""iJ C ~, f _ ,c .Paloo, o .w...... A ."""'~HF Af-OA 116, acao"""""", .. """",,,_
crb/O"""''''''''''''' "'-"'o<;odo,.nom <""", ~..- _ On I'toma<ol n... j(} J72- J78, I QQI
""""" _ 100- dodacto< ..."",...
 CI1AJlTU 20

a. l' n -pare a p lol of til(" Increaw in In-art ran - H'nus I{)~aritilln uf plasma d n lg con-
centranon.
b. E ~tilllatt' Ilw approximate \·a1l1es for E-.. EC~ I> ,un.! ., lISill~ tilt' mudd

4. :\11 t':l.(lI·rin....ntal anesthetic agen t. C I...'j.fj l . pnxlllo~ ccma in human suhjt 'C1s. Table
zu-z .. hu\\"S tilt' 1lK'",Ul dnra non of Ollila a.. a flllK'tioll u f tilt" is. (10...• uf C I...'').'U atlm in,
i.'h ·n .c.J. l Do mino . E."'.. C IKxlo fT. P.. ilnll COn..WIl. G .: Pham ldc:o loWc t·fTt't.'ts of C I...>"!.
a l K'\\ ' rn!>.... K;afiu· an(-sthe.1ic. in man. Cltn. Ph.mUa('Ol.l1H-'r .. 6 :2'jl}..29 1. 1965).

' . . . . 20.2.
~ IrngA gl 05 10 15 20
[).,ar,on of coma (mil'll 17 58 90 10 0

St'wr.tl ~lIhJt.'('ts. illllllt'dialdy afte r IlIt· initial o una h....1 (·lItte·d folte,....in ~ tilt· U~m w
l J: do",,'. n'('t'in'tl a S('(ulUl 1 .().. Ill w\~ dose. The duration of (Uma assoda h'(l with thls
Sl'('Ou(1ttel!>(' wa .. .'S.O min .."-ssulllin~ a O il(' compartment moclel.
a. Ddl'nniIH' lh(· minimum (leN· of C I ~ I n"flllin'(l to pnJdu(, ' ('Ollla.
b. h tht· i1K'n'a\( ' in duration of co ma ...-en \\ilh tiM' Sl"'(uml tlow n msislt' nl with lilt'
infnn natioll ohtaillc'tI folk,....illg lhe.· s i n~ll' &-N.'?
.'>. A compound is ~u'n a\ an i.v. hollIS to a p atient n'( luiri n~ a minimum plasma con-
n ·" lrdlioll uf 4(l mWl. for il t1wrd JX·ulk (·fT(",('t . Ghl'n t1",1 1>tN:' =- 1000 Ill~; k - 0 .10
I'T- I; \ ' =- ~ 1.. allli a.••.\lI ll1illJ:: a OIJ("-<,UlIljlilrtllJ("ut na xk-l,
a . ClIk11Ialt· IH,....' lonl-: til(' cltnjcal dTt"(.'t Ia... ts wtth t1.i!> dUM' .
h . C, llt1'lal(· I" ,....· 101l~ tln- cltmcal effect lasts fnll(,....in~ il 2(1(1()..1I1~ ,lcl'o(·.
r-, Det emuue IIIl' duration of (·frt'('t foll(,....i ll~ a WII()-III ~ ,lc r.t·, if k .. lI.n ') h r - ' and
tilt· t-h;III~I' ill lilt' k is a n -sult u f (I ) a rn1lfold d('(:n'.L~' in dl'" rano'; and (2) a
dutlblill~ of till' vnlurm- of distrihutioll II)' inl·n ·lL\('(lllulI..,x"(.; fi(." tis ..m' hiIUL n~.
d . 1)( It·s d'lIIhling Ih(' doS(" o f a d m~ ~id d the- Si Il IJ(' dlall ~c' ill duration of dinil"ill (·fT(,(1
iL.. donhl in ~ tln- half-life?
6 . ( ; uI,'ov./"j t'l ul. IIIl·a."II"'(1 tile plasma and salivu l'UII(" lIlmliullS of procainanude. an
Oln liarrh)tlllllit· agem. as wd l a... Ih" pmlolll-:atioll of Iln- QT interval. an t'!('(1n ll'il.n li-
c~mph ;t, 1Il(·ilsu n - nf (In ll-: n -spoIlSt' . TIlt' mean data are ~i\l'n in T llhl(· 20--3. In till'S('
..lllIli(·s, fum " .IIIIlh't:·fS n '(-'c'in "(l 511(1 m ~ o f pnll.""in'"Uitl(· h~ll n K'hlllli()(~ h)' constant-
mhoi.v. infllSioll ll\'C 'r 30 min . Each saliva Sll lllpl(. was ohtllilll'(l d u ri ll~ a period o f 2 to
-I ruiu spa nning til(' tinu- of ''t'1I0US hl' llxl collection. TIl(' pIiL\IIl.1 and slIli" 1 conce ntra-
ttous lish '(l an' JIl('iIllS of tilt' conceutranous of ('il(:" illdi' idual m l("tllah'( l, I" , 1lI(lllc·1
fjllill~. In ha\1' fl('l"tlm"t{ al th c' tiJll(' of til(' d("('tmt~.l.rtli()gmphic n'(,mlin~. '
a. I'lot " ''',Xllls{' \l'fSUS pla...ma pm(~.linamitl(· nlll('(·lItmtioll. h tlw rt· ('\id" I1(" of 11)...-
h 'n-si s ill tilt' n ·laliomh ip and . if so. is it c1o(:kv.isc· or nMllltt"n:kiC."kv.ist·?
h. 1' )(11 rt"S(XlIISC' \l'fSUS saliva p nx~.li n a lllid(· C'oll(1.·ul mlioll. Is the' OhSf' l'\"dtioll simi lar
to lhat in -a-? B ridl~' dis<.'I$.\.
c. h Ilph-n·sb nhSf.·f\ t'tl in a plot of saliva \"f.· fSIIS pla.\llla p rot"Uinamit!c.' o)Jln'ntrdtions?
COIll)'lan'llw pInt 10 thclSt' in parts -,,- and -h.~
d. R("!I)ItIllSf." \'f.'nus t'tmt'1.'nlr.lt ioll plot s Ibat she,....· "~"lih-n'Sili an' soml'timt'S modck'tl
\\idl an - t' fTl'C1 oompa.rt llJ("lIl.- Brit'fly npl;tin wll~' Ihis appnlil(:h may ht' u-w ful.
CI1APTEIl2Q 36'

T• ..,1.20-3.M __ PI. . . . ." . .II. . ce_........ _.1HI PNI.~_"QT

1 - . - .1&*-I""'al_ .. 500 . . """.1_.1,,,
tIyII......Ieri... Ov_ 30 . 1.
I. I_It" ,_, V.I.........

.....
"" ,
w.r..on AJw So:>< <J

12
23
0
8
""""
CCf<£N1iJ.f'(;::N

'""'" 0
23
30
42
".""
CCNQN1iJ.fO.J

"'" 0
19
3.5
6.7
-
l'9OIQNG.J.f'(;::N Of
0 1NTl:....""

0
37
15 7
176
33 4I 87 203
44 237 70 16,9
52 1 88 56 160
70 1,5A 4I 123
97 1,35 34 12,9
127 1 20 30 11,3
157 1.06 26 11,2
194 0 .92 22 72
257 07 A 17 3 83
370 0 50 104 03

r, T ahlt' 2(~ lists tilt' d uration of dTt'ct achi."\'('(t with till' neuromuscular hlodcing agl'nt
pancurouium fnllo'ling thr- administration o f it 0.0"2 mglkg i.v. dose each time the
rt' S! )(Ill '>t' ret urned to 10% of maximal t'fTt'<.1 . Assu me that dm~ at the site of ucnou
rapidly eq udibrates with dru g in plasma.

,.It•• 20-4. N••,.••ac.i., .1_11.1•• I,,"," s.cc.HI.,.. DelMa-" h ac..... I• •

OOSI' 1\l.IWlf: ~ Z 3 ~

Durcr>on 01
Ellecr (mmt 14 20 36 >54
~ood\oooo~ ~ ~ 1Jo.oo-.• rZ7l4-7~ Z.'97t Or'9"""JI dao::l""""~.J .
.. (.;.l;",o;.M .l-r.G ,ondw--..l>.H
~, ~C ond~, " Tho~I:b:u.g<xlO'ld~ .. "U'do.onng~ Ilo-l ~ .4 VW-J l 0. 1970
~OZ"'9-"~"
"'_0>_o-9O:l<J"""",","",_

it. SII!!J!;t'st why the duration of e fTl'<.1 p~ressi~·t>ly Increases each lillie a dose is ad-
mmisn-n-d.
h. Will the duration of e ffect cou ttnue to increase if drug admintstration cont iuues to
lx- admhnsten-d in the same malllwr?
k . ~ Ic Dt"\i tt , I) .G .. and Shan d . D .G .: (Plasma ccucentrations am i the time-course of beta
blockade due to propranolol. Clin. Pharm acol. Th e r.. 18:708-i I5. 19i 5) observed a
linear relation ship be -tween efTN1 (perce nt reduction in exercise tachycardta] an d tlU'
I~a ri th m of plasm a conceutraticu of propranolol. 111e slope of the Iille \\'3S 11.5%.
Tah lt· 2(hS Iht s tilt' t'!TN1 'lith tune after t .v·. udmtuistrunon of 20 109 propranolol.

lINE (!wI , ,
Peceer 'ed\IChon 'II
e~efc j~ IOC hyca,d lO 28 255 22 15 8

it, Estimate the appa rent hal f.lift· of p rop ranolo l in plasma.
h , Citk ulatt' how l un~ tlw n '(!ll<.1ion in exe rcise hK.'hyc-.mlia is t,xpt'<.1t"tl to remain ahm't'
1511 (I ) afh' r a 40-m g i.v. dose and (2) after a 6O-mg i.v. dosc .
 CHAPIU 20

9 . Pn-dict till' ~I 'Ill'ral h-lld('IWit·s (d od . . .vise, counterclockwise or 110 hyst t'rt's is) fo r tilt'
oIN'rn-<! n.·lutio nsh ip between "-'SpOIls(' and plasma drug concc ntnuton af'tN a single
oral doS(' of a dnl ~:t~ a l 'UIlM.'f IIiPlll't' of P ilch of dl(' follo....in~ con drnons.
;I . Sit""· di strthutkm 10 sitt· of action.

h, Hilpid dt'\l·loPlllt' lIt o f tn lt'mlll'! to the dm~.

c. I> m~ ~\'t' ll in coutrolh-d-n-h-ase <!O!iilgt' fonn. Activi ty re sfdes so lely \\;111 drug.
whic h t't luilibmh's ra pidly be-tween pla.s mil ami sit!" o f al1ion.
 METABOLITE KINETICS

OBJlCTlVI5
The reode! will be able 10:
1 Slale the phormocokinehc parameters rho! influence plasma melobolitecceceenouoo and
01 merabo/'\e in the body loIlo-Ning drug odmir\lsrroliOn.
o mounl
2. Delet'mioe jf elimination ol 0 melobo/ite is fol&timi!ed by il$ lonnation.
3. De\e(mine if 10101 clearance 01 a mek:lboIite is Ies.s thon tho! of il$ porent drug, given plasma
ccocenncnoo-nrre dote fOf both drug and metabolite following i .v. drug odminiMrotion.
4 Describe the consequence 01 hepatic eJdrocliOn on plasma merobolile concentrations 10/0
Iow-ing oct odministrolion 01 0 drug
5 Slate the phormoco'.ine!iC: parameters thol coorrol the cceceoectce 01 metobo/iteot pIoleaU
followIng oominisll'oliOn of drug as eirhef 0 conslonl'fO/e i.v . infusion Of a mulhple-dose
reg imen ,
6. why efiminatoon holf.life 01 melobolite is the delerminonl ofcccccl 01 metabolite.
Descr ibe
when a ccesont amount of drug is maintained in the body.
7 . Describe why e!imiooliOn half.lifeol the slowest step, drug elimination, Of melobo!itee1imi-
notion conlroo accrual 01 melobolile loI1owing drug odministratiOn ei/hef by conrontfole
drug infusion Of as 0 multiple-dose regimen.
8. Cokulate the OV'eIoge ploloou concentrohon of me/Obolile lolbMng on oral multi~
drug legimen, given the dosing inleM:ll and the AUC of the metobolile aftel a single dose
of the drug
9 E"pIoin why the holl·life of a dlug, which i~ ,enolfy exceed unchanged 10 onlya ynoR
exter'll and undergoes intercortvel~ion wilh a metabolire, con rocecse wlOnlially in pc-
lienl~ with renol function impairment.
10, Cclcoce the apparent fraction of drugcceeoed to a metabolite u~ing AOC mea:w,emenls
ofdrug and metabolite after sepcrote doses of each.

'I'll" n';". III Ii Ir uu r inn-n-et ,ifill {'(JI I{'('n1 \Ii lh m{ 't;lI Mllih '~ {"a n hc' .~1 1 m m l" I II Jl ill (illir wCln k
'I(·tic l1I. It,\i, 'it ~ , ililliliiticul. ancl d i'pla('('m"lIt , .-\ 11 tCM llllil' n Illt'tal Mllih 's an ' 1'"u I ~I.t Ilf a ~
wl'a kly adi\ I' or illadin ' wa~ h' pn MIIl(·h . Fo r mall )' this b <;1"1. hilt ,l~ "'i'll in Tahlt' 21 -1 for
Illall.' ·., tl!t·r, it i' IH,I. SI)lJu,tillU " lh t, ae;l'nt ad mini''''n,,1 b a n hu-rt p n Mlnl e;. wl.k h c l c'pc' l lI l~
on 1l11 'laI M,Ii'1ll lilr adh a lio l1 . E \a1l1p l,'s an' r-naluprtl. \l'llid l is h~ c1rlll~-/c 'i l to t'nalaprilat.
an a(·th t' ;llIt;o h'n'iu ·('(m't'rt iue; " 111.)'11 1<' L\ C El mhrlutor. a mi prall'jl;\m , w llidl is lI11'tal>-
oli"..1 to tlu - adh'c' 1"" llzlM li,w'pilll' t1t"Ill"t llyldi,w·palIl . SmUt' nlt'l al""lih's h"n ' ph.mua-
('(,llle;i(' I' mpt 'rt i\ ' ~ ill rouuuou \Ii th III(' ,"'trt'nt d Ole; ami au \.(ull'nl ils ('Ill",t. SOUit' lI1\'t;\I>-
o litt" II;ln ' a di lli 'n 'lIl pl.aml,udllt;1' profih- alll lmay P H 'II 1M' lilt' 1';I1 l'(' of tmi(·ily. ( Jl IIt' T
rlld "IH 11 il< " a n- ill.11'! hI' hill llIa~ . h~ ;1(·till\.( ,l' inhibitors , pmlolll.( o r \'1\11;111('( ' IIII' rps po llsp

367
 CHAPT"Ei121

CCWK.ll.N:> C~
~m't D ·.\f:Aj<o-,.'H ~TH'l:D '11.1"",.1<

.\.r''',1'>O r,' (l(,(J 1'>0'00<(, {lo.' 'l'n hOI(>

;.- ;Xl'" 1'.' bocco.oe
Ar" ;1~1 ,. 'v'".p<:,.~ ' w'
Ca'tJ('-'(l.',..P ..... ."""'o!ph,r""
P""ro , ..,1 '0£'
C':>' "".,·r" p,(u- rnm
-~i<y j"l."?' ' (", P,cdn !.OI ....
ell '1"'-""">0.',,,,,, P,-~
0<*0(: Procu '\<..I"",j,.
D v,:,r~;'T P'ol"()'doi
01' a,''<l' Q"n'd ''''''
E'<lk"" Sul.~<io<:
Erco n 3..' VerO I:oQ'T
floo "·',,,,, ZIo(l(MJ(l,'",
h I~Qf."r,'

to <l t101~. Sti ll ull w rs 1ll00y " lTc'(1 tilt" di s pu~i tinll of a dnl~ hy ('Uml..ti ll~ for p la..mil ami
tisSllt' h i mli Tl ~ siks. It ts lIut su ffid t' lIt, 1l1J\\'C '\ l'r, to kno w that 11 rm-taboltte pUS.WSS(·S tile
potl 'utial lilr allY or ,1I1 u f li lt'S(· pmperth-s. Unlt,ss a su lIidc'lll conce-ntmtkrn exists at tI n-
site· of action, tilt' p Tt'St'lin ' o f a T1lt'talxllitt· is o f littl t· th erapeutic concern.
This dlaptt'T c xamtnes IIIC' factors th:lt illfhlt'llt't' tilt' kim-tics o f metabolites ill tht' " ud )'
and tilt' t'C IIlSC.'l lllt' l\t't.'s tlMt ensue. 111l ' pa lh wa)"S i ll\~J ln"( l and the silt'S o f metabolism art'
dis<'us!i{"(1 ill Chap . II , Elimiuuhon, Fo r PIITPU!i{'S (If clanty, it ts ass umed that lilt' 1I( I(Iy
alis il.' a si n~lt ' l'CllIlllUrt lllt' llt flIT both dru ~ alJ(llJIt'ta!ll,liles , Illat all ktue tic pnll't.·s.\C's a n -
Hrst-onk-r, and that no dlilll ~t' in plasma p rot ein hilld ill ~ occurs, unl t·ss stah'(l nt ht' r\\ist',
111t' ~i lual i{)n in wllil'1l metabolism is satu Tllh le is (li.\(''1IS\C"t1 in Chap. 22, Dow am i T u m-
Dt o!x ·lldtoul'itos.
l nformatton aho ut a IIlC'tall(llilc' is usu ally ohtaim-d full(J\\ill~ dnl ~ administrauon. AI·
IhulI~h thi s infunnation is argu;ahly Ihc' mos t releva nt to d nl ~ the-rapy. sttua nons (10 arise-
that reqnln- indt'IM'nd('1l1 information UII tilt" p harmacokinet ics and adhit)' of til(" metah..
" Iill' . Tln-n lilt' nlt' I;aII( ,lilt" IIIl1st he ad mlm sten-d !i{·(l;lra tely .

SINGLE DOSI OF DRUG

Rate--Umiting Step

T n app n -ciah- tilt' fact ors i ll fl llt'l l d n~ lilt" ,1I1l11unt of lIll'tal l(,lilc- in tlu- 1 I( MI~" A (m ), \\i tll
tilllt' f()I1 Il\\i ll~ a si ll~1 1' i.v. duS(' Ilf drug, conslder till' w llt'lIw:

Me tabolism Metabolite
A
Drug in Elimination. l im}
Body
CHAPTH '}I MfTAKlUH KINE TICS ,.9

in which dnl~ is (111\\'t,rt l'll to a ml'tabolitl' that, ill turn , is eltnunated , 111t' two sh'ps art'
d lanK-ll'ri 7'('l 1 by Ill(' fl'Spt'(ih't· Hrst-onh-r ran- constan ts kl aml k(m ). 111t' 1J\'('mll t'limi -
nation rate e ursta ut u f ( I m~ ( R) is tilt' slim of k,aml k,,,,,,,,,.l hl' mit' constant for ul lll'f routes
of dm~ l'Iiminal ioll . Also. at any ttnw

Rate of cha nge of kf • A l(ml -A(ml

omount of metabol ite Role of Rate of
in body formotion eliminatio n

Slridly sl'M'aki ll~ k, ' A r efi-rs 10 r un- (If (' nil)' uf ult'taholitl' inlo till' systl'lIlie eirculatton.
It nlllY nol I II' its r ate u f Ioruuuum . SUllw lilll('S, a Ilwl"ho!ill' fonned withlu ;U\ 1l~,Ul is
further Illl' laho !i7'(11wh ile th ere, !"l that onlv il fm(i inn of Iht' fonm-d metabohn- is fel(',N'l 1
From tin' o~all into IIII' hlollllstn'am . l 1lis' is refern-d to lLS ,w'f/,w rltln/ mrlnboliwl t111rill~
p"L...sa.~e I hl'tltl~h a n organ . A llll'tallll!ile fonm...1\\i thin till' [ive-r may also II(' I'X(·rt·h'll into
the fl"(...t~ ' ;a the hill'. FOf Silllp lidly. in tltl' SUhM'lIIlI'llt discussion. o nly the case in whk-h
all o f till' Illl' taho !ih ' f(lOlIl'l1 n-aches lilt' svste-nuc circulation is 1.'tlllsid t' rt'(l.
In tlu- scheme lIhll\ '(', ('illll'r sll'p ran '1)(" mlt' -Iilll ilin ~; till' rute-lmunng slt' p h,L~ the
smaller rail' constant. Fi,gtlrt' 21-1 . two '\{·milo~arilhlllit., plots (If tlt e amou nts o f t1n l ~ anti
Illl'lalMllih' ill lilt' 1MIlly a~ai nsl time- fullo'\;I1 ~ <I si lJ~I I' tlu'\{' of dm~, shows tilt" l."Ill1M'lIUt·!ll't·
o f <I m it' ltnutanon in t'a d l ~lt ·p.
A ra te limit ation in d m ~ d i spo~ition . tilt' most common situation. hll'i a numbe-r o f cnn-
s('ll'u' nl."l' s. First . till· half-lift, of t1m~ is lllll ~('r than l!lat of lIlt' lIwtahol ill' . Second, tln-n-
is ah\-.tp ilion' d rug than lIwlall(l!itt· in till' 1M Illy. l ...L'il, /lU'ttl!Jillitt' t'!imirwtlml i f ! ilnlltltiilll
n ll('-I;l1I it l'fl ; Le., lIlt'tlll Mllitt' is dt'llf{'11 so mpidly that t1urin ,g its dt oclinl' phase wIJall'w f is
fo n llt'll is almost illlllll"lliutl'l y eliminated. Ap proximatl'ly, Ilwn·fof'e

A 100 B
100
k < k(m l k > k(ml

"i
0
10
Drug - 10
~
~
0
Metabolite

0 0
"0 , Metabolite "0
C , C
,,
-- '"
...'"
0 0
0 0
E 1 E
<

0 _1 +--~-~-~-~ 0.1 +---,..l-~--~_

o 3 6 9 12 o 3 9 12
Hou rs
.1". 2 1_ 1. C.. m' ~ I' ''''TK~''S "r a n. h· lnnil alit.., SIl''''l1 in ",,·mit."I:"'rillllllk · plots uf dn,~ ....d '1M'T"h" tilt· , .-\. \\l "'n
11..· ,-l im inal k nth' mmt.... 1 of II... tIn,jt is .. n;o!lt- r Ih"" Ih.., ,,( IIwlahol ilc·. n......tdil l' (t-Illll n "li .....,IIt~I Ii , ..·)
n
,I."C."i. - in 1' II.·1 ...1Ih IIIf' "n,~. H. 011"""'"1:-'. ...t ... II..• t'limin.<lit,n r...lt' (UlSlanl uf Illt't;o!II""1' b sm.. I"·, tI"",
thai <lr .lmR- IIIt III"il.· ll""I"ll"Cl ll''''M ~I 1i I If' ) .Io~:b ll'~ " M'''' st.",,,· II",,, d n'lt- In It... f........., ca.... (Ao), . ....... iIM· .. r
nIt1a" ", !,' is ~ n M..II", .. tirnin;tliull uf d nl~ ;t,..1. ill til<' latter t~... (in by Its IM'll ..-!im irudit'll. 1111' KIlI.I,I.. an'
si m IlLt,,~l llsi ll lt "I'
t..,.",.. lUli l kIm ) ',.]'''''S <If 0.2. 0 . ",III 21,, - '. r.-spt'l1i\'l" Iy. in 11M' r",m.. , 01-.... 0l.<1l12. n. ..,..I 0.2
1,, - 1. .. 'SI".....i' ""I:-· ill II",· I..u,·, .
370 f./iTA8QUTE fTC CI'W'TH 21

' 1m) . Aim)

Elimination ro le
- For mation ro te 2
of metabolite of metabolite

Amountof metabolite ... (..!5L). Amount 01drug 3

in body klml in body

In th is ( 'LSI' , ,Itt' Ilwt"ho!itt· declim-s with til(' sann- half-lift· as ,Il(' dm ~ .

:\ metabohn- accrue-s snh stau tiallv ill t!lt· hod" 0111" when its ('!illlinatioll is the slow(·1'
Slt 'p . That is. til(' Imlf-1ift· of 1IJ('lal xlhtt· is IOIl!?:t· r' thai; that o f til(' 11m )!:. \\ 'hen this (K,(11f'S.
d n lg is Illos tly I'lillli na h '1! hy lhl' tiun- till' md aho litt-I)('ilk is n-ached: dcclhu- of lIll't aholill'
is tlu-n (1Illtm lll't l hy its l,lim inat ioll " air-li ft',
III E l l S. I III 3. k (lII ) n-fers 10 the ra il' cons tant for Illdaho litt· ehmiuutkru. Jmt " ow
lIl il lly path ways an' involve-d ill lllt'taIMllif( ' t'! imi! l<ltio ll is no ! Important. \ \11<11 is i mpo rtant

is 10 know w lw tl Wf cllt' t1m~ or Ilwt aboli h ' clt nunutfon is Il.t· ril tt·-l i lll il i n~ ~ tl'P ' In an y
S('(j!l('lIt't·. ~ lI h~ t:lIlt't·~ fO flllt'( I I)('} o nd til(' ntte . l i mil i n~ sh' p dt ,(:line \\i th tilt· ha lf-life o f thi~
vlo we-st Sk p . Tn l' lIlpha..-"iii''(· this point tUllsidt 'r tilt' f(lIl( l\\i n ~ scheme.
C F
.~ ,>
.>- -" - - - -
ow
A " B E " G H " " J
,
0
in whi(·I1 .-\ n Oft·" In till' d nl~. C 1 1 1R1lI~h 1 f(·ft' r to Illt'tahol ilt·s. J is tilt' . '-'u·f(·ftod Illt'taholit l'
1. und tlu- number ahoH' (·ad . arrow is th t' value o f til(' respecnw rute constant in hr - I .
(). \\1.at is II\(' rah· .limi t in~ stt·p in III(' entire s(·l l lJt· llt'(."~
A . Elimination o f nu-taboltte G, t l 12 =
0.69.1,10 .05 =
13 .9 hr.
Q . \ \1 1at are tl ll·lmlf·!ivt·s for dt'('ay of A , D , E. 1/. and I Imm ti lt' 111)(1)" foll o\\i n~ adnnn-
istrution o f d m~?
A. Di sl lt ,~iti()11 o f .-\ ratehnuts dl'(.,lim· o f lJ am i E. t va = O.69.1I(O.C l1 + 0.2 + 0.3 ) '"
1.31 l rr for A , D . and E. E lilllillalioll of G rate-limits terminal d('(,Hm' of 1/ and 1,
t ll'.!: ". 13.9 hr.

Ot '(1Islollally. till' hal f·l i \"{·~ of d nl g illlIl 1I11'tallt,lite are cotuparuble, and then Ileit lll'r
~ tt·p is mt (·- lilllitin ~. 1I0w(...-i-r, metal MJlik dt '(:lim's IIIOrt· slowly th an anlidpoth '(l Innn its
hillf·lift· akuu- lx-cause SO/lit' dnl ~ remains to sustain tl)(' 11...·(·1o f 1I11'tal MJlitt· fo r 11I11(:1. of
its (·Iim inalic)ll.

Plasma Concentration
Tla- pn '('t'(li ll ~ di M.·llssiun . Iwlpful ill n 'a lii'ing tilt" im po rta nce of rah· · lim iting ~ h·ps. dt 'als
\\it h amou nts o f IImg alltl lllt'ta IMJlilt· in tilt' Iltl(ly. 1I0w('"\"(' r, plasma coucen trutions a re
1I11',L'> u n'( l ami an' of Kft'llh 'r Interest . F urthe-rm o re, ill most (:4""OS. a uwtalMllitt· hilS llot
bceu d l' ,m '(l for hum an use- hy n~u latOl)" allt horiti('s to perm it ck-n-n uination of its \,,11111l1'
o f di ~trihuti llll <Ind . the-re-fore, its amoun t in th e' hIMI,... H owever, much e.U1 he' gai nl'd Irom
dt·ar'lIlt'· concepts. ,I' iIIust mt( '(1 with severul examples.
Till ' first t'XillJlp lt' concerns lllt'tt.~lprt'(llJis(J I(JIll'. Oning to I(j\\' so luhility. fonn ulation of
all i.v. pn -p aranon is (lifl it,llt. YI'!. clin ical situatio ns. f· . ~ . • In'lItlllt'lIt of shock , sometimes
CHAP1H 2 1 MfTAflC)lJfE I:....ETlCS 371

tlt'III'111d rapitl input o f tllis .~ It' mi d. One solutio n I.<L~ lx-en to adrninlste-r Iht" water-soluble
1lt' lIlisul'd llalt' t's tt'r which is rapidly h' 'tlm lp J.'tI lo lllt'th,1pn..Jlli ~ll(JJw hy e-ste rases within
l ilt' Ixxly. Shown in Fig. 21-2 a rt' tilt' pla sm a conce- ntrations of hot lJ thl" hemisucciuate a nd
m t·th~ [p rt,,< llIi sol ollt, fol1 tl\\i ng all i.v. IXIIIIS dose o f tilt' ester. It is rt'ad ily ap pa n ' nl th a t lilt,
1lt'llI isun :inalt' is \0 rapid ly h)"d m l' "lJ."<! to sterotd t ha t cluninatlon of IIwth)"lp n ,,<lnisolm lt' is
no t ral('olim ih 'tl hy its fo rmation . Tllt,Sol' dat a also permit tilt' cunc-lusiuu 10 lx' d rawn tllal
tilt' d p.ll'illll"{' IIf mt'l hylpn '(!nisol ol\(' (nwtalxllitt' ). (' /.(m ), is IlllIl·h lower d ia n that nf its
lu-mtsucclnate. TIw ar}{tl rlJ('1l1 is <1-\ folluw!':
"\1 'IllY tinu-,

Role 01cha nge

o f om oun t 01 = C~ .C CLlm} · q ml
melo bolite in body
Rate 01 Role of
melobolile melobolile
format ion elimination

wln-n- C l../ is ti lt' d t·ar.l.l1l" '1\<;(Jl'ialt't! \\i th Iht, hytlmlys is of tht' 1lt"lIlislll"(;na!t' (",IN to
IIwthylp rt't lui<;(IIOlll', SmUt·tiUlI's n -fe rn-d tu <L'i theJim/ltlliflF! clearance. Cl)m ) is tln- to tal
d t'a l'illll" IIf tllis ml't; llxllite, am i C a nd C (m ) a n' the n ·Sjx't."l:hl-" pt l'illla concentrat tous of
tlm v; alltl llld'llxllili'.
I n tt~n1t i ll v; the fort'goinv; t"(lliat ion v;inos tilt· a mount of nw talxllilt' in tilt' IXKly at a ny
time . As no lIlt'thylprt't lni<;(llon l' is prt'S(' nt in tilt' Ixxly initi ally or at infi nity, it follows,
IIIXII1 intt'gl'ill inv; El l, .. Ix,twl.'t'T1 tln-se l illlt' limit s, that

AUC{m) _..3t.. 5
AUC Cilm)

wlll.'rt' ACC( m ) mn ] A l 'C ' In' tilt· total an-as under Iht' 1Ilt'lalxllitt' a nd d Ol ~ t'Hlll"('ntnllillll'

10 .oIK. 2 1_2. l>i-pt.~ . ..1 " ·"' ilo"l:"rillo.

"'i<...I1~· ....· II..· pi ",,,, n"""'I.",I;' '' I'
"f tlJ.11,~ tl'"..lni.t1l , lel "" ..I iii Wil·
1,·r·"" I"hl,· I"·mi.." ..';n ,,,.. • "sh' r (0)
r"IIe"';"1: ,m i,\·. I.. ~, .. ;n;', 1;'..1 ur 0,11
'''I: "f II..· ..,.I,·r; ....,..'S ,,f II .,,1>;'''1' .
T1... ,I,"(·lin.· " f lt l<' t "~ Il'rN ln;,,,lu1I<'
It ..,, - 2.': 1Ir) i . r"h.. Ii",;"..II~' ili .li, .
p".i1;'lIl. tI.>! I ~' tI.., 01;'1'' ''''1;''' 1 ur iii

.... I..·",;" ; n",'" ." I<·r (' 1/1 - n , 2.~ I.r).

n... ( · M ul mdl,~tl'n . lni .. oIc"...
i. Ie,...·! t1 n Ii ....1 " I iii 1o,·mi" K'(;""'lt'.
'" (..."oJ".."" ,ll1lwTl f""" II..· ,~ ""'."
I;'", (",..' n . " , .. ",,", ,,,,,,,.. 1;"1:
.
h,,, .
pI" t) 11...1 II.., ..K e "r "..11,~il' lui.
.. 010 _ · is II... la"""r ,,f tl..· "' I K,"
,Iuwn rrom D....·",lur r. II., \ 1,, 110
u....m. II .. K"I..Ie'\\'IlnI. I'.. 1I.·h. le·r. J,
"" ..I S.:I,mi< lt. E.W.; Ki,.. 1i<... ur mdl,·
0.1 ~ 1 1>n ..I"i.. oIo".., .uKI ih I..."';.,K" ....I'·
o 2 4 6 8 ,·,It·r, Clin, 111afl"....~ . n "·r.. J;-,.'it ~2­
.~ r.. I Y-'I.~.)
Hours
3 72 ME1ABOlJlf KINETICS CHAPTH2 1

till\(" profik-s. rt·slx "(.1:iwly. Sllh stit ll t ill~fm . Cl. for C' 1' wlwft'fm is the fml:tioll of an i.v.
dnS(' o f dnl~ ('011\1'111'(110 systt'lllk a lly <I\'ailabl(· lIll'ta hoJill', til(' foll(J\\ill~ n-lsttouship is
uhtaillt"tl:

AlIClmJ _ fm • Clearcoce of drug

6
AlIC Clee re eee of meta bolile

Ih ·t.. m i n ~ III Fi~ . 2 1- 2, th e' data SIIAAt'sl that th l" an-a fur met hylprednisolone (A UC(m)
is ~rt'ah' r than that for tilt' adruini sn-n-d ester (A VG). Calculation co nfirms this; the re-
"pc'd i\'(' a n'il-S an' 3 .9 am i 2 . 1 Illg-hr/L. Al1:'(m IiIlKly. sinn .' th e value of 1m cannot (·)('('("(1
unity. tilt' ck-arunce of lIlt' th ylp rt'i.lnistJIIlIll' must 1)(· les .. than that of its es ter. If the rat ln
o f areas Imll h('('11 It·ss than I. then. 1I111(·ss the value o f fm is kmM11. tilt" n-lative total
dc'ar.lIll't' "" IIIl's cannot lit., a.s sessed. Because no kllowlt'd~(· o f lilt' amount of (! m~ ill Iht·
hCltl~' is Ilt'{'('s sary to um w at lilt' ahoV{' conclusion. thi s an-a !Ilt·thud of i lltl'rprt-'tin~ me-
ta ho lih' didil can \)(' t' xln ' nlt'ly IIst·flll. t'sl)(,{1ally in cases uf dnt~ poi solli nJt ill which Iht'
amoun ts i n~t'stt-d alii ! absorbed an ' fn 't jllt'lltly unknown
111t' Sl.'{"lJlld example- deals wilh propruuolol. Hil-'il"tl on tlu,.o dala in Fi~. 21--3. obtained
aftN ~hi ll~ propranolol illtnt\' ·lIollsly. tilt' d nt~ has rln- followin~ cha r act e ri..til's : tot al dear-
uucv, 1. 1 L'mln: volume of t1istrihutioll. 3,<)(1 L: ami e limiuunon half-lift' . .. hr . Other data
S ll~t'st Ihat almost tilt' enure dost, is mt'labo li7.("t1 in tilt" live r. ~ ft't ahnli h's of pro pranolol
;ndll( lt , Ollt' o r mon- ~1 1I<' ln lll i dt,,, ami napht hoxylat1ic add, which was measured "1)('{, 6-
(,'a ny ill this study. \\1lat m il 1)(' learnrd frum lilt' data dL"p!;t}l"tl ~ Ill i l()~a ri l h m iedlly in
Fi ~urt' 21--3?
From (,'1I11Sidt'ratiolls o f areas o f dnt~ am i metabolite. one 111ll.s1 ('' l llld ud(· tlmi tilt' cle-ar-
,iIl("l' of naph lhm:ylal1il' add is 1IlU('1. lelw('( than th ai o f propranolol. lt oWt...·N . lilt' p arallel
t1t'{'it\, of ml'laholih ' and dnt~ im lit-.tlt,s that elimination o f thi.. lIlt'taholitt· is rate-hunted
hy it:s fo rmation. lI t'II(," , the- elinunariou Imlf· lift' of this ilion' po lar nll'laholile must ht'
s!.nrt Pr. am i tilt' amo unl in the- hod~' a\\m~'S low er. than Ihat of the parenl drug ( St'C Fi~.
:21 -I Al.
111t' o nly (·\planat io n ("lJJlsish·llt wtth th ese observations is that volunn- of tlislrihuti oll
o f llIt'1alM,litt·, \'(m ), must 1M: smaller th an that o f pan'nl drug by a fact o r ("-1.' 11 Wt·att'l' tlmn

t 'il(. 2 1_1. s. ·"' ile 'K".uillulIit' l'lot uf th.· r1.l-'tnlt .~ ..w.~·"' r.llio,,, or p" 'I'm".... oI lO) 100
..,,,I uf "I,,· " f its 111.....1...1110' . " ..p1,tI..>~~t..1ic·IK-;'; I I ., .~,I..r ). (me'''11 :!: SE M) Itf' ..r It
'; 1ll:1o. h . •Ie....• ur 3.7 llll: pn'l, r oI"l ,u thr...· , ,,bjo'l1', ~ "t<' ,1...1 tl.., ,·Ie" -al...111...1..1.. 50
,.lit<· \.........·" t m' i< ... ' .Io'l·hue.. in 1 11..1"'ith 1,..,...111 ,Iru !( 1,,'(,..01.. •.. f It Io",..'r ' 01.1 d . ,...·
" ,...~. a,,,1" "nalle·, \1,lu",. · .. r <li,' Mhu li< ", of ''''l ,I,tl'' >1}t..1ic.- ..del t"lIl1"'n~ l ...i'I. I'ro ,
prd,,,,le ol. Fur a ,Hid t" "'I>an'''''. tI,,· "al' htl......~t...1ic.· lKiel .J'"UItl he' '''1,"",-"..1 in
pn'l".t'''.lc.l ' ''' '' I\;olo·nlo. hUI tI" , ,liff.'rr'" ..· in th.';r ",u""l'\,lar "'''';1:1,,, lZ6l1",,,I 2Il4. is
" "IM'(1''''~' ) ; ' ' '''all U "'WI, uf pn'lmu".teol - 3.Y ).1\1 ). (R' '1Ir..w" (n,m Will..•. T.. ~ 10
Ce",r...li, EC.. Walle·. t.:.. Fi\J:"" . T.e .. and (:..fT"" ,. T. E., ~ ..1" 't1.....}t..1it:· ",."Iafhor
,i,,~Ie· ;ul< I Ic"' J:-t<'n n el.-..... of Im 'lm'I " ,le ol. Chn. 11,.tn"",~ .l . n M·r.. 21);S4'h'\.~ . HI7il, ~c 5
11' 1'" ..1",~ ..1with p" nni"i<"1 "f (;.\ '. \1 " ", ,:\,,)
<3
5
a:

o 5 10
Hours
CHAPTH 2 1 M.ETABOUTE I<J'.lETll:::S 373

til(' ratio (lr t'!('arrlllt'· values. l1ds conclusion follows from a comparison or tilt" elim ination
rat e con stan ts fe r metabolit e and drug:

11m} ClIm}/ CL
- 1- ' I1m}/ V 7

For k (m )/k In ht· v:n'aIN than 1. the ratio \'(111 )1\' must be smal ler than CUm )/C1~ . COIl '
firll\in~ this {'u ud usioll is a concentration o f un-tabolit e m uch blghcr than thai of tilt' parent
drug ( F i ~. 21.....'] ). despite a much IOW N amou nt or ml't alKJlitl' in the hody \\11(:'11 elimination
o r lIlt'taIKllilt· is form ation rate-linnted (Fig. 2 1- IA1. TIlt' fiu dtngs with propranolol an-
quite {"{IIlIII1(mly eucouutered . part icularly \\ith IliL~ic d rugs that an' conve rted to acidic
IIwtaholih·s. ' n i t' volumes o r distri bution or these ba sic {(n lgs art' ortl' lI in e xcess or 100 I...
whereas those u r the-ir addi{' metabolite-s art" do'St'r to 10 to 20 L. These - metabolite-s not
ouly an- ilion' polar ami tend to hind les s to tis.~lI(· constituents than the p aren t d rug hut
ulso an' bound mort' sln lll}?;ly to albu min. thereby further res trtctmg their d istribution .
Kint'l im lty. ghillg an i.v. bolus or d m " and measuring the plasma me tabolite conce-n-
trunon is similar to ~hi n~ an oral doS(' of dr ug and measuriug its p laslll" concentra tion. III
IXlth situat ions. Iht' aplx'ar.IIl('(' llllli disappearance or a species [metabolite in Ollt~ t ·<L'W:' .
d m~ in the otlu-r] an- monitored after plad ll~ i/o IXIIIIS dose ill tilt" Pf("(."{'( li ll~ co mpartme nt.
thus
) It'lahu liml

11m}
A A(m) I

Meloboli! m Eli mino tio n o f me ta bolite

Drug in Metabol ite
body in body

10 I
Ao A
Ab sorp tion Etiminalion of drug
Drug 01 0,"9
a bsorption ln
site body

Hecall from C hap. 4 (Extrava scula r Dose) that tlw peak plasmu concentrunou of a drug
~iH'1l t'x1 r.1\1l\t.'u larl)' reflt'<.1s tht' halallt't-· 1)(·I\\·t"l.·1I r ates or d r ug absorption a ut! elimination.
Conv ... p<)ndi n ~ly. tln- 1..5 102 hr req uin-d for nap hthoxyla<.1 ic add to f('adl i/o pe-ek ill Fig.
2 1--3 reflect s til(' 1",laun ' 111'1-.. \1'('11 rat es o r Ion natton and elimination of this metabolite.
Tlu- lust examph- t,,{lIIt" n\S tolbutamide, an effective oral h)1lOl?;I)'{,·rnit· agt·nl. lliis t1 mg
is (·.\tell siH·ly llI(·talxlli".("tl to hyd nJ~10Ihutm llide. which . although active , is the rap('lltiC'dll)'
unim portant . As seen in Fig. 2 1-1 . the concentrations of 1J)'d roX)1olbllt amidl' art' so low
thaI they never augment II\(' (·fT('(.1 or tolbutamide. On e possible e xplanation for the low
coucenr ranou or md alxllih' is that litt le is formed. H owev er, ill tile case or tolbutamide,
IlilS{"t1on uri na ry n'(.'{)\·t'I}, almost all the d m g is converted to hyd m X)1olhu tam ide . 111at is.
I". is d oS(' to I . At"t-·o nl illgly. tln- 200 -rold mtio or drug ami meta bolite areas f(·f1 t'(.1:s a
t"{IfT('sj)(md ing ratio in total clearance \11Im'S. wtt h that or hyd roX)1:olblltamidt' Ill'ing the
IlIlIdl hi~llt'r or tlJ(' 1\\'0 .
374 ME TAflOlfrE KJNETICS CHAYTH 2 1

100

. '111:' 2 1-4. ..\ . "hj",.1 n-e.~,w~ Ii I-RLv. I.>lus .. f ..,,- Tolbutamide

1."I''' ''it lo-, n M' (U ll't·" tr ;l./ i"" of lu lh" t.. ", it L.· ill
pLI.\lllil f;o./l. "ith a I.alf·lif., " f 4 h..\ ltl....'ll;h uu Llliu..
'" l,u lr"~\1. "IMI' al1\it "· i. ;d,,,...., ..I,lilo:;dnrY fur ,,"-
hnl;'''it!t-",·li'''illli tk'''. II... 1'La." "li .'tIlK't·" trolliu" ,,(
,I,i. II.. 1... ...il .. i. ;J...1I~' ,,'':\"' " M ', ' '''' 'inl{ In ih t"' -
I"''''' '~' hi!4J d....nonn ·. A' 1i '''''''' ''Il'lIn'', '<iIK' - th.,
...." " ..OS <If ,1i"riIMJ!illll ;m' , i rnib.r {O 1.5....o ,3n I A Rl,
••i<lah"" o f 1,"Io"I..",il l.- r.." · li,,,ih 1",lrtl"'1,>I' ..,lam·
ill.· ,·lirninatiClII . (T'''''"t..m itlo.·: I ",I:tt. ,;.
3 .7 fol ~l;
.,
~drOxytOlbutamide
1I~t1 n ....~1"11>" l a "'id,.: I rnJ(l1. - 3..5 1I ~ 1.l (H•• I"""..
("mil \ I.lin. S H.. a'll l K<.....ia..d . \ 1.: l). 1,'n ll i" "h" "
Hf ,,,n,nl""'lcl.· a'M I "..1al,,>I, I,", in hl"luj;(it·..1fl"icL. ,
",,;0/. 1. 1.. ·n.Ii :M>.'i--II7fi. lyj3.1~· (• •Il r1.~' "f \ '.trn·1
1),·H.•·r. b.....)

0.1
o 10 20 30
Hours

Impact of H'patk Extraction

IIl~t'sl i n~ d m K" Ihat an - (']l',Irt"t1 bytln- hvr-r is Iilw l akill~ a mixt ure of dm~ and lIll'taho litt·.
111t' n -ason. it" Illt'utimlt'tl in C ha p . 2. is tha i all ill ~" sft"tl d rll ~ lIlust p.L"S thnlul.:h tilt' lin'r
I",·fort, t' lIlt'ri ll~ tilt' ~t' l lt' ral circulation. 111t' t'o lllpc",itillu IIf till' mhhln ' ]t'a\i n~ til" liwr
dt ·I'lt.·l\(ls 1111 1111' 11I'patk extrac t ion ratio u f tilt' d m~. \\111'11 Iltt' t'xl rad ion rat in is hi~h .
Illl't<lho lislll d tl ri ll~ a bsorptioll is ,·.d t·l\sin ', a nd lilt' sit ua tion t'ornt'S (']u<;I;'lo that (If admln-
i st l' ri ll~ jusl metabolite . Table 21-2 lists sonn- d m~s II l ldt' ~{, i ll~ ,'xlt' nsiw fin;t-p,l"S hcpauc
l'1imirml inll an d fun niu!-: at1i\'t' Illt'tal"" liks . Fo r 1I1t'1ll. t1lulim l IIlIlSt hl' taken u~ai llst at-
It'lIlpli l\~ to n-lat e p lasm a llml!:coucent runon aIollt· tu elTed fnllc Mi n!-: {Jr.11ad ml nis lration .
To appreciate tilt' turpact of fin t p,Lssa~1' of { I m~ thmll~1 1 IIIl' Iin 'r 0 11 till' p h slII<I <:011-
eeutrution of nu-tabolin-, conskh -r till' data ill Fi~. 2 1....5. nh ho ul"tl fnl1 n....111 ~ oral aclmin is-

A;p<~ '.., pror'1I<Je

Air· I' ply"''' 1!>O'>OIn.de d n,lral'"
Bu5P '00<" ,~rj"",
Cod<,o,r.... '\'0'1'00<00
Des rscmoc ,\~,p', r."
O"••,'opr~<\I~ rcoo-o-e
0' ,dr("-~golOm oc Perlo ' ;1 "".
0:'0':e ,.., Prop<"~
Do,,,p·n (;>, n d~ ..

Eoco-n 0., V",r<J(Xl'" t

C HAPTH 2 1

tration of pr opranolol. Compan-d to the situation follu\\ing an i.v, dose (M'(' fi !?:. 21-3), the
naphtlloxylad: it' ;u... ld-to-propranolcl ccncent rauon ratio is m uch h iglw r. am i th e meta bohte
l'lIln'ut mfiu ll peaks ;1.~ I.·a rly ;1.<; the pa IT'lIt d m ~. TI ll'S(' observations an' understood by
t'xa lll i ll i ll~ th e f(Jllo\\ill~ scheme:

Gastrointestinal Body
"~t
Drog - - - •
Drug -----i<:::
J
liver
Meta bol ite - -+ •
As alliidpah'<.! fm m its high lwpatit' clearance and con fi r med hy l11mpa ring AVG values
after oral and i.v. admtmstratton wtt h co rn-ction for di fTt·n ·lIl't·s in dose, onlv 2 1% of an
oml du st' o f propranolol filters I);L~t thl' liver; till' majortty enters lhl' !-xxi}' directly ,LS
Illt'taholih·s. TIll' smOlII fraction of propranolol ah sorbed !o)-stl'm il'alty is th en handlcdhkc
all is. dose of tilt' dmg. Thus. till.' OhSl·I'\·t'<.l (1)1ll't·ntralion of ea ch lIIetabolite is till' slim
of tht· amou nts dl.·ri\'t'<.! from tilt' two MIUrl"l' S (F ig. 21--6).
TIlt' tlu-rapeutn- illlplil'iltiolls o f lilt' pn'('t'<.!ing di st'llssioll dt'I)('1I(1 on till' <u:1hitit·s o f
d mg and IIIt'1aho lih' . A shortt' r OIlM·t and a ilion ' inh'IlSl' rt·.spolls(o llIay (1('('Uf wln-n ghi ng
a l'lllllxlIlIld omlly. rutlu-r than inlra\·l'1l0usl),. if the compound is a prol lmg, is mpi d ly
ubsorbod. an d Ilndl.· ~( 'N.·s t'xtellsh'l' first -pass l'tlll\'t'rsi oll 10 an active metabolite. In thi s
casr-. a low hioa \'ailahilily o f prndmg doe s not mean a pour the rapeutic df("(1 follo\\i llj!;
ora l mhmmstranon. On the lith er hand. if only the administered compound is al1h'l', a
larger ura l than pan-nn-ral do S(' is n-qum-d to ;K·h it,,\'l· all t'tillivalt'n t therapeutic n -spclllsc ,
111(' situation wj th pnlprallolol aplx'an tn lit· somewln-re 1'N.'h\l "t'n these twn extremes .
Follm\i ll ~ a single llral dose, tilt" ph annal'oln¢ c t·fTt'(i is maxtmal at tht· (X·ak p rnprdJlulol
l'tllll't·ntration . hut for a ¢ n 'n plasmaconcentrutlon u f propranclol.jbe fl'S(X1II M" seen after
; 11I oral doS(' is ~ n'a ft'r tlrau that obS(·r\,('<.1 follo\\i ng an i.v. dOM'. TIlt' explanation apl)('a rs
to he the pn 'M·II('t· of a siWlifit-ant concent ration of one or mort- phannat'tllo¢cally al1iw

Fl!it. 2 1~. ~'",i~ ~arill"ni<' 11~J( "r Ih. , rlll-' llla 1.~ .. " ... "II'I<ti"n ' or 1'" '1 '1'1<,,,.1,,1

~
100

50
rt. to) and 1l;IJ,hlt..,~lat1i<· ad d (e . ,:01...), {<"O';I,,, ;!: SE ~ I I ill... ;I, .i n~ 2<l- m~
.....:1 d.....· ..f 1'"'11.;1,,,,,10>1 10 Ii ' 111,;...1, . lu ;I, ('OI ' I'''~I('('' "r ..rt ,·n, i... 1"1"d ir
""1 ah.>I" "" '"'~''' , ,,,..:II f 1i"<l ..r II..· .10... i, ..1 >rI"...1inl..d . nM' n·IIIiU ,..I.r-r
al'l" '" '' , " " "I,,>lil<.,;. so.. -I, ...~ JI..p1'lt.. ,,~-la.1 i<· ;o(id. "tlktl n·....-I, .. 1".,,1< ,...I'M'
0 ..I II,,· ...." Ii" , 1'"'Im..." I,,1. l.5t.. 2·1,. ..fiN ,Imlit I",inht n.llio". t'''r .. <dr>o.1
.:; "''''I",n.. ''I . tI,,· ""I>!,tI"n:ot.o.1K- ;Kitl oh<..,IlII 11· 0'\1'0"' 1in I'm!' ...." ...>1 '''I',i\ <
c ;1,1.." IJU l tI,,· ,lifT,·...'....• in II,..;. " .."'....,L.. ''''iW'h (2fi(1 ..,,, I 2'>4 !i""'!<'. 0 ' -
.2 ' 1""'1i ~· ) is ,,,,all ( I "'WI. ..r l'"op."I..,l< >I - .1.9 ~~I J. ( Ht-.;I. ""T\ fmm Wa[I.r.
;;; 10 T.. C"".d,!i. E,G . Walle'. K. t'i\lt'.IJl. T G , llrKl ( ;;olT,,,"". TK : Xajll'II,,~I;oo.1 k

'"
~
0
c
0
U
5
ad.1 .trw. ,inJ.:"· an,1 l<..,Iit·I, ·n" ,l<.....,. "f P"'tmllK,l<>I eli" . l'h.orm;.n >l. Th·r.,
21i :~"_";''H . 1!J79 H 'l'" "I' K~ ..1";11. I" 'mli"iu" "r e x M , ,,t ~-.)

~
E
~

if.
0 5 10 15
Hours
3 7. CH....n u2 1

. "1" . 21-6. FOIIIc..., ,,,, an ,......1 & .... uf .101,,,- tI... 100
.. h"·f\·l~l pL••",,, coece- ntr auon o f ", .. l..ho ll,,·
1--1 10 tI", " m , ..11l,,-t;d••I.I.. ("'m ...... . .... , n.~ ...' ~
lhoo. f" nn...1 ,I",; nl( lho' ,,1"" "P'MIIl of anll/: (••• ) .3
.,,,1,10., f"nn ...1fn,m "I"".,,"•..J tin,,, (---l. :""1...
Oil thi. ,,·milc'f(..ritlm,io; p'ut . !I". ,L..1 i lM' .,f ,,"". ,."
~

l ;a}. ~ ' l.· f" n"....1 tl uri n " al""'>rpti..., i• •1o ·m ' i 1 i;
~
,,~. ,10.. ,-limin..lin" h..lf.hr.- of th.. ", "hohl . U
~
"t..· Io........i n...tal.,li"· f,>n'M,J (mm tI,,· Ill>·
....10 1 elm/{ i, ,1e1,·m 'in...l lry' tI ..· l...Jf·li(.- "f II..•
0
u 10 , -,.,
dn,~ 110.. r..I.·.lirnili"lit \h1' ""..... If tI..• 1.., >atM;· .~ I .', '
....tn.d ,,'n r..ti" cor tl..· .1"'1: i. hl~' . tI..-n "'.", ,i :8 I
I . , -,
'. '
';
II..· ,....... i. (~",...rt ...1to n...... I..J,It> durin" lhr Mil- 'i! I ... '
.. orpti.." .i ,Im,,- ..",I tI,,· ,it..-li,,,· p6. ...,.·..n
"'I>ll;l.\ic-. In thi• •iuml.diorll'. lim" ;t1111 n al,,>Iil.·
h.o... I,alr-I".... " f :l..'!i..,,,I 1.1lIT. n"'p"'ti\'..1~.., <lIMI
" ,
~
E
~
I

r
".
:.
...
"

\Il ~ u t.Ml\.-rh,1 h. 1"... .01••"... du m 'lt ,Inll: ,.I... i!.

.. ..-pI;,.,

o 6 12 18 24

metabolin-s. fon m-d on till' first I"l-\~ through rlu- liv('f , C..-rtaiuly, Ollt' idt'lltifit't:l llwta bol.ite .
4.hytlm:l.) p Rlpr.1Il0Iol, is ll-\ acti ve as propranolol .
In Chap. 9 (T ablt· 9-2), ('umplt'S of dru gs stan-d to 1M;'IMrtiltlly Ilwtaholi1.1,'1.1 within the
~'l-\tmill!("slillal tract are ~\'('ll . For SOliI(', t...-ideuce- fa\'() ri ll~ thi s sill' of metabolism is the
failun- 10 dt'!t'(.i a lIwt aholih' when dm~ is wwn parenterally. )'t·t siPlifil'ant co ncentrations
o f thls Illt'talxllill' are meas ured afle r oral d m~ administrat ion. \\'e n ' metabolism to occur
primarily wtthtn tilt' Ii VN, 111t'1l tilt' fmd:ioll of tl l(· dOM· 1,( >!lV.. -rtcd leItilt' JIlI'IaIM.!iI..• should
1M;" Iudcp-ndeut of tht' mule of dmg admlnt stmnon . 11I11S, ~w n that in~('Sh'tl dm~ ennrely
I mw~'s lilt' ~a.st mi ll h'sl i llal wall and that hepatic rm-tabohsm Is tilt' onl)' route of e ltmi-
natlou. dm~, wln-tln-r W V('1l ol"'dlly or pan·"ft·mlly, is t'f!lIally and fully availa bl..- tc tilt' liwr
for metalohsm. 111t' oral bin'l\ mlahility I)f th.." d rug lIlay be low if its hepatic extract ion
runo is hi!!:ll, hilt till' fml1ieJll of dose l'tlll\'('rtt, 1 In a uu-tabohte mu sl he mdepcudent of
tilt' rout e of dmg administl"'dtitm. 111l' da ta ill Fig. 21- i support th is I'LSt point, ~I OIvh ill e
is "i ~hly ami alll1U~1 ..·"d llsin-ly clean...1hy 11ll' livr-r. Usiug .\ t'C as a 1Il("a.s un· of th e amount
of lllalt'ri all'nh' rin~ till" IXM!)' , tilt' o ral hioa" ;tilahi lily o f morphine is 1,1'\\' (2 1%). bllt the
amount of tilt' act ive lIwtal Mllile , morplJ ilJ(· -6-~IIII'ln>Tlitl .., [orrm...1is lilt' same , when com-
l"lring n -sults afh' r oral and i.v. dm ~ aduunistrutiou. Ukt.....-ise, till" t'fillali!}' of areas of
lIapht!loxyl,u.iil- ,u.'i<! follo",i n~ 01"'.11 am! l.v. ad ministnltio n of propranolol (Fi~5 . 21-3 and
:2 1~'i) appmp riatd y l'tIITt·(.'I ing for d iff('n·nl'(.'S in do St:' ad lllinistt·n ... 1. suppo rt s the format ion
of tlJi~ 1Ilt'lal Mllilt·, primari ly if lIot lot ally, ill tilt' Iin-r, TIlt' fillllin~ dot·~ not suppo rt for-
mation in till' ~'lslrnill!t'sti ll al tract .

CONSTANT·RATI DRUG INFUSION

In C hap . fi , llw kim 'til'S of it con stant-rate i.v. infusion was examine... 1. Heca ll thai Infusion
mhoand d t'a mlln ,' rh-n-mnne Iht' p lateau e unvnt ration and that half-lif(· alone determna-s
tln- tinu- to approach plateau . 111t'S(' ohSt·r\.'atio lis {".I II be- t'xtt'nt!t"ll 10 metabolite. The
('SSt'nti:11 Ii-at u n -s ('lUI 1M;' und t'~hMX I by ('flll si d('ri n~ llll' {'unstant· ralt· infllsion of dm~, Ihe
"l:lwllll' n il p. ,'l6S for lJU'talxJlite formation and t"liminatioll. and th t' (...·t·llt5 d"pitirt1 in
Fil!:. 2 1-.').
C HAPlf ~ 21

1000 1 A . ' Jt. II- 7. S..hjr"l·h l't"(...... ~noor .

phl, ,u.Ifal" ......11)·(11.7 m~~~oIow.I

100
t.
b ) and In t............wy (.5 m~ bIri
h ) on .".r>&I" '1IlTL\I"M. f't...\ ma
('(Jfl(..-nlrat!'IR' pf dot( IIral; • .
h .l (AI and .....-th~ "",-tal.>I,t...
mlJrphi....·6- ltlun ln>ni.1.- (.0.. oral;
O. I....) lS) "' ,........nod \,~
.Lola in 10 hfro<11 T1; ~~"' .
CT'ntratl<wlI .. f .1nI,t (A l .-od ...
bl.. (Sl ..... n",nnaw..d to a ID-n"lt
J,.... murphl Iulfalo:- T1wo .Wa 101-
luwil"lt lmnu.tr-.ot:i<IR o&l'l' .... >1.
"",,l .o\i a -r......... •1 rd......,...
'nt-pa twp.1K- mrtahul:llm . t ....
oral \&il.l>tht~ of "''''rphi i.
J...". «F • O~ \. E,", .... It... ........
.unounI of n>rt~ ....lr rntrn I ctr·
1
('(,t..n. &Io "~ I~ I.... '"J'~· .I
o 3 6 9 12 A l ·e l ' .M -iaI.... with t.... ...........
Hours 00 10:- f..U lIllln.,. I\Ou 1'Ol~ of mor·
phtl'" almlnHtndOUll ( I ~!L -
pht.... w1f.ot:o:- . 3 ..5 1ol \ 1•. UUlarn....
100 ()d.-uno:- ft. ..-I. s . T"""". D I
S.... ;n. M., M phi.... and nM"Lol• .Ltr
hrh." iur ..fir, . !lffr ornl n>.. I~ of
""'.-phi .... .tm... j~rah" IN .
of"" of Ilwo Itnp<-.t al l ..
m ;oh.oIllr " . " -6-(1 ' 0 ...
nilI.-. Chn f'twn ~>1 n 4;":12-
11.1. 1""11'.1
10

1
o 3 6 9 12
Hours

The Plateau
At any l imt' d ll rin~ t1 m ~ infmiull .

Role of change of
k,. A ~ml · AIm!
melabo lite in body
Rote of Role of 8
metabolite meta bolite
fonnot;~ elimination

ur, l " pn"!\ \i n~ till' l"fI\l;lfiulI in tenns of plas ma ('OJKT n t rlltinm

378 METABOlITE KINETICS CHAPTER 2 1

Rete of change of metabolite in body = CLf ' C - CLlm) . C(m) 9

\ \ 11en steady state is reached for both drug and metabolite. the rates of infusion and dru g
elimination are equal and so are the rates of metabolite formation and elimination. Equa-
tions 8 and 9 then simplify to

k
Amount o f metabolite in body a t steady stale = ~ • Au 10

Conc entra tion of metabolite in plasma 01 steady state = C~%) . CD 11

As fm is the fraction of an i.v. dose of a dru g converted to metabo lite. the term fm . l\.
must be equal to the rate of metabolite formatton at the plateau. namely kf · A.. or e Lf' C...
So

im . R
Amount of metabolite o t steady stote = k(;l 12

and

3 CaseA 3 Case B
k < kIm) k > kIm)

Metabolite

~
2 2
~
0

"'
.a
E
~
0
E
-c Drug Drug

Metabolite

o~
o 4 8 12 o 4 8 12
Half-lives of Drug Half-lives of Drug
F ig. 2 1-8. Two ~itllalion~ rolloo.\in g constant-rate dru g infusion are dt.-pic.ied. In caw A. the more IlslIal situa tion ,
tlk" m.-taholit l'" half·l ifl'" is sboner than tha t of tilt' drug. ThrouglKMlt nKKl of drug accllmu lation, mclabolitl'"
I'" liminahon is fonnation nlte-limited; therefore. the approach to the nK"l:abolile plateau is dcte rmtned b)' the half-
life orthe drug. In lhe less co mmon situatio n, case B. the half-life of d nlg is less than thaI or metabolite. Drug is
al Sll'"oo, ' statf." w....l1 he fOT{' mctaholite. Approach of the metabohte 10 plateau is 1lO\." df"tMlninl"d by its ha lf-life.
 379

1m · R
~
Con cen tra tion o f metaboli te 0 1 stea dy store .. 13
CLlmJ
Suppov -, fo r (·"-lI lI pl.' , thai a d rill! is infll , t'il OIl ,"i lIllV1 IT. f m is 0..'> , kllli l is 0. 1 I. T- I, alill
Cl.I m ) is 1.0 l vhr. Then.

A mo unt of 0.5 x .5 mg/hr

25 rng
metabol ite 01 pla teau .. 0.1 hr - I

Plasma co ncentra tio n 0 .5 x .5 mg/hr

2 ,5 mg/t
of metabolite at pla teau = 1.0 tlhf

TIme to Plateau
Huh" 1' 111" 11I(Il'.illll , TIl<' li l li" n-quin-d li lTa IJlc·I ••l oltu- to reach " Jak au d" IM·IIl I.. 011
wlwt lwT OT not a holus of tim!! i-, l!i\l '1l at tilt' ..tart of till' ('Oll, tan! -Ta'" IIn l!! iu fu\ioll. If a
ho lm is c:in'u aml tlu- illfllSio ll mailllaiu\ thut ,11 11011111 of d m l! iuI ]u- hod~ ' . t llt'lIl ll1'a ppro;lci.
of till' Illd aho lih ' towa rd " Jail-au 11\ 'IM·nds flll l ~ ' fill its ha U'.lif.,. T h is poill! 1 1< ,( ~ JIl I \ ' \ apl Mwn l
WIWll lll '" n 'a li/ l's that al (,(J1ls1alll d n ll! ("Ill't'u l ra!in ll, IIw tahn lill' i~ li m rle·d at a ('Ill..tau t
m lt- ,JIII' /In' .\ s th is i ~ a na logo us to ~i\; nl-: a ('(J1I, la lll · ra l(' illfllsinu " I' lIll'laIH,lill-, il td lnw,
arum Chap, fi} th ai tln- a pp road ' ln p lat"il ll is ~o\'l ' n ll'd,·"f, ·fy by till' 1l1l'lalHllih ' 's half· liti ·,
T Im., . ."')4 )'1 und !,1W',f Ill' tlu- p latt ';1ll a re rt-al'l wtl ill 1 a nd :1..1 md al Hllitt , half.lin's, rnp''( ''
li\l,ly . I k-n o -. rt ll' laIHll i lt ,~ w il l. sho rt h alf·li\l ·s rt' ad l plalt';1ll quic kly ,
I n fu ..Inn A I" II(' , I I' lin I H .l ll ~ i, gi n' fl, tln- situutiou h men- (' " llp lkah -d. T Ilt' tum- fo r ;1
lIw la IH.lil. , In TO-ad I plal "au cuu IH' ~.. ,,'rll.-d prilllarily by ,'i llll'r IIII' d n l ~' s or lIll' laI H.l ik \
Ilal r· lift' , u·hirl"'fU is IIII' fOllerl', T o app n '('iah' thi s poin t, nl n..idl' r h \O , il ua tiolls . !loth
, 11' 1\\11 ill F i!-:. 2 1 -~. 11 111 11- IIIOf(' p n-vuh-nt , it llal il'll, <:;L\l':\ . 1111' tl n ll.!; l ias tlu ,I'>lI...:, -r Ilalf·
lili '...h " \ lll'd,',I, 1111 ' ,UlItllIlI1o f dru g ill IIII' h' Hly rmd ll'.s p latl 'all in 'lp p ro \ illlah' ly':3,:3 e1 rug
ri,.·".
Ilal r· li\ . -, . T Ill' al lln' llIl ,If m l'l al Hllih ' allll lll' II('I' 1111 ' r ate- clr IlIc·tal H,Iih ' 1,lirllillal lllll ..1,,1,
110\\1'\ 'l' r, IlI'(·ar.....' c·lilll illa tiun of lIlt' IIId aho litt , i' a 1I111eh [avte-r prfJ(, ,'S thuu Ihal ,,1'1111'
!l nl g . l ile' rutc- of IIlI'la lH ,lill ' c·lim illaliolL \lH'1L 111 '('1 111 11'\ Hml,, '(1 by a nd a ppro\illla h· ly l'I\lla l
In ii' rat .. o f Ii ,n ll;lli oll . \1 l'l a llillih' is thr-n a l \"irt lMI ' It-ally slall' w it h n" llt'd 10 . and canuut
ri ..t · a ny fa.shor thuu. d rill!.. T h i' 1i,l1ows. , inn ' 1I1111(-r th i.. ('lr n lil io H (E'I ' :\ )

.
Amoun' 0 1 me'oboille -
(kfm)
k) , drAmounl
ug
of

i..... tIll' ;(1111111111 o f Illl'\ a lltlillc' Prol lt lrt iollall~' fI ,Ut 'l '" III(' ;I1ll11IHlI o f IIm g , Tln-n-ton-, IIII'
nu-t.. lltllil.· n 'i1dlf's pbte-'Ill wi tluu ap pro\i mak ly " d m ~ half· Ii' I''' ,
III Ca'" B, lilt' d rill!; j, I'!im illalt'd I;\,,,"r than IIId ahlllill' , :\OW d nl g read ws ' l(';u h ,I"tl '
11I'1I ,r(' IIII' 1.., .. 1 o f tIll' ll\.'la IH ,litc· I.as hMl' ly ri" 'Il . F llIlII 1111'11 'UI, 11U' rail' o f lIwl ;'dHllit< ,
fo r ma lio n i, I' m, lan L ;11 11 1 ;l' ,, 1""('\ 1'11 pn ,, 'ioll , I., ', ,, 111'11 a ll .tpprupriau- 111.111, o f d n ll.: i,
~i\ c· lI . ;!("t'ulll1lLtlil lll o f md alH,lil . ' 10 p l.lh'all is c urtrolk-d hy its IMlf-lili ,. 1':\ <l lIIpl(" of ( :a " '"
,\ aud H a n ' II... o\id atlo ll o f lol b illa lllidi ' 10 h , dlll\\ t o llll ilalliidl ' uud IIII' 11\ll m l" j.. o f
1 11l '1 11~ Ipn 'cllli\l ,h >r ll' 111'l tli'II('I-illalt ' II' 1111·lllylp n ·;llli' (lilllll" n "I)('(·l in '!y. .

Postinfusion
:\s , lulu!II III'\\' III' al llidpa lt,(I. •OI l shl l' l,illll; a ll in fllSillll . 11 11' (11·d ill(· of Ilu ·I<l IHllil. ' is "':11' '-f111'(1
b~ till ' lo ul!;c·r Ilall'.lili ' , i.c·., elm,,: or IIIl'1aholi lt ,. Fo r e·\ a mp l, ·, 1111 slo p pill g a Inl hill amid,·
illfll'i'lI1. Ilyl ln l\yh ,l1 l1ll;llrri, Ie' \\1 11 11(\ t11'(,liru ' I ,~ ellll,· IMlf ,' adl 1I IIIIIII;u l,i.I" II<llf-lili '. w lu'rl' as
31.

uwthylpndutsolonc's dccltnc would hl' det emuncd by its half-lift· afkr Sl (jppi ll~ an infllsioll
o f its Il('lIIisll(:t.1Ilil lt' ester.

MUlTIPlE-DDSE DRUG REGIMEN

Tlu- l'OUet 'pts that apply 10 Ilwlll ho!ile roll( l\\i n~ admhnstmttou (If d m~ a... a s i ll ~lt' dlls(' (I f
;1 consta nt -rateinfusiun r un rt·ad ily hi' app ln-dto lIlt' most common situation of a multiple-
dost, oral d mg rt·~TIIt'Jl . As " 1111 Infusion o f drug. accumulation of IIwl aI MI!i!(' til p la l('1111
t1t'pt'mLs us Illll ch Oil its half-lift • ;LS Oil tha i of tilt' p;m' ll l dOlI?;. For exatu ph- ( Fi ~. 2 1-9),
al'(1111l1 11aliu!I o r :"o; -<1t'salkylhala7,{·p;ulI . a llll'laho litt>o f 11](' 1ll.·Ili'Hd ian ·pim·. halaa-p.uu. la~5
IM,hind pa n -nl compound du ring d m ~ administrati on and falls mort' slowly afh"r ad minis-
trutiou is stop pe d. Both Oh M'l'\'lltiolls occu r b(·(."llll ~· th is Illl.'tllhol Hl· hll~ II IUIl ~l'r half-life
than that of tho dm~. In addit ion. tilt, plan-au concent ration of :"'-d('S1llkylllaJ.w.'ll1ll11 is
h i~h ('r than that of balazcp.un. si~ll i f)i ll~ tha t tln- lIJ('ta),ol ih ' h;L~ tilt' 10wN dt·ar.Ull'l'.
Fluct uat kurs ill rlu- pJ'L~llIa (·OIl{'t·lI tratio ll.~ o f both dmg allll llwfa!tolitt· an- tlu- u nly I\I ~
til-t'able difTt' n'JJ('t's (·xpt'(i:t'l.l ht,tWt'!'1lall infusion an d a llltl it iplt' -( Iu~' f('¢II1I'U. The dl.'~n't·
o f lIm:tllalioll depe-nds 011 tilt' dosi ll ~ ff('l. llIt'l\(" am i half.lin's of d m g absorption . <Img
t>lim inal ioll, and lllt't;lholit l' I'lim illatio ll.

PREDICTION fROM SINGlE-DOSE DATA

Tilt' coucent rutjon o f nu-tabolltc- dunug an ()OIl lll ll lt i plt' -dn~' d m p; f('¢Ult'l\ cau f('adi ly 1)('
c alculat ed fro m the pla.\lIla ml.'ta!tol itt' (1l!1('t'utr.ltioll·t imt' profile ufter a single o ral dost'
of tlnlg. Tlu- ap p roach is analogo lls to tha t take ll for drug alom- (C hap. 7, p . !'l7). Ti lt'
IIlt'tal)(,lite ('(lTll'\'lItmtiun lit ally tilllt' in to tilt' <Imp; n'¢llwII is ohtllillt'(l " )' llddi ll~ tlu-

~
§.
c 0.1
.2
];!
naiazeoam
"tl
c
0
'-' 0.Q1
~
E
•
e~

0.001
0 4 8 12 16
Days
. 1" . 21-lJ. 110.'(..,.".... il hoi-' tI..· i<..,If'.' 1,.,lf·(;f.·. II..· " "1..1".Iil<· S .. I.....JL"\II.... t..,.. l""" (<>. mI.", I" otl, a'''~, '''"I ...I...
"..,... ....1t·".i\1' I~: iU,,1 (••11. "",... .It ",·I~- I I...,-, it. 1"'' ''''1,lno,,- Io..t.llc·I"'''' '. '. •turi",: ",,,I;tfiN ,t"'l'i,,~ II..· i"I: ti.."
.,-lj
<lr 10 11I11: loaLu.,,,,rn ...... hr Ii.. 1.1 u", ~,li Lt~~. TI..· ,,"·I;tI..,Ii,,·..I" , I ~, ;t ~ "" ., t·I.·" r;t' '''' ·. ill.Ii'·"I II~'
it> hi~"'r pt."';tUU""'t'T,tr;tlit",. ;t,,,1" ,,,I..ry;to. , II'K1";tlit.., m ltl' ........I .. ilh I...n·,,' .Iml:. 111.,Lw l"'''O: I '''WI.
- 2." 1oI \I ; dc""I1,~n,;tI;Vil"'l1l : 1 "'Wi. - 3.7 101 \1 ). Ilt,..lr,." .. rn"" ( :1"",11.. \I ., 11 , 1I ,, ·rt .J , ~I .. ( ;" r,.l. R I' ., It ..d -
",.,." ,LI. E.. S~" K"""'i<'Z. S.. ",,,I ;-.. "'1"'1:1it....-. ~ . : ~1 "lt i l'l.· ..I."'· 1,;tLv,1""" lit"""", <:li" , 11,;t" "''' 'I1. TI,,·r..
,J.P c1-......... z. IWW _H., ,",,h,,nl " ith p,·n",..it", of c.v. \1 ,...1,:\ .)
 ')[IA80 UT[ ' I NfTlC ~ 381

lIlt'laholih ' I'JIlI"lllralillll' "\1)( "('\1,1 fro m ,'adlllf tlu- pn'\iou, tlo'>! " : tlu-n - i, IllI lIt,,1 til
1m,",· allY pl,armal"I.Jlldil' parall1l'h'r of ..itlwr t1nl~ ur lIll't aIMllit." For I'\<n"ptl', if I',ur
oral .I"" " of c1m~ a re' ~i\l '1I atll, 1:2, :2·1, ;lIlll.1(l l ,r. Ih.. n 11ll'(',m,'" l ral i,, " o f mdalMllilc'
at l~ hr is ' ''pial t' l 1111' ' 111I1 of tilt , 111, 'I" IM.lill ' " II'('('I1Ir.llil 'l1" ;11 ,l ~ ,:lfi, :2·1 . ;11 ,1 1 1:2 lrr a l'tl' r
it ,i ng:I, ' dll'" of dnn::. 111l' ;1\ , 'rag" 1'111("111 rati on IIf 1111'1 ;11101 ,lilt, ;11 pl.llt -uu t-au a l\l' I,,· n-adi I., '

l 'all'llla", 1 1'11>111 .·\ l'C n 'll\i,I, 'rali'lll' . TIlt' an',l umh-r IIIl' lul'lal" ,lih ' ""'('('"lralillll·tillll ·
I'UI'\I' aliN a "ing t" .In,, ' o f .Inlg, ,\ l 'O /II J......".., i" 1.,';\1 '11 hy

AUClml = Fro ' Dose I.

''''9100 CLlml

whe-n- F... i" II.., fradioll Ilf II" , ad rnilli'!t'r'''I1 d"",· <If tlmg Iltal r-un-rs II... ~I 'IIN,II t-in-ulatiou
'I" rnl'!<tl",lill' . .-\ 1 platc -nn, 1l1l'IalM,Iilc ' (unlit'll i\ Iml within a d",iug: illh ' n.al . t . '" 11];11 IIIl'
;an 'ragl' 1l1l 'lal" llilt, t, IIlI"'llrali, ' II , <:(mJ..... ' i,

f ro ' Dose
qml".a>" = 15
t · CL(ml

16

rill' ,',ampll', if IIII' .'\f r/lll ).,..~.,.. i" l ~II IIlg.I,r/l. ati"r a WII'lIlg d""" of dn, g:. 11... 11 IIu-

1·'I)l"l·lc..1plalt'all lIu 'talM,lih ' reuro -nt rati, '11 i, 11) 1I1WI. whe-n thi s cll'''' i, Wn'l' t - ,' ry I ~ hr.
Ohviou,ly. if IIII' 1l!l""l"\t,t1 an 'rag.. plalt'au 1Il1'tal M,lilt' (' )I\n'llt rat illu dil Tc'1'\ [n un Il.,lt ..,.
IM 'I1I'd . Ih" 1L dtlw r 1-'"" t'1,',ualln' IIf IIll'lalo"lih', o r 1",111. ha ' I' 1" " '11 alt l'n.. l dll rill~ d troll il'
llnll.( al lll,il,i,l n llillll .

VARIABILITY
:h will i 1l<,n'III dm l.(, II", pl,armal"killl't k , o f" md"I",lih' \ ari,·, witl"l~ ill t ilt' IMli"lIt
IM 'pllbtioll , " 'itIt add ili onal \; lIia h i l il~ in d l'a ralll'l' of ltl1'till",lilt, rim tMlioll . t loi, O t'l I '1I
lIt1'i1tl' tllal i"h-rpal i"tll \ ariah ilily ill ltu 'tal" Jtih- " 'Il(l' ul rali llll 1·,1It I" , ,'\I 'll I.(w"h-r thun
IIMI \1"1'11 \\i l l, parl'lll tlmg. SOlin" , of \ a n a bility ill 1lll'laI K.lilt ' k i ll l,ti,~ arc' lIlt' " m il' a'
lit.. "" ,tIT. '1"1 i It I.( Il,lWlII t1ml.( alld ittdll' I., 1.(' -m-tu-s. agl', eli\l 'a"" , "lid ililt 'rat1illl.( t1ml.(' . l Ji f-
fl' n'IIl'1'~ l"i,t ,lIll0 lLg: l"'Iil' llh ill IK III. d .. aruno - ami \'Illmlll' of c1i\lri llll tillll " f wd ,tIKll ilt·
;1I 1l 1a.' with ;1 d nl g:il,,·If. pn 'f,'rahly '111 1l<lr;UIU ''''r<. "11l 1,, ld 1M ' n '!..h 'lilu rln- u"l " auul "1"Til·'.
ClIllI, 'm al " ,,,1 lIll'laIM,lilt ' ~ i" I.( rl'alt-"t wln-n tl,, ·y ,'lIll rih llh' ,iglli fil'a ltlly tn tlll'ralll'lIlil'
rl'~ IMlll~" co r I", j. ·i l ~ . Fn " I'll'tltly, ti lt' n",.,'"l r.,licolI .. f lIll'tal " Jlih ' h h" ,I" w 10 I'n"III"" ,1II
d li...1 , 1"...·,11 1\1· o nly a , ma ll [r.u-tinn o f d mg i, 1''''\I ,rt,..1to .. p,lrt kub r utda l",lito- ;", d t ill'
d. 'a r;ull" o f II... Itld ;.I" IIi", h I.igl. , Sitllatioll\ t-au ari se . 11l"' I'\t'r, in \\ I,id l 1I1t'l a but ih-'
r" ;ldl " 'lIl'I'lIl ralio n, lIil.(l, 1'110111.(1, III I" , of ,,>III"\'n! . Thi" 1>('-''' ,"" !)"u1kllb rl., ill lMli" lL t,
\\i ll, n 'lIal ill 'Il ITi l'i"I 'I~ . 1101 '1>111\1' llIall~ ' mdal ",lih-' a n ' n 'tati\(·I~ l)lliar and an' p rilllari l~
' '\IT,,tt, 1 lll,d ,allgl'd . FI.r ,',alllpl, ', t l... " Iiu ,ina lilll' Ill' 1IlI,rpllilll'.li -l.(llll'llrOlIlI!l,. ;11 1 ;lI·thl'
IIll'tal " ,lill ' Ill' 'lIlllVhilll' i" n ..IIlt,..1 ill IMli" llh \, il l, n 'llill d y, fm' di llll.
J' n ..I,dioll .. f 11ll' tot al adhily .. f dnl l:: a mi dma~1' "dj ll, l lltl'lIl 111""11,..1 in 1",l i"lt h wil li
n 'll,11 i ll' 1l 11it1I' lll~ ' is Illt'n,li,n' mor.' 1~ ' lII p l,'\ tl, ,11l " 'Ha l. 1' 11" 11 ' ,In' way' lOr tn-;lli ul.( '"l·h
"il ua lio m . TIlt' Illml 1I\1 ,l'nl i, loy IIIl' ' '' ';llly." I'lh ' a p p ru;'I"h. Tn illll"l r:!'" IIII' II'" of tl, i,
a p prco,tI"ll, "'ll,iel, 'r II... ",·1"' 11I,' ill F ig. 2 1- 1lI. "I, il-It , how" lIlt' illl'"1 a llli tfl'IMl'itioli o r iI
3 12 CHAPTH 21

. '1" . 21- 10. \ 1,..1.·1 fur .d"" ''llti..n 00'"

... lll ,Ii' p." 'li un "f .. 1 1 ~·pc >t l"'l k ..,
,Iml: ;1",,1,li' p..' iliClIl lOr ih ;o<1 i\ ... Tllt"-
~ ''''''''
Metlbohles
ta h"lit ... Th..ll l'llt numbe r In 1""'''''''- (O.2. 0 .4) (0.15. 1.0)
th... iJ n-f..rs to the frat,ho n of d roit
"r mt'1 aholit.. l hoot I. nonnally ..limi- """,,,bOO (0.3.0.61 Act. .
OntO in
",,1t'J by l IMo pathway . h"wn "'1th loi n • Body
Metabolite
a(JOW, The second number refers 10 • Body
11>00 l a m" f';K"h o n wh..n Ih....... II no (0.5. 0,Oj iO.t15, O.O)
rena] (unci;o"

~
~
dmJ.: and Its adj\'(· nu-tabohn-. T ubh - 2 1-3 lisls ;\ \'(' r .l V;c' vulues for several pha nuat'fJkindi{-'
IMra n lt'h ' n; o f this d m ~ and its ' l(:t in " mt't;tho litt· in til(" I~vi ('al pat tent ....-ith lInim pa irt"(!
n'II"] Iuncuou. III thi s (·xalllplt· both d rug am i active metabolite art ' (>t:luipolt'n l and cqui-
tu\k ill t(' n lls o f plilSlllUcone...-ut rauou (wit h £'ileh ill1hit~· a<ld ilh-.:·). Ti lt" "\ I 'm~t' nltt' of
dm~ "dminist raliu n is IC M) mWl,r.
:\t sh'ad~' state. rlu- pl.l\ lIla dnl~ ccnccut runou ma)' be - (·"k'ilatet! fmm aVt'ntgt' nih- o f
ah\o rpliull and tot al ck-arau ce-,

_ 0 .8 x l OOmgfhr _ 27 IL
Cla...... 30 Vhr ' mg

T Ill' mit ' of fo n llalio ll of tilt' at1iW IlIt'l aho litt' is 0.3 tnm-s ti ll' mh ' o f input of the dmg:
then-fon-.

l OO mg/hr _ 2 4 I l
q mJ....o.. ., 0 .3 x 0 .810 xVhr . mg .

III all auuri c p atient . tot al dt' amnl ,(' is estran-nal d l'anUlI,(' , Fur thts d rug. cxtrun-nal
d";lnl.ll{,(· i\ 15 l AIr: for IIll'la holih ', it is 1.5 LAir. Therefore. Ihl' p n 't litit't l ste..<Iy-sluh '
l'tll\('(' n t m !ioll of d m g in the a nuric (latit'n t. C(d t ..... is

qdl • 0.8 X 100 mg/ h, • 5.3 I L

...,..... 15 V hr mg

R''l';l\ISt, O.fi o f lilt' total ,'!illlillatioll, ICI4/ (Cl . - e LI! ) or 9 l A lr/(30-- 15 ) lAir ) gOt'S to 11Il'
ali i\'{, Illl'taho lill' in lilt' unuric pa lit-nt . thl' slt'ady-statt' concent rut ion IIf Illl'tabo litt',
G( iliA '''.<n ' is

T.ItI.21-3. " ' . - . . ........_.kl.... c P........." . . . D_......... Actt••

M...ltellte

Toto! ciecrorc e 30 Lltw 10 V "'"

Reool cleoeooce 15 L1tw 8S Llhf
FrQdl(ltl e. oeted UIlCho~ 0 .5 0 85"
0 01 BoOO\IOilob,l,Jy 08 0,31>
"Ct*"""«l1obo,"9 o d o - _ ~ .....,.,.,...
"1<0<_ ~ <:hg ~ "' ......... '""*>t:oI<to
CHAPTER21 M..
"lAl\Ol.rTE KINETICS 313

qm dl _ 0 .6 x 0 .8 x 100 mg/hr ~ 32 / l
• P ,,,," 1,5 V hr mg

:-';nl l' that till ' lI\1.'m.L':l' dnl.L': l'Olln 'utmtio li is twice :t~ .L': n 'at ill Ihe anuric patient. wh ilt,
th e itl1in" lI11'tliho lill' l unn 'nl mli oll is inl'n'iL\t"t! 13 ttnu-s. \\'ilh d rug and al'th 't' meta bohn -
("tluipu!t'llt and adtliti\'t, ill t lw ir activi ties , tb l' r ate (If ad mhustratton in the an uric pa lit'lIl
should be (2,7 + 2.4)/(5 .3 + 32) o r (1.14 Ihill of normal. Thus, the anuric p atient wo uld
n -quire o nly 14 mWhr.11lis e cunpk- Illustrates d t'ar ly thai although a uwtalMllitl' lIl il~'III <1k, '
" minor l'tlllirilm lio l\ to tilt" tot al acnvrty in pa !it'nls wit h normal n-nul fu nl't ioll, in all unuric
pat ient . it Illay he pri marily rcs pousibh- for al'thity.

ADDITIDNAl CONSIDERATIONS
Four o the r a.~flt-'(.is of u\('taholilc kinenes wa rran t 1't)IJsi<!('mlio n . Om' is ft"!iPOIlS(', anotlwr
is illlt'ft't)ll\1.'rsion ll(,t\\,,"1;°U nu-tabolitr-and tlOl.L':, am i till' ot lu-r two an"the u se of IIwl a holi h'
d at a 10 IJmlll ti ~\· lIlt' taho lih" d ear-lIIn " and to idl' lI li ~\' po~sihl (' 1',l\Is('S o f a change ill phar-
IIMI'tlkillt'lk.,;.

Response
\ \ 1I('u " II illii\;ly o r to)(id ly n -skles wit h a part icular IIIt'1aholih', rd atill~ res pt lllS(' In II\('-
tabolite coucentrution is 1l.·la liw ly ~ I mi~h t fmwan l. 11 11' problem is more d il1k-lilt wln-n
IMlih t1 01 ~ and lIit't aIMllih ' contribute- to m.ihi l>· o r loxid l)', Occa..ionally. il m ay hi" possih lt'
10 n-lan- tilt' n 'spt)IJS(' 10 a lun-ar o uul unanon u f IIII' pl.tsnm conceutratlons uf d nl~ and
rm-tabolin- ll-" "11.~ dom' ill ti lt' h..l sec tion. ~ I on' often, ho w ev er, the relationship Il(·t\n 't.'n
n'~lxlIls.t" and eonceutrutjou is mo n - complicated. am i uo simp!I' n-lariou slup exists . Fo r
example, if till' n.·sIMIl\s.t' produced hy ti ll' dm.L': ,,1011(' approaches tilt' maximum, E"",. , ti ll'
ft'SIXlIlM" d l a ll~('S hu lt· \\ilh i1K'n ''''' t'!; in tilt' ("I l11l"1'n lntlion of II Illl'taholil(' lhal ad s ;l-.. a
I'lJlIlllt' til in ' a~on ist , Ah l l ou ~1i there an " lIlallwmal it',,1 ap pmad lt' S to this probl em. 1);1<;1;'11
for example 011 modiflcanou o f Eq. I ill C ha p . 2U ( I'han nal"lliogi l' Rt'sptlll st» t1lt'y all.'
unlikely to 1M' 11<;1;'11 d in ic-.ilI)·, :'\Ulll'tllt'lt·ss, measu n-nu-ut of an act fve Int·taIMllilt· l"IlIlI't'II-
tra nou can help I" explaiu an oh~ 'n11I i' J11 an d account for \'a riah ilit)-' in d ru g n 'slx lII\t ',
:\1"l"l lnlin ~ly, slldl II1I'a.s un-meu ts ca n wrvt- ,l-'> useful sl'm i1lu,U1 titillin" ~llidl'S to Ihl' r.lpy .

Interconnnion
AlIIlJll.L': the hst of t111'nI(lt' lIlkall y uupo rtaut 1IIl't"IMllih 's iu Table 21- 1 aft' souu- tll ,ll all.'
('II~lmtl itw.il ly converted bacl.. to III(' ad m iuistt-n.'11 d m~ su!JstmK"I-'; they iuclude Iln'll ni<,(..
lone, 1(.1' lIll't al Mllih ' "f p n-dnbom-. ;lIld slIlim l!e s ulfidt" till' IIll't alMllih" o f sul iudac. Bo ll.
t1 n l ~ aft' prescri lxxl a... anti-inflammatory <I~t ' lJ ts , h ili ill {',ll'li case tln- al't hity rt'side s with
tilt' IIlt'labo lit(', 111l's(' and otlu-r l'xaTlJplt's of t1 m~-Illl'laI M llil l' pairs Ihal lI llt lt' ~1I tun-non-
ve-rsion '!R· lisll'lJ ill Tabl," 2 1-1 .
Fi ~lI n' 21- 11 illu str ate-s 'il1IIlt" l"IlITllIIIlIi Featun-s o f Interconversfon. S I.( J\\1 1 <I n ' IIIl'
p l,t"llla l"lIl\I"I'lIlflltiollSo f pn-dnisoknu- am l pr ednisone- afiN atl lllinislr.ltiuiI of (';ld l slt- mi tl
1111 S('I);lflllt' fll"l'll-..ioIlS. :'\olil't', iITl'spt '(.'1i\'(' of wh ich is ad m ini...tl'n 'll , IIotll slt-rui d ~ ;m '
p rt'st.'nl in » Ia...ma. Also , Ih(, m ho o f pn'llniso lolll' 10 prt 'llll i ~llll' mpi d l)' rt',ld w s ,I fl-\("II
va lue of 10 : I , afll' r wh idl lilll l' the slt-m i(l.. dt'(.,lillt, ill pardlld nn a semilog"ritlllllll' pili!'
It ow ' Juickly the ('lIuilih rilll ll is (·!otablisllt'll aliI! WIWfl' till' flilio li('s Ilelx'nd nol o nly Oil
tilt' kint'li l'S of inh 'n."IJ1l\l.'rs iuli IIut alSiI Oil IIII' irrt'\·t'rs ihll' toss of ('ac h spt'(.; t·s fn Jlll IIIl'
IMMly, iL" l'lUl 1M.' ,1su'lli/.l'l1 in th e Sd ll' lIIl' Ill·low .

Metabolite
1
, .. WTA.80 UTt KINET ICS CHAJ'Tt11 '1 1

,.ltl. 21-4. . . .. ,.....tott•• Drv•• That UIHh.... M...ltellc 1nten:.......I••

(','-r. ""',
.' b< oc

(,'<I."
Dcps ,>

H(] :P,H'~

'" "'.:' .
',' rh,1:"l.'d' sc r-e ,'.',,- ,<:-- .,J' SC
f' ..+
,,, ?'C'<l' !IO :;.<It.'
":0 '1~"

......."' _<l ~ """' - ~ -.,._

~
_ ...._..
"'''''''J-., ... --'''".,.,......-~
~_~"""<nagon<~ ~"'- d~l<>'e

Q:J.I:,. < 0<".. ~0Id>,<J>'" ,_ _ ~ _ .....< 1-" ~ I..,rl."",,,,,,, "-' '''9 ~

~ 0 Iotu. .. I.,do~.-j., """ ."'Q'OPO"'Od ox.d
~ d.i_ a> "d<vg~
~,"""P'o<a'Od by ~C'J'<~"9 cJ ...w.do< awl """"" J.>o

.. ill:. 2 1_11. ( hK" "I'"lil,""", j . ....' .lloh,I....1. II..· 1.0

u ..... ·lI'r-~I ...... <If pn, tni" " '" Un l. ,I"rl a'Kl l'n. l.
",,,.1.,,,,. l in hl...·11l in I'L.""....n ' i"..It·p''''M It"" "r
" ,I,kh .." '''I....u ..1 j. ,",I",jlll'h-n..!. I>.d.. an' ,.I,.
1;oi' I..h.·r ~ . ill":" · nr-..J ,It....• nf .'!Ill "'I: pn.I";" ,,,,·
(""I, I "'KI "" h - .10....· " f 1'".lni."I.....· (1; ..-1... ).
..., 1>n. I"i"oI." ..• ,u...iu.,h · l ·j.U n,,~) . I" M•.,IJjo't1 n" 0.1
" ·I"'r..... "n~ ..i<".. _ 1" . Ir" " ,,"....· .".:,:;,,,,10', 'KlI:
, I......" . j, 1,~t1 n>ly'u l w~ r"l.itl~· I II I'n~I",,..oIt,, ..·
(l "'l{i l. l,"~I"i"'''..· - 2.'~ ,, \ 11. d t" ["",,. 1"" 11I'
II.....-. J V.. ~' '' n ~ ~,l . , \ \ 1.. J". lm. \\ J . "". 1 1~,", ·1I .
1>.; HiI "" 'w la"ihl~' ..Hoi oI"[...'lit,,, ..r I'n~l"i ..... ",,·
,..hl.·1< 11" '1" ''' 0 11 D o ,1o: D" I' " 1 :z.l7-2~' , llf'll 0.01
Ilt-l' ri "I. ~1 I~ I,, ·oni~.it .., "f J<ll", \\";1..-:- & Sl".. .
U,l )

0.001
o 4 B 12
Hours
CHAPlH11 ME1ABOtrH ( INEllC5 3IS

Eadl pat l l \\ ,l~' is d larad t'ri zl'tl hy all iL\sod a!t't1 cleurane-, am i t'iK·h spt'd t>:; Illay (lilTt'r
ill Its \ -II I U lIlt' of distrilllli ion . 1111' lenllina l l.alf-Iife of tht' tuterconvertcd pair is it !l~1 )rid
of all tlwse llilr.llllt'h-N. T his S,",WllIt· n-sem hles the 1"\\"fH ,,{lInpart lllt'll t dhtrihlltin ll Illtllll'l
diwusw-d ill C hap. IH ( Fi!!. 1 ~1 ) . t':\('(' pt tilt' hm (,,{)lllpartlllt'llts no w represe-nt ( I m~ and
lIld aholih-. 1111' dilTt'n 'lIn ' 1)('h \l"{'11 tilt' 1"\\1) lllodds is tha t \\i th Iutercouvi- rsion lo s s t-au
al<;() occur from till' "pe-nplu-ral" (nu-tabolitc] {,OIlIpart lllt'lIt. ludced , if no Sill'll loss occurs
then. \i t...\,,,1 From d m~ in p liLsma. thl' nll'tahnlitt' is t·lTt't.iiwly a component of d m~ di s-
tnbution viut't -. under tlu-se- circumstances, 110 t1 m~ is irn,\"{orsihly lost via this pilt h\\~IY.
111t' tlw mpt·llt it· impo rtallt"(' o f Interconwrskm varies wi th the d rug ant! Ihl' circum-
stam"l·. For t·\i llnplt '. illlt 'n "f)lJ\'{ 'rstoll I)('h \l"{'u sulnulac illltl Its sulfidt' ln-lps to mot!t·m !t·
ami sllstain tlu- t"llllt"l' ntm tioll of adi\"{' sulfide. In contrast. mterconverslou 1)('I"\\l"{'1I th e
aut ih-protu- t1 m~ t!apstlllt· and its It·ss iI{i iVt' IIw lalll)lih ' lIlolltlilt:t"tyltiap st)IJt· has 110 tlu-ra-
I)('ut it' n ,lt'\'allW ; till' equilibrium is ulwavs stm ll~ly towa rd dapso lle. wh kll is pri mari ly
I'Hlllinilft'tl via pall l\\'I~'S ot lu-r titan X ·:tt't'lyla tioli. Xonnally. lnterconwrslou ht'l \\l 't'n d u-
fihri l' add (dt·ri\,.'tl Imru till' rapidl l~drtJl~'S is of tln- admillisl('ft"{l t·thyl es tr-r, dofih ratd
am i its ill<lt'tin' ~h R11 mni tie is not u f o uuvm: tilt" 1!:11Il"lIn midt· is t'u 'f('lt"{! so r.lJlitily Illal
~111 ('ll n J1l id<ltioll enu h. · rt'ganll't l iLS a p;'lthway o f irrt'w 'rsiblt· lllSs of clofibnc ad d . Couse-
fl"I'lllly. as onl y fill o f clofilmc add is usually t'Xt'n'lt't l ll lld l<lIl~t't l and all tilt' ad i\i ly n-sides
with d ofihrit· ac-id. 110 d lilllgl' ill its pharmacokineti cs is antid p;llt"tl in pat ients with renal
ins.. ffich-ncv. !l owen 'r, iLS SlllMl l in Fi ~. 2 1- 12. Iht, unbound dt'ar.lIIt't' of clofilmc add is
ma rl.."lIy r:..IIlt't..1. am i its half-lift, is prnlo!l~t'tl. iLS renal funti ioll decn-ases. 111l' explu-
uatkm lit's ill n 'tlu('t·d dl'a rall('l' uf tilt' ~1 11l, m lll i tlt" which then at'l·lllllula lt·s ant! is hytlm -
l~-/.('( I h;lt·l.. to lilt' pa n 'lll adtl: ,·lTt'tiiwly. a major route of eliminatio n of clofilmc add is
imT' ·il-sin~I~· hlcl{·l..t"t l. To what r-xten t IIIl' observation wit h clofihric add ap plit's 10 ollw r
dnl~s Iha l 111'1')('111 1 ht'il\i ly 0 11 ~lll ('lI nllli dal ioll fur eli m inati on is not known. C lo fib ril' add
glut ·lln midl ' is an r-vh-r; UlallYotllt'r d nl ~s form more slah lt· t't1w r glut·um nidt'S.

300 o "·if!;. IH-U.. r lll . ,,,,...1d ..·""",,,,~· ill p"liI'llt , " i th

uIlimpoU" 1(0) .." ., t~ ""lm Klli .. ~ 1 . ) n·'....J fur.....
li.." i. ,I ~,_ h l. K'~' lilllt· d" fihric .-;...1 i' .."1 •
o ..-n-l,... IUIK-J,anlo:, 1 if~ l l - IHlfi In 0 ,I ) " I. " " ·nil
o f",...1i,," i. """'....J. III.· ,1U1•• 11...1d.·ara' · " f r~,..
o
fill rit· <It; " ,,,....-n rnarl< U~' with .." i, 'n~.... .· in
o ...·n"" (·"·ah"i'N· , i " ..• • "N'''''''" ''''/" "."..! f,u "
o
lilK', Tle- appan'''1 '''1'''r''''''IJ<~' of t-loJi hril: <It h
""hl.u,,1d ,·;1.""''''''' "" a {"'liI·nt". ... ua! f",...1i1 K' i•
.....pl;lirlt.. . I I~, ih i"It·n.... JI,,~Nt Jl, In a p"L, "', ~, ..,..
"i.k·. forwt,i<'" 10.... fm'" c:I". I". ~· ''' 'f''.....l''N' n.aI
r'n ...1ioJll (1 InWl_ - ~ 7 1i "1 ). ( 11....1 ""'" f"lIT' ( :nl:-
It·r. I'.. " m tt- Il. j.\\'.. J,·"...n. <:.J.. " "·hr. lJ.. ,,,,,I
lIartlal'P. j. : <:\,,1;1>.....1.· .h' l"...ilit,,, ill .. .,....J f;lil,,"·
","I Ill"" I'· ","Id'""'irI..,·r tl,,,·....·. E"" ,, J, e li",
l'h,m nam l.. IS:.l4 I_147. 1\l79 1

o
o 5 10 15
Serum Creatinine (mo/dL)
316 ( H....PTH 2 1

Estimation of Metabo&te Formation

From P la."m a ~ letaJM)l il t" ('..on{'t"n (ralio n. 111t' amount o f adrninis!Nt'() d ust>of d m~
convr-rted to svs n-mlcallv acatlabh- IIwl ahol itt' ran hI' cak-nlan-d if IIldabo!ile ch-arance,
Cl.( m ) is 1(IJ(~\ll. Silll~' this amount ('(Illals tl.t' amount of TlIetaho lite elunlnated.
CI .(111 ) · A UC (m ). To g:ilill all estnnnte o f CUm ). till" IIlt'lahn litl' urcds to he ~H' 1l intra-
vr-nou-dy. I n till' ~(, l ll' ral l~d.<;I· . lilt, rati., C I .(m ) • A UC (m )/ l)o"p ~ n's tilt, fr:ldi llll o f ,u lm in _
tstered dm~ available systc mlim lly us mdahnlitt' , This rah n 1ll1l)' I ~· Inw, ('.J.::., if a <!mJ.:: is
~H'II orally am i it has a low hioil\11ilahil ity <lilt' 10 mcomph-te- tlissn iutiu li. A ll (' slimak of
lilt' Importance of a partit111ar metnbolic pa thway In rln- r-lnulnution of a d m ~ t~1II Ilt, made
ill tilt' special e d-OW' ill whidL metabolilt' data an.' a\<lilahlc' follo\\i l1~ i.v. adlllillistfittiull of
both d rug and Illl'talxliitt, nil st'p'lfittl' occasjons . Sudl data fur istN lrh idc··,'j-lI1unollitfittl'
an-ltsted ill Tahlc' 21-.5. !snsorhidt,..'j·lIlfJllon itmh' is 011 (' of tilt' adi \'(' nu-tubolitcs of bu -
sorbtde dmnrutc. an lill t i a rl ~ nal drug. T he amoun t of lIlelalxllit l' forllled followill~ a 5'1Il ~
i.v. llost, o f parent dm~ [CL(m)' AUC{m)! is 1;.3 L'h r X 0.3';' mg-hr/l.. i.e., 3.0;- 111.11: or
3 ,1'S- 1ll ~ dm~ l"' l lIi\~II l'n I S aflc'r l'um't1in~ for d ilTl'f('lIl"C.'S in molecular wei .l1:ht (dnut ran-, 2:36
g/ moll': ,')-lllo nonilmtl', 191 Wlllolt·). Cle-arly. wil l. 3.Hmg of a 5-1II~ C!lN' n )ll\'(·rtc.... 1to IIIis
IIwtalxJlilc' , the formation of Illl' 5'lIIommilrah' is a major fCI11h' uf elimination tlf Isosorbtde
dinitmte.
Fru m M I'lliholi(c Eu"n'linn , ~( any IlIl'taho litl's art' IXIIar ami t' lilllinah ....1 almost ex-
clus fvelv IJ\" renalcxcrcnon. Tlu- d im iuat ioll [excrt'finu] of thl'S(' 1llt'lalxl lih 'S in till' n-rnunal
phase.' i~ f.:c-<l,lt' lltly (onnatitJIl run-Hunted. t'itl lt'r hC'<." dll.'>(' tllt'Y llil\"(' a 11l11l'h hi.l1:l.l'r ch-ar-
ann' , smalle r \'olllmc' of distribution. ( I f both. t·olllll;.m ....1....ith pan'll l dm~. Bt-c-all. when
for malion is mlt'·lillliti ll~, llS a reasonable apprll'l.imatinn dllrill ~ tilt' n-mnnal ph:l-"C',

Rote 01 metabol ite excretion - Cl f ' C 17

ROIo of metabol ite formotion

l1U1s, hy mt'il-Sllrill ~ tilt' rates of oxen-non of IIlC'lahulilc' am i tilt, l'C l m'Sllt md i ll~ plasmn
dm~ « mcentrauon. dt'a r.ml'C' associated " i t II fonnation of 1Ilt'lalxllih ' may Jlt' es timated.
:\"ol l' tha i ,,11l'lI Eq. I ';' applies. tllC' fall ill l1It'!aho lih ' l'xl'relioll run- is dc'le rm illl'tl hy, am i
can I" , USf.·d 10 t'~ti fllalt·, tilt, half-Iifl' of till' d r ug. El luati oll I; is mos t accurate under stc'atly
state condutons .

Dtttdion of Chaages I. PhGfrnocoklnetks

Comparison of dm~ and nU't alxllilt>areas is helpful in idc'lIlif,inp: lilt' {)~,11 1 u f d n l~ me-
laholislll (i.l' .. g,l-"twilltc'~li lllll truct . Iivc'r) wlu-u { I m~ ts adrn inislt 'f('t l h~' t1ilTl'fc-nl routes

Ta b la 21 .5. M aa n Phar lltacak lnat lc Data for IloloriJlda .5-Mananltrat. Ahar

Intra v anoU l AdMl nlltratian o f 5 1It9 o f b a lorbhla.5.Mo nonltrat. and b Ol o r.. lcI.
Dln ltra t. - an Sa parat . Occal lo n l

"'IHISQSC::*flCJt "'lU~
~~Ul! D"II !lA1f ~

AUC Img-Il'/ ll 060 0 37

Cl il/lu) 83
Half-life lh.l ' 2
~1rom~ .P ~, I L orodScho M liooo'bodot~"""""""'_orod~~....,...".,_ l,_.Qloo".....,...,.,."orodoool'*-'9
( "" ~01 It.oo 30" 8~ "91 198<1
-o-""""~, p atdGoiootl> . IL ~<k_booo.o.iobl.f., ' ''''''''U atd......,.",...... cw. ~d n. 38 14Q-14Q l Qfj ~
CHAPTfP 2 1

(p . 3, 6 ). An ';l ;lIIal) ",is ('1111 al'>!) I"" u....'(1 to examine possible rause-s of it d mngt· ill tln-
plaarlllHeokim't ies of a d nl ~ or mdaholi te , Suppose , for example . thai whell ~\lm o rall)'
till' plasma concontrunon o f a d nl~ of low clea nuux- is n-dnced ou O('C:iLsiOll B compared
to tlu- ,"ill lit' 0 11 Occa sion :\. Po'> sibll' ('\planati olls an ' : rrdno-d oral bio.l.t\ll.i1l1hilit)', incn-ascd
d eari lllt'(', or hoth. E Xillllillil!iOll o f t1m~ data ulcm- llli~ht WH' a d ill ', hut the sitllatioll is
Iwlpt 'i.l (,(lllsitll' rahly hy simullum" llls list' of IIlt'taholih' data.
·n ll' roll ll\\in~ r-xamph- is th at or u s i Tl~l e t111Se or dm~, An anal (),,~uu s allalysis can hl'
t'\ !t'Ill!t.,1 to sh' ml)'-state o uulinons. Foll(}\\i ll ~ a s i n~!I' dose. til(' are:l ratios for d m~ ,II'P

Occasion A; FA ' Dose - CLA ' AUCA 18

Occa sion B: Fp, , Dose - Cre ' AUCp, 19

Occa sion A: fmA ' FA ' Dose - CLlmlA' AUC(mIA 20

Occasion B: fms ' Fe ' Dose - CL(mls ' Auqm)p, 21

\\ 1 11' 11 till' sau ll' do ....' is ~\l' lIll11 IMlth l",-'(.'asiolls,

22

AUqm)8 _
23
AUqm)A

ami Sillt'(' fill ' Cl . = Clo"l hl'n

24

AUC1ml ] Ei.L
[ AUC 8 - CLlml8 25

t"{lIlsidN tilt' va rious possihilitit·s.

:'I: ll W
I>ossihilit), I . Re d u("(.>(1 b inanlilah ilit)· t hat i.. due 10 Incomple te d issolu ti on of
d nl~ ( f l\ < f , ), If thts is .so, a..s dt>armll't' of neither drug nor metabolit e is aln-n-d. it
follow s from Ells. 22 ami 2.'3 thu t
Elpt'C.'llIlilln:

AUC, _ Auqml,
AUCA AuqmlA

Th at is, til(> rat ios of an-as o f d m~ am! lI1etabolite should be l"llua! and les s thau l. O f
('fIUN', tilt' n';l-'>! lll ('fluid illsll I"" lilll' to tilt' patil'nt's flti! i n~ to talt, tilt' tk)S(, us instruct ed .
a {'(llllp!iallt'f.' probk-ru.
Po ....ihilit)· 2. Int'rt"a '> l-d clearance or drug (C I. a > Cl~,, ) , If this is th e reason for tl l('
dt 't,rt',l-'>!'(I d nt~ eonce-ntrutjou. then tilt' expt't.1 t't 1 outcome fur til(' Ull't abolite ( 11 ·1'Il.' nd.~ IIll
 MflA.8OJTE KINETICS OtAPlH 21

till' Illt"t:hanisllI n's po nsibl,' for tilt' ill('I1"('il' ill t1 m~ dl"lr..u ll't' Iliinw!y, tlt-'C:rt"\L>;('(! hillliing
of d m~, l'U1)1111' iudncnou. o r inl'n 'lN '1! n-ual dt',U<lIIl't' alll ! also tlt'lx'mls Oil till' ('\Ir.u.1i oll
rali os of Ilm~ allll llldaholih '. Gi n 'lI a low l'\I radioll milo, I IIl' l'\pt't.1aIi1i1lis tln- follfl\\ill g:
a. IJn 'm u ('d bindill/!. (f u t>.
If Ihis O("(1 Irs , CI 1 is ill('n ',(>;('(1hul fm is IIlMItI'n·tI, hl'1',l1l~" dl·'lr..i1l('t' s II)-' all Jl;lfhways
o f dm~ (,Iiminalio n art' t't l' lil.lly alTt"l11"t1. As neitln- r hi();t\"ailahi hty nor lIll'taholit(· ch-a r-
,till"(' is aln-n-d.

E \ pt.·c:tal io n :

UClmJj > [AUClml

[AAUC s AUC "
!
10. f:n=Ylfll' h lll1ll1ioll.
If tllis O('C1 Irs , CI.(, may or lIlay 1101 dlan~(' d( 'p" lIt1 i n~ Oil whkh IIld aholi<: pall.\\"", · is
indno-d. Hemem wr, tln-n- is ofll'u mon- thau 0111' <'111)111<" n -spon-dbk- for drug me-
laholi slll , am i all a rt' no l ("tpmlly slI."(1'plihlt'lo tuduct iou b,y a wn' n ifl(ludll~ a~I'Il I .
t, I . Fon lUltiHn of IIu1(//Jo !itl' i,lllmn/.
Sinn ' CI is im:rt"L>;('(1. il follows thai
1
Ex pt."c:la t io n '

[ ~]
AUC e
> [AUClmJ]
AUC "

tln- Illt'labol ih ' an-a rari n d l'l1l!-:t'.. tlt'IX'luls (Ill Wlll'tl ll'f or not Il.t' IIwtal x,!ilt'
\ \ ' ld lll' T
is til(' o n!y pal IIway elf d m ~ clhulnation. If it is, then. since fm = I and cannot iU{"fC"\L"C
furt he-r, 110 d lal\~1' Iutlu- IIll't alxl!ilt' an-a ra tio is t'\jx't.'!l"tl. Otht'l'\\i w ,
Expec...at iou .

AUC(mls > 1
AUC(ml"

112 ...\ " o tl ll' r IIIt't"bo!it' Ilf/llm'''y i lld lll'rt/ .

Si1\(1' CL, is nnl d l ,lll ~t"ll hu t fm is d("l'fl"lN "t1 (as CI. h il1ert 'a"''1Il, il fnllows th at
E xpt.'d a litJU;

AUClml' ] >
[AUC(m)" I

[AAUC
UClm'j _ [AUClmJ)
8 AUC "

c. I II('n '(", ('(! n',wl rI/,(lmlU~ ' (e LI( i ).

Tlu- Ulltt'lIIW ill te rms of till' llll'lahnlih-' is tlu- sa U\l' a.' t hat pn "tlil1t"t1 fur ('il-O;(' b2,
I " "(,<III \(' CI., is uualh-n-d a nd fil' is decreased.
(HAiTH 21 /liTA8OUTE 1<1Nf.T1CS :II,

AUClmlA,l' l < I
[AUClm
[AUClm'j _[AUClmll
AUC 8 AUC A.

Fmm tilt" ahu\l' anal~~... il is apran'n l that 1ll11ahulih' ILta Illa~· I.d plu Il<ImlVl· IIII'
number of li l(('~' n'a'\un.~ for n-dllt"t,'l! plasma ('ont"t,'ntr.l.lion\ of a dm~ . Gi\in~ IlnlJ.: intra-
\l'noll\I), uUlIltI t.a\l· n 'suhl'l! tiM.' issue, hut it is IKII a1uay,. pt""..ihll· Of pr.u.1kallu do -.c '.
M t'".l\ Urt"I IK·llt of pmh'ill hi lKLIlj;!; ami of dnl~ in urira- ulKlkI t"t,'rt.unl) haw lu-lped distin-
!'tllish hl '~l"'Ol 'n till' \1I.riOIl" pt-..\ihililil-s. of ('unnot·, it is p' ......ih ll· lI.al I.ulh h.ll\t\Olilahilil~' 'Uld
clearanci- of hoth (Im~ and IIwlabolitt' had d,an~('l l . Sudl (:b;lII~t'!> compbcan- till' in ter-
pre-ration. :'Irr:ulu i lh\ lamlinJ;:: ..uch tl)lIIplic-"diuns , it is often (X......ihl•• to 11m".' n· ......mahlt · (lJII.
du..iou.. a... to tiM' likdy can.... o f a dlaJl~t- in .Im~ plaannatlllindio fmm ('llllhillt'li .I nl~
and 1ll(101holih' data.

STUDT PROILIMS
(Answers to Study Problems ore in Appendix 11.)
I. Elson ('I al. U-:I... m. J., St n Jll ~, J,M., Lee. \\".-1\._ and All..in...m. A.J.: AnliarTh~t1l1llit'
(XIII-IK")· of :'Irr: .at.,'~ lpn ){·.Li Tlam i( It· . Clm. phan nal' ll. Ther.. 1;':134- 1-10 . 19,5) (ltil'f-
milll'ti tilt" ratiu of plasma (llnt,·nlr.dinm of a.:1i\l' 11It·laholitl·. :'Irr: . al"t. ·t~ lpn ){"li n;l m id, '
Isee- Tabh- 21- 1), alltl proeainumuk- in patient s on Il)n~-h'nll pn){-.ullallJit!l· d'l'r.'r:-'.
Fij.,,'1In' 2 1- 13 i, a Ithhlhrr.UTl of tilt' res ufts of 3.1 p;.lli,' ut~ ; 1111"n- is um..itk 'mhll' \' Iria!tnll .
G i\'('u . ;t .. is Iikdy, that Ihell(' values an' reasouabh- ."tilllOllt'S nf lilt' mtin ;11 plateau.
UIIllIll('111 nil ",hid ) phanTlall ,L.illl'tit· p<trdlllt"h'rs of t1m .e:: <Iu d IIll"labulilt' u lIll ri h ll lt ' III
ti lt' ulN.·l'\l'l;l \'ari;thili l~' ill ,h" ratio .

j 10
~

'"
15
~ "i~, 21-1 3.
E
~
z 5

01 23 456
N-AcetyiprocainamidetProcainam ide
Plasma Concentration Ratio
390 WT ABOUTE ~ TICS CHAPTH 21

2. \ \11k-II (i f ,IllY) of IIII' ,oxplanaliolls offered h...Juw ;t rt' (is) constsn-nt wtt h all im-n-ase- in
tilt" ratiu of ,\ l/ C(III)It\ UG a rk r 11 s i ll~I (· o ral dose.
a. Induct ion of the lilt'lahulil," Ionnat iou pathway.
b. Heduct ion of th e volume of di stributioll o f t il(' IIwlabolilt',
c. 1III'rl',l-<;(' ill doS(' o f dnll-!: ubsorl x-d.
d. Hl't lll('fioll in t:lt'a r.Illl1.' o f an altt'malin ' pat hway of !·Jim in at io ll of d nl ~.
3 . Carba llm:t.t· pilll'. W, l l-t·poxide is a n ucrive a mi slIbs la nti\'t' IIlt'ta bolilt· o f IllI' illlfit·pi .
leplit' d n , ~ (·arballl'l7.l.·pine. U sh'ti in Table 21--6 an- lilt' II W illI slt 'ady-sta ll' plasrun
coueeutra tious o f ('a rhalll;l7A,' pi lw and tilt' ratio o f th e nu-un ste ady-sla h' pLl'illl<l ,'011-
cent r ations of car bamazepine- tu.l l-epoxidc all{ ll~trba lll 'V.l·pi ll l' fol [o\\ill ~ i lle n.·il\ i n ~
dail~'dust'S of l~arlli,maz'·pilw. Giwni llal l"iIliliUll;U.l.·pillt· is wel l ah~orl lt"(l. and that tlu-
clea runce of tilt' epoxide, to lilt' diol, tlOt·s 110 1 d l a ll ~I' \\i tll tilt" do~' o f carluuuaze-pinc,
what pharmaeoktncrk- pa r.llnt't en; o f dmg am i erw)),;ide nwtalwll ift' han ' ehall~t'll tu
explain till' tlata ill Tailit' 21-6?

T.bl. 21 . .. M_.ItetHIy C. _ . .pl_.MI lMltte PI__•

Ce_••IratI•• D... f.II 1 .1 D.lty D._ C pl ...•

Dot,emoreplne
Co
cee Imgl 100 200 400 800 1200
CCltlCef'lIfQ"on [mg/ll 26 43 57 73 00
Rcro01 Co,bomozep;ne .
1O. ll e spoeoe to
Cofbomozepine 01 0.1 5 0 17 0 20 0 21
"-..ood ...... ~_ I 8 . Soooo l" ~ GI ~ Gorto.- ~" ~ """"""""" .. ...... "d,,"'''' ~ pfto<"""""lI'"
aopoodO 8< / 0.. ~ 33611-61 .1. 1m o..."'W1~• .l. l J,.M

4. Eidll'IIMUllI t·t ill. (Eid wUI<IUIll . ~ I. , T omson. T ., Tybr tng. C .. um ] Bertilsson. 1..: Au-
tuinducnon and slt'ady-s tall' ph ar m,t("u killt·tk s tlf (·arlliUluv..t·p illt· a mi its Ilmjl)r uwtab-
olttcs . C lin. Phannan lJ..i lll't.• J();XU- 911. 19S.'i ) found tlmt tlu- n-ruunal hal f-liw s o f ca r-
lliu nov..t·pillt' am i its traus-diol lUt'lalwllitt' \w n' t'filial. ,Ippw),;imatl'ly;}n hr. full ll\\i ll ~
oral mhninfst r atton of ca rbamae-pi ne. Do th e data S ll ~t's t till' possihility o f a run-
limiting; Shop ill till' p m(, -ss, alld if so. whe-n - doe-s it lit·?
5 . GIY(.; lIe l,(lIIj u~a t i un . \\i th till' Iorrnanon of salkylu rit· add . is nile o f till' major pathways
for th e e1im inatioll o f SiJ kylil' acid ill h um ans. Salil')·lil' add is clean-d slo...d y fmm tilt"
body. whereas Sillil'),ltlrie adtl is clean-d SC I r.tp id ly and (' lI l1 p lt·td~· intn urt nc lh ilt till'
p lil\llla roncentrution o f this IIll'tlllw)lilt· is \"l'ry 10,",'" D ist.:uss why Ill eilsurill ~ Sitlil')'llIric
ad tl ill till' uri ne (,(l1I ld 1)(' successfully UM'l1 to asst·s.~ its ra te- of for mation.
6 . As dtscussed in th is chapte r (p . 3H6), isoso rh idt· dinitrate- is t.xtt·lISiw ly Ilwtal wlli:r.l.'l l tn
tilt· 2- and 5-llIllnllnit r.lte s. Tahll' 21- i lists tilt' mean pharlll;l('(lkilU'tic data fo r iscJSl.Jr-
h idt-,-2-Ill0llon itm tl' fllllll......i nJ;: : Independent is . ud ministr at lou of 5 1l1 ~ of isoso rh itle
dimt rate ;Ull! tht, 2-1Il0IllJllitmtl' to a p'Uld o f ""llunh'( 'rs. ( ~ I IlI I,,(:ll lar wl'i~hts : dinit run-,
2.36 Wlllote : 2-mo llonitm te . 191 WlIlole.)

AU( Img--h'/U 0. 22 0044

ClIVh,) 23 0
HolHile(hll I.Q3 182
~"""'SotooN. p c.::o.o.u.. i l , ondSdn<>.M ~ ~"""o .... ond~l.....,....,....I.-.dt.~ond~dc-g
0.. ~ The< JO .l.8 j..,( 91 . IQ8..l.
oo.., loan ~, p ~c.::o.o.u.. 111 ~ <J,_boocJ,obboI.., l. ,,,,,,,,,~~ .... 0.. Pto-xoI n. 38 14Q-l .1. 9 19l1~
OW'7E R21 META80UTE K1Nf OCS 391

a. Caklilall' 11u- fract ioll (If isosorbide d inilmle mt'la!J,oli n '(! 10 rln- 2·mOll1Jnilmtt'.
h. \\llal assumptions haW' youmade in your c alculation?
e. By reh-rem-eto Ill(' {'u ITl'!ipo lid ing: da ta fo r the 5 -llIl)lIollilrall' pnl\idt'(l in this chup-
IN (I" 3-')fi ), what l'N.'n 1· nt a,ge o f i.\,.-lId minisleJ"t'(! Isoso rlnde dinilmll' is eltrutuated
bv dl'-nilration ?
, . Dollt·n.' ('I n]. (Dollen.· C.T.. Davies. D.s., and Co IlOU\" M.E.: Diffe rences in the tne-
talMllis~n o f d m ,gs dt'I~'lldin~ UpOIl their routes o f ad min istration . Ann , ;\I , Y. Acnd. Sci ..
1, ,9 :In'i--114, 1971 ) exanuned tilt' inHllt'n("(' o f route of admhustra tion on tilt' metabolic
p m fil(' Ilf ho p rotN t' lIol_ 111ls IM'!<I-ad n 'llt'rglc-sHlIltllating dmg is 1Ilt'lhrl ah'(I to 0 -
Illt'lhylisopmt N('llol; lxuh d nl ~ an d Illt'tabolile fon n sulfat e {'Olljllgales. Tahlt, 2 1-8
lists lilt' urinary n '('(I\'(' IY of all four compounds fu]Jov.i n~ udministratjon o f tri tiatt'tl
isop roterenol inl mH'nously, orally, and hy inh alation to volunteers. On ly pa rt'lIl co m-
pound h;l\ ,I ea rtl icJSt i m ll lati ll~ dTt 't,!.

eon lSOPllOTHINJI
'~!IJl:Er-o
cC>VO'. ""''''''
ISO"lIOTE iENOI
""''''''
lSOPllOIEiliNJI
~.

i_~ 6 22 0 130 ,a s
0 01 63 6 2.0 '6 E.3
Inhola~on '0 893 00 4]

a. O n a tlOSt· h;lsis, isoproterenol is much less act ive in hlCT"l;'a.~ing hea rt mil' gin'lI oral ly
th an intmn 'nuusly, which i.s dllt, I" a pronounced ural first-pass lIll'taholic Ins~ ,
prindpa lly by sulfatl' l'lmjug:atioll. Com ment o n III(' Iikd y primal)' stte for con]u-
gation of isoprote renol admmiste n-d o rally,
b . 1)0 tilt' data SUp pli rt .Uly l'\idt' n{'t' fur Ovmcth ylenon occurri ng presystcmically fol-
Il l\\i n ~ nrul ad lnini.slmlio n?
c. Gin ' n the rt·lat in ' similarit y of lilt' ex{n·I0I)· profiles (ollO\\i ng lilt' nral and Inhaled
r outes . comment Oil tln- likt'l)" fait' o f much of lilt' lnhak-d d rug .
s. U sbortu- e-t al. ((h IMm w. B., JIM']' S., T rew, D .• and Slt...-in , ~f. ; ~ 1 (Jrph i lle ami metals-
util(' ht·ha\;nr afl N tlilTN t'nl routes o f mo rphine administration : Demonstration o f tlu-
impo rtance o f rln- act ive nu-tabolttc mc rp htne-s-glucororode. C lin. l'harrmnol. Ther.
4.:12- 19, 1!1!1() s!ud it'\ l tilt' I'llarm:ll'llkiudil.-'; of tilt· allal)!;t-sit,: lIItirp hillt· ami Its !"''II
ghll'Um nid (' nu-tabolites . rlu- adiH' morphtne-a-glucnronfde. and the inac t ive mo r-
ph ine-3-j!lu(·uRmide . Tablt' 21-9lisls mean ( ± SO ) A UC am i C..... data obtai ned fol.
ll)\\i n ~ uchrumstratiou of morphine sulfa te us an l.v. bolus (5 m~ , o rul tahlet ( 11.7 m~.
und sllhlingu al lahld ( 11.7 mg ) 10 10 heallhy voluntee rs. ~ 1 ()l a" lar wt'igh t of morphine
is 2S5.3 WlIlole; mo rph ine sulfatt'. 669 Wmo1<--. contains 8.S.3% morphi ne Illlst'.

,.ltl. 21 -0. M. ... ( ± 'DI"'U~ ..... C-l' Data- fer M-,.hl ts Glac._..lcI• •
• • ne.I•• A...I ..I.trwtI_ ef Merphl_ II' DHter.-t .....

•• llCllll!>
AUC Inmol-hr/l1 229:!: 37 43 :!: 13 48 :!: 10
C-. Inmol/ll 273 :!: 65 21 % 7.7 19 :!: 4 5
lv'orph,ne-O AUC Inm<fhr/ll 313:!: 87 37 1 :!: 159 2Q8:!: 159
glucuromde C...,.lnmol/lI 80 :!: 15 84 :!: 26 74:!: 19
tYorph,ne-3- AOC Irlll'dhr/LJ 1765 :!: 300 2 180 :!: 808 166.4 :!: 485
glucuronide C...,.lnmol/ll 407:!: 100 440:!: 125 386:!: 8 1
 .vtTA8OUlE KlN£ TlCS CHAPTER2 1

a. ( ;a!ellla!t· tln- hiuiw ail<lh i!ily tlf mo rp hine follo\\inl-t its o ra] a<lln inislm lio ll.
h . (;in'lI Ihal ti ll" h lutKI. lo.pl;l_'m l<l l, ml'c' lllmtiu ll m tio of IIllJrphilll' is 2.2 and thOit S%
o f <Ill b '. llo..e is 1'_'l"n'h'(l lllll'h, lIl~l'1 1 in u ri ne, dn th l' i.v. dat a fill" IIlUrp l.inl· itst,lf
s u~t's l t hut Its [o w om! h it);l\"ailahility is din- to a substantia l fi,""t' p;l\S ht'Il<ltk loss?
c. Do IIII' d.a la for hoth v;lu('unlllitil's support til(' 1'1I11" p l tlml tilt' lin'r is thl' p rimary
silt· of for mation of tl lt'st' IIlt'tabo lift>s?
d . () III' n';L<;(JII for th(' list' lIf sll h l i ll ~ ml ta blets. in V;1·lll'rd l. is til iJlt'n'aw tilt' !i)~!l' lIlk
hil);l\";\itlhilily of a d m~ Iha l l',hihits a t.iV;h fi rst-pass In-pane loss. iLS hlood pt'rfusinv;
ti lt' hut1:al (';I\i l>' dr.u ns din'(11y tnto II\(' Sllj"N:'rio r \l,'11ii cac u . Do till' clnta ill Tuhle
21 -H sup po rt thi s nltion;(!t' fo r IIIl1rphilll' ?
e. CorllllWll1 bm-lly as to wh at 1'\!l'1l1 lilt"('sti nmlion nf oml hit);IHdlilbilil>' of mo rp hint·
I ml~' he 1/<;('(1 In ,guidl' ;1II~' di lTt' I'l'nt" in dus;(,g(' rt"t lllirt' lllt'llls u f morphine v;i\ l,'n
u r.llly am i illtr.t\l,·nollsly.
f. StI~I 'sl why the- C.-t fur lIl11rp hilll'.;}.gluI1Imnidl· is !-tn.,tlN tlum that of mo rphine.
afu-r i.v. 1Il11'llhi lll' admiuistration.
,g. Ind t'I"N:·llIIt·lllly. O sholln w l't ul. (O sho unll' . n.. Tlrompsou. .... [oel. S., T rew, D.,
l'un-l. x ., am i SII"\in , \I. A.: 111l' ;lIlaJ!-tI'sie adhi ty of lIlorphillt'.fi.v;lul·unlllid t' . Hr.
J-e liII. I'lurmacol.. 3-1 :130-1 3-'\. H)lJ2 ) studn-d ti l(' pIHtrl llal' lkint'tk s u r mu rphillt'·
fi..~!m·l lnlllidt, artt'r its i.v. admiui... tnmon to t~lIIn'r p at k-nts. (; i\1'11 th at t jn- dt'ul'lmn'
fou nd, 5 .~ 1./1Ir, ap p lit's to tilt' \ul ullh"t, rs who partidll<IIt'l1 in till' sludy tha t V;t·n ·
I'ralt 'll til(' dala in T aM(' 2 1-U. l~lk1 1 1;lll' tilt' fraliiu ll o f onl.lly ;ulministl' rt"tl nlt' rphim'
1,111\1'111'1110 tilt' fi..~l ul·umll itil' .
~J, Shll\\ll ill Fi ~. 2 1- 14 an ' st'lIlilt'!-tarillu nk pInts or till' IIlt',1I1 ( ± Sil l p la.\lll a couce-ntru-
liom uf p n>p r.lIlolo! (0) and its al1 h t' lIlt' taho !ih' , 4 - "~ t l mX)]l Olpr.lTlo lol (e ), anN nrul
adminixtmtiou of p rop runolul (MI ITI!-t) to six llt'aIthy subjects. D i Sl'u s_~ \\1 1~' Iht· p lilSll10l
(,llIt"lltm!ioli ur .I-h, t lfl,lx)llm p m llnloi peaks t'a rlit'r and initially dcchnes 111mI' rapid!>'
tha n 111;11 u r pr opranolol.

50 !

~20
c
\ Propranolol
t ,n "" 3.5 hr

~E
1l
c
0
10
'<, 4·Hydroxypropranolo1
' ~ 5 hr
u
~
E
~ 5
#1.

2
0 2 4 6 8 10
Hours

. ·.1I:. 2 1- U .
CHAPTER 21 METABOlI1t KlNETlCS 3.3

10. Listed in Tahle 21-1 0 are the plasma concen trations of a dr ug and one of its met abolites
follO\\ing oral ad ministrat ion of I g of drug to a subject . The drug is fully bioavailahle
when given o rally, abso rption is rapid relative to its e limination, and the volumes of
distri bution of d rug and metabolite are equal. Th e molecular weight of th e dmg is 3C)'~
g/mole. th at of the metabolite is 3 26 glmole.
a. Calcu late the fraction of drug converted to me tabolite, the fonnation clearance of
metabolite. and the di spositio n kinetics of the metabolit e.
b. TIle recomm ended dosage n,' gime n of the dmg is I g orally e\"el)' 8 hr. The phar-
macokinet ics of both drug and metabolite do not change with time on chrome
dosing. Calculate:
I. The average plasma co ncent rations of d rug and metabolite at plateau.
2. The plasma concent ration-time profiles of drug and met abolite within a dosing
interval at plat eau .
3. The approximate times req uired to reach their respect ive plateaus.

lable 2 1 - 10.
Time (hr) o 0.5 1 1.5 2 3 , , 6 8 12
0"9 [mgfL[ o 25 32 3D 32 16 Q 12
fvletobolile Img/ll o 10 22 85
31
" " 32 25 16

II. Predict the general tendencies [clockwi se, counte rclockwi se, or no hysteresis) for the
observed relat ionship between response and plasma drug co ncentration afte r a single
oral dose of a d m g a" a ('o nS('<luPIK't' of e ach of the follcl\\ing conditions. See problem
9 of Chap. 20 (p. 366) for co mpleme ntal)' information on co nditions productug hys-
teresis.
a. Activi tv resides solely wi th a metabol ite . Low-clearance d rug with metabolite elim-
ination rate-limitin g the de-cline of the meta bolit e conce-nt ration in terminal phase.
h. Acu vt ty resides solely with a metabolite. High first-pass me tabolism of d m~ with
drug e limination rate-hnuting the dec line of me tabolite conce ntration in terminal
phase .
 DOSE AND TIME DEPENDENCIES

OBJECTIVES
The leader will be able 10:
1. li$f or least 10 soeces of dose lor Iimel dependence in drug O~pllOO . d<$lrib,,,,,on. and
elimination.
2 Recognize dose- (01' lime-I deceodeot kinetics Irom either plrnma or urine dolo ~1f19
such behavior.
3. Gfophicolfy depicllhe kinetic behavior of a drug when the situation and the cccse of a
ccee (or lomel depeodeoce ore given .
A On analyzing dolo in which a dose lor bmel dependence occurs, identify which pharmo-
col.inehcporomelels ole affected. and o~ign probable couses to the cbseoceco.
5. Dernorooore!he kineticconseqveoc:es 0'
~ store of a change in the rcie 01 inPJ1, Vm
or Km, of0 drug sOOMng ~rulObie MichoelisJv'en1en metabolism .
6 Define 5Oluroble fir*fX!s.1 metol:dism, describe now " con occur , and d,scu$.! liS kinetIC
cooseqceeces.

:\ 11 l 'pi!('plit' pa lit'lll willi has nol responded to plJ("II~1oill aftt'r 2 weeks Oil ;Jon IIlWd"y is
llhwnrtl lu 11;1\1 ' ;l pla\l1M conccn tranon llf .. mlifL. Twentv day,. after tilt' daily do't· has
I"-'t 'll i1 1('n';!"l't1to .'il KI till!, the pa tit'nl develops Si ~lS o f tu\kit)". 1Ip; la~IIlU s . alltl ataxia: t l.t'
ph\I/M co ncenrranou of pla-nytoin is IInw 36 lllWl.. \\1 1~' should o n ly a 67% increase in
dai ly d o , t, ~i\l ' riSt' 10 a n irlt'fo ld inl"n'a.~· in pta.\1/1il l'Ulll'l'lltn.lli o ll? 111l' iUlSWt' r lit's ill tilt'
dO'ol ,-dt ' pt'lIt1t'lIl khwlk hd1a\;or o f t his d nl~.
\:llnlla ll~'. pla'l ila (o r I.IOUc! l l"t)fll'l' n l nat io ll, unbound conceut ra tion, aml ulIlllunt of dnl~
and its nn-tabolite-s C'\('rdt,tl in urtne i1t all )' ~\'t' ll till lt' ill iucn-aw in tlin'(1 proportion to
tlmt', whe-n ti m !!: iv atlllli lli,h- rl't l in either a sing le tlUst' o r ill llIultiple d ost's , Therefore,
011 l"t,rn ·~:t ill!!: \l ldl (1!1\l' I'''a li' lllS f,,1' tIll' dose adlllini sft'n'li. tile va llIt'S shOlllt! SUPt'rillllxl ,>('
ill "Bti lilt' S. T h i, i\ reft'rn't 110 il' the ,,"rIOI,le (/f.\·1I1 H''1)(" ~ItI(/,, . \ \ 11l'1lsuperpostnon (M.OCUr'S,
tlu- pllannau,kindil'\ of a tlm l! is sa id to 1)(' dmw-l,ult']lf'ml. ·/d, 01' linear.
Tln-n- an ' lIlall Y n ';lSUIIS \\' I I~' the p rinciple- o f slIpt'rpt>sitioll lIIay 1I0 t hold. A III{JII~ the m
an ' t ltt' ,Ullllilli,traliull of a IJnlt.: ,,~ d ifTt'n' nt routes. ill t1ifTt' n'nt t1USil~l' fo n ns , or by t1if·
li 'f1'nl IIlt'lhl MI, Illtllll' ur illll lsi,m 1. T Ilt'M' arc e u m p lt,s of t1t' lx'lI t1e lll'it,s uu dosa~t' fonu
,tile! rolll<' of atimi ni,lmlioll , T h l'y a n ' 1101 tln- suhj ect o f thi s chapter. Other n -asons fo r
lat,,, Ilf sI1lx'rp'lSi liou illdllllt, (·ll<lIIl-:c·\ in p harma(ukillt'li<: pardI/wier'S t1Jt'l llst'! n 's \\; 111 sin'
o f tlo,,' adlllillh!t'n 'ti or t1m illl! mil", when all otlu-r facto rs an' hekl constant. TIlt' phar-
lIlal"tlkint"lk.. of Slid . t1m~\ a n - ..aid to Ill' d(~\('-dryl('llt/('ld . \\11t'U then- is a lad , u f Sllpl·r·
po sitio ll Oil "tllll inhlt'riI1l! a d m t.: 011 S('p<tm h' oc easion s or a lad. uf pn'llit1ah ility fnllo\\;1I 1-:
n 'p,'ah't l or t"tllltillIlOII\ t1f1Si ll ~ . 1"' \l'd 0 11 singlc,-d uS<" data , III(' dm~ is sa id In s111l'\\' tlm.t'·

..
dqwmll'lll ki""tin . SUI'II IM-Illt"10 r'S an' sources of \lIriabilif)' in ti m );!; J('SpOIlSl' , A ltlltlll~h

,
OWTf~ 2'} DOSE AND TM D£PENOEf"JCJE5 39S

n 'l ali\l'I~' uncounnou. Ih,'y txx-ur fn "(llIt'ntly t'JlUU~1 1 in t1 m~ the rapy to warrant spedal
conskk-ratiou. In t1 m~ u\'t'n loS(>, tlll'Y an' mo n- till' rule th an tilt· (·'(('(>plion .
This chapter dt'al ~ \\i th idt'ulifk alioll and eOIlS("(IIIl'Jl(,('S of dclSt>.dt'!')(>lldpnl and ttmc-
dt'p, 'n d" 111 klnet k-s . Til t, major Intent is In es tabhsh a ~(,'J('ml awa n-m-ss of this topic.

EVIDENCE
Fin ' ph annal,,!.:hll'!i(· pa ra llld,' rs ( f , h " V, G/'H' and G 1.1/) ha... k~J ly dt>fltlt' allt l suuuna riz..>
lilt" ti n lt" ('( 'lI~ ' of ;1 t1m~ ill tilt" body. U ~ll ally, mill" of Ill('!it" pa nlllwll"rs J.-ys h>m;ltim lly
(·laall!-!;t's wi th dos,> in the snuu- ind i\; <! u;ll. Hut in dow -(/' 1w Ill /nd k i lwi ics , any O ll(' or II
(, Jlllbillati(m of th t'st, pa num 'lN s a ppt'a rs tel change \\i th ad mi nistrat ion (If <1ilTN t'Ut dnsl>~ .
T Il(' panullt'le rs ('h'Ul ~t· d ll ri ll~ coutmuous or repeated admlnistrutton wln-n kint't it.'s sho w
ii ll '" d r/wIIl /n ll'l',
Botll tloS(>-tll'jWntlt>1l1 and till1l>·dt·I)t·lltlt·nl ktnetl c l)t,h<l\; ors dl' ~\' t ',l"~' (Iua nti t"tiw dt'·
scri pti on am i pn "(lit1ioll . TIl(' first sh 'p ill l"\lll uati ll ~ this ht'ha\ior is to idt' lltify its u('(...rr.
n-mx-. SUbSl'fjlll'lIt stt-ps ill\uh-t' d,·lt·n llinill ~ tilt" pa nllll('tt-Th alTt"(1t"(l alld !ll(' Ii kd~' nn-c h-
allislll(s) of tilt' non lilll'arity. 1111'r't' an- Il\;UlY potential causes of doS(> am i tinu-
dq )t'lIdt 'lld('s. Tah l(' 22-1 lists examples of n-p n-seutative ca uses t f ~t'l ht'r wtrh tilt' phar-
fll<tt." kiud it.· paralllt"lt'rs alTet.1t't.l. Let us no w conskk-r examples (I ( t1 m W- for wlait.·h then-
is (,\; t!('II('(' o f nOlllilleaf bt'ila\ior in absorption or dispns itioll. For ImUlYo f th('S(· exa mples .
tlu-rape -uth- implications ..ndnn-ans u f al'('III Ull(ll.latinJ,: or dn"'l llI H>n ti ll~ till' problems an '
!-or in 'lI .

ABSORPTION
DoS(' o r tiuu- t!('I)t'ndt'nd t'S in d m ~ absorpnou lIlay 1)(· rt,II("(1('(1 hy a dl<l1l ~t' in t>itlll' r
hiflilv;tilahil ity or run--nnu- pmfil(' of absorpttonThcse t!l'I)t'nd ell l1('S mos t o fte n ariS(' from
thn-e sou rces fo llll\\;I1~ on d aduunistmnon. F irst art' so tllh ilil)' and d issolutioll limit;ltio!lS
in tl\l' rt'i p;t'i(' u f d m ~ fmm a dnsa~t> form in tilt" J{a.st mill t('stin<tl tract. S('('(JIld is s;ltu nlhility

T.It'. 22-1 • • • p.......totIv. c.,,_ . at D._-I.r n••-JD. p..-d. ... KI....c.

_. Se len-d D_. ' • • • pl..
folV.y,nUvrecnc-
I Gmrro,nte5:,f'>(]I4bSOlP""" '''"''' ,,
A SaMoble ~on$pO'f in g~t wall A.moxicillin f
B [),-ug comporOI",ely insolubje G<i-:ivlvin F
C. Sowcbe gul wall 01 bepcnc metoOOlivn Qf\ f,,~ pa ss Nccrdrpee F T
II [),5~.bvl.""
A Sowobe pIoYTlO ptolern bnd,ng Nop'o~en
V, '"
T
B Sal~roble !i\.love binding V. fur U
III, ~t!fIOl E.ere''''''
Pefli(:illin G CL, ,
A At:.l.ve secret.an !r.oturableJ
B »o..-eleob~pl"", tsowc bel
C. Dec-ecse in uure pH
A$cOlbic acid
Salicylic ee-d
o,
CI, ,T
D. Sal~rable pIo~ p<oIern bend,ng
E NephlOlOxl(rry l>
(),sopffamide
~O$ide~
CI,
CI, ,T

-"
o, T
F. tocecse in urine flow I>
IV Hep:J~,c fv1e.obo/'5m
"00
,
A CoptX,ty-liml!ed kinefl(~. coiaclO< Itm'lOl.an.
B Enzyme,ndochonl>
C Hepololo' l{:,ry b
D. Sowobe plo~ p<oIein bind,ng
'" CarbomoX
At:.eIom,
Prednisolone
CI"
CI"
Cl"
,
T
T
CI"
E. Decreosed beootc bIocd IIow PrClplanolol CI" I
F. Inh,b,j.an by metabol,lel> lidoca ine CI" I

.,~"' ..... "'---.

'tJ.oeco"'"~ <~ I """""" I de<_"" .""-....gdooo
396 OOSE AND TlMf DfPfNDfN( .IE5 CHAPTH n

Iua trdmpmt 1I\(,( - hanistn fur p'\,~S;I~(· at'mss tilt' g:ilsfm in!t·slinal lll(·IIl)m Ull's . LilSI is satnr -
ahilil)' in IlwtaholisllI during: ,I dmg:\ first I);.LSS th nmg:h the ~"1.I 1 walt alld rlu- hvr-r.

Solubility
D issol utio n run 1)(' IIU' ( '<lUSI,' of do'i(' t1q)(' mlt ·!lt) " in hioil \'ailahi lity fil l' tl m )!;s wit h low
,UIUt'C IIlS ...uluhility, wln-n Wn ' ll orally in rdatin"Iy la rge dus(·s. \\'jlh a fiw t l truns tt limt'
tlmmv;h til(' g:,\.s trnintt'slinallral'f. tlu- amount of dmg: ahsorbt"() is Ilulilwly 10 iucn-ase- ill
proportion to the doS(' atllll inisk n '1 l. An I·XOIlllp lt· is g:rist·o fu hi ll ( Fig:. :22- 1). Fo r this spa r-
ing:l)' slIluhl(· dmg: (soluhility is It) IIIWL). bioil\"ailahility t! t'(:rt' i\'<;l: ' S itS til(' tlu M' is ill t'R' <!S( '()
frm n 2S0 In .3(X) mg:.

Saturable Active Transport

For it few dmg:s. ahso rptio ll (mill lilt' g:;\.s lrnin le sli na l Ira ti occurs by a (, II)';ld ty- lilll ih 'C,!
transp ort mechanism. All ('xalllplt, is lh at of umoxicilliu. a po lar ~· l aet alll annbiottc. Thi s
d m~ is ahsurht'C,l hy a p t'phdt, t r.U1slxlrt mechanism in t ilt' s ma ll iut e-st im-. This conclusion
is sup ported hy tilt" Ohst'l"\lltiun t ha t biflil\"ailab ilily dt'C,'rt'il'it'S with iIllTt',L<,('C,! t!Ost' , h u t tilt'
Ilt'ak timt' t'I l<Ul~t'S littlt' (Fi ~. 2.2-2). T ilt, t1t'C:rt'lL\l' in hit li.lHtiiahility is ('xpla illt"tl II,· tln-
(011),;1('ily- lim ilt 'C,l lIa lll rt' of tln- tmns po rt p m('('ss . 11,t, luck of a major d ];lll~t, ill lilt' Ix 'a).;
tinn- is a l '(lIlS('( ltlt'lll't ' o f tlu- Iuuucd n ;;oll i ll Iht' s ma ll mn-stuu- from which ahstlllliio u
can occur. TIlt' t ltlS(' si7.l' t!tlt.' S uut illflllt'Ul,(' ti ll' time- IK'I\\"t'('1I in.L:tostiulI and movemen t
I)';L\ I Ihl' site of transport .

Xk'anlipiue, a t1ihyd mp"ridim' calcturu-chaunel blocker. exhihits tlO\(' d t' Ill.'mlt'lll"t, ill its
oral h itl;.l\"dilabilily (T a blt' 22-2 ) IK'(,IIl S(' o f sa ill m hi lit)" in Its 1Ilt'laholislll Oil ri rst jlll\S

n l/;. 22- 1. 1'LL' n", nIlKn lt...fioll. 3

11I,"Imli/~~ 1 11l ' ~"" . ;<.' .. f"'Ki i<II' Il f
lillll' f,~ k""i lll: 1111' or..! ",1",lni>lr...
liell' or ...." 1..1>1...> (ul'l''' ' (~lrH' 0 )
;lIMI ('"l r l..hl..h (k w nol"'....1
<~.n~· . • 1 o{ " 1I ..."'k II'i,....1 !U"'
...,(" hi ll (12.5 m\'.l'lilhl... ) (I mWl . -
2." "Sf l. (Atl ,I'I....1 {n lln dat il ill B.lr.
n11. W .E .. IIIMI HiIlIK-iliTW,J. fl.: 11", Two Tablets
IJic'''' '",IiI..hili''· ,,{ nll...mlcrnni/A'l I
wt.....,(uhin (GRIS' I'EG*j ta""." si ll
man , CUrT. 1111'r . R... ., 11j:.5tI I ....5lI9.
1\175.)

Four Tablets

o +---~-~--~-~
o 6 12 18 24
Hours
 DOSE AND Tw,E DE PfND£NCIS 3.7

.'111:, 21-2. ~l """ arnoudlhn I'LL,,,'"

n""...,,'....llo.... JI.... linftk· "na! ,Ie...... "f
3~ le t ~ (. J. 1.'500 1. 1. "IlII.1tW lU
(.AI mil:. TIlt' c<II" 'lndilll ', "n' ,......
",,diu.I ,,, llll"", "1" i ... 1fu, II 3'S,mJi:
< Ie _ C (oI ·n T'll ) x 3'iV
n -(ml!:)). S u' " ,b.·
',""'Tl''''''' lit ti lt·
e:-. "IlII At 'C ,,.I..... , 1lJlII 'I..·.i"'il..n'~
in ' -. '"' it...-n",-.t~ llll· <....... 11,,· , ...
,,·,,"'iolt" aR' "pLot 1 I,:,' " r.a1 hM...
""'I.i1..hi lit),
' '"...n .... ;nl!: 1t h ,'"........ i ll,
lInlo·o' no d w 'Kl'ill l" 'llit lin..-. (I "'Wi .
- 2.• ", 'I ). 11>..b. fnll " Sjol\'all. J.. G n,,-
n.;"" .\ n,1 W N .. r1,,",t I) : 1), ...,...1.••
p' .... I. t .. 1......1";.... of ..", odd ll ", ,,,It I
1_""mpiOliin. e h" . I""'nn",~ " . TIM" '.
3'd~-l I - :!5lI. 11P'lS. In"''1' ni ill1' ''' rn""
H''; j(TM'' . It C .• COIIt1 . w.".. (;... ~ I. ...
I -I'.. " umt illan. j , B.. lI.I ltl T,......·,. T.~ . :
o 2 4 6 8 10 s",,,....hI... r .al.. ,,( , ... fil'rizi,w ..1""'1>1:io'"
..tit·, ural Al lrninbtnatkll' ,,, 1"""",,, J
Hours 1't...n " .....~ "';' II-1: . Hio,......n ll.. ll'i l'~'M ,
IW I.)

, ..... 22-2. .......... '

INte .ell• •I•• 0-1 D._ t.hu Met-HII. . . . NIc.r4I,I_ ott-etI .. .....,
10 to 40 ... h • ..,.. ......

10 19(4jb
20 22(51
30 28(51
'0 38(61

thmll ~h tilt' Ii\'(·r. TIll' da ta in tlw labl.· Wl ' n ' at'flu ir.'t l dllrill J,t all 8- h r du,;illJ,t Inn-rea l at
stt·ady "tatl' (3 da}-,; intn n,¢nl('n ). An i.v. I1lt!io lah.·I.'t1 trace-r dUM' ( 11 . ~ III~ ) W,t" ,I.,'iwn
U)lJt'u ITt'n tly wi th tilt' 311- 1lI~ du.... III dt·!t·rlllh tt> tlml hio;l\'a ilubilit}'.
Saturable finit -p'L"" uu-tal jolism nn..- urs fo r u TlIIIllIJt'r of om.! l)' admtntsten-d dnlJ,ts tl mt
an'I'iJ,thly ext ract ed hy till' UWf or intest inal tisSIlI'!'> . :\ t1d itio llal l·:tamp l.>s arehsted ill T ahlt-
22-3. For st·\'(·rotl of IILl·S(· d m~s . d ost· ck-pendenc...· in oral bio;I\1Iilah ilil)' is ohst 'rn 'tl wit hout
an appa rt'llt dl<i1IJ,tI' ill eliminatio n half-lift·. T hL.. hv-havior can be Ilndt·n;too.1 by rt·alizitlJ,t
tlmt t jn- I'(JIlt,<-'nlmlioll of dnl~ rt·;aI.'hillJ,t Ih.. li\"..r d ll ri n~ abso rpnon ca n Ill' nllld, hiJ,tlll'f
than Ihat uft..r absorpnon is ove r . C ouskk-r . for l·x<I1nplt·, til(' foll( ,,~lll ~ condrnons: D tctn -
bulion is in!'>tanl alll'tlll s; all dntJ,t n-aches tilt' lin 'r intad ; input o f dnt~ from thl' ~,Ls t m i n ­
test inal tract Is first -onk-r wnh a kn o f lI.n ') min -I ( lot -min half-life ); oral h io;m,ilahility at
low dust' s is 0 .1; volume of d istrih ulio n is 2S() L; tut;alllt'pat k hlond Ill,,"', Qu. is 1.3.';
m llmin; an d ahso rp tkru is fa...te r than t·limill;ltioll.

, 1. 2~ • • • • • , ..... D..-•• lltewl

"'._po"'. Do_.
,.... 1. ,Int-'." .",HII...

'-
I LIYer.r o.t w.n After 0-1 1.1
,"p",,"""
,S-fluooOUfocil Sollcylomidt:t
Hyd'olt::wne Vetopomil
,.. DOSE AND n.w: DE Pl:NDENCIES CI-W1E R22

TII(' in itial rah' of inp ut iuto tlu- portal w in. ka . Dose, is also 11...• in itial rate o f ('II11} o f
t1 m~ into tilt" hver, 91/ ' C,".,,,J' Ctl1lst'(!lIt·lIt ly. a(tt'r a 1l)1I -1ll ~ d uSt"

T ilt' concentration in th e hlno..1 ('nil-ring, lilt' Iin 'r arkr absorption is fiuisllt'd wo uld have
a maxtnunn \';\111(' o f

F · Dose
C""'. - V - 0 .0 4 mg/ L 2

TIl(' netuul vnlne o f C....... ~ "o l\ ld ht· less 1N. ,(~dU St· souu- dnl~ is d imina h't! dllri ll ~ tIlt' ah..
surp tioll pIHl-'>t·, As can h.· seen. the- con tn bunon o f ahsorl x-d dmg, to tla- ronceutrat ion
t' ll tl' ri ll~ till' liwr dUrl lll-t 11r<i1 !);.LSS is much greater than that n-cyclcd [rtuu the n -st of tln-
hody. Indeed. IIIl' rauo nf C1,,'/1oII to C...... is

Tl usv, t ilt" l;uW'r IIU' \"alllt· of k(1 o r \ ' o r IIIl" smaller tin- " aim' of F at low (llo lls al u mting)
<I0M·S. tilt' g rt' ale r is III(' rati o C'''U.JC'''''I a nd tln- mort' likd )' tln-n - is to ht' a se-paration in
tilt" d t"grt"t· of saturattou of md a ho lis lll du riug a hstJ'lltio ll a nd eli mi nat ion p IJil\t-S. All tilt"
t l nl~s Ih h '(l in Tahlt' 22-3 sllu'l! satura hk- first-p ass metabohs m a nd han ' pharruacokim-tie
Il<lm llld t' rs th a t fau )r a hig h vahn- o f C..., ,~C'''''I '

SATURABILITY Of PLASMA PROTEIN AND TISSUE BINDING

A luutn-dnumbe-r of hi lld i lt ~ sites c xht O Jl plasma p rot eins. Hrcall fn JIII T ahle IfJ.-I th a t
tlu- p !.ls ma concent ra tio n of alhunnn is Il Sll llll y 43 WL o r flnn I..I ~ I (molecula r 'l't" i~h l ::
fl , .000 Wlllolt' ). At nne bi ll(lill~ silt' lX"f albumin mck-cule . there is tln-u a Iim ilin g l'(JIll"('II-
trution o f fiOO J.l ~ 1 fOf till' IMJllIld t l rtl~. FOf (II-ad d g»1:llpmlt' ilt, t he limitatio n occurs al
al Mult 1.5 1..1\1 , a much low(' r ccncoutranon. The silt's to which dnl ~ hind in th e tissues
may lx- stmtlarlyHmued . Consequently. the volume o f distrtbunon depends Oil dnlg con-
ceutration. a ('( mn·" t m tlllu~JryJ('"mJI·" t Ill'!la,io r. C ha ngt's in hi nd ing n-nd to 11l"l'OlIlt' ap-
pn -ciahh- when mon- th an 20% o f t he a\'a.ilahl t, silt's a n' 11l"l'lIp it't1. Th is number, rorn--
spolltling 10 120 l..I ~f for one h inding silt' o n nlbumln. is a rhit m T)' hilt usefu l for pn"llk ting
t hl' likel illtMKlof couce-n trauon -depcndent binding. Fo r a tl n l ~ \\i lh a molecular we ig hl of
250, 120 J.l\t corn-spends to a co ncentration of 30 mWL.
Fo r dmgs tlm t show sa t urable biuding til pl il.\ mil p r oteius, tilt' volunn- o f di sl lihlliioll is
t'xpl'l'! t"(l lo im.' n ';Lst' 'li th plasma conceut ratk m . l' X{'t'pt when the \1)111111(' o f di slrilmlit)ll is
smal l (1(' SS t ha n U.2 L /k~. St:'(' C ha p . 10, D istri lm tio n l. Converse-ly. for tl mgs t hat show
sa tllr.l.hility ill hi ll d i n ~ I tl tlsstn-s, tln- vnl uuu- o f distrilmtinlJ dt"l'rl'll'i('S as p lasma co nceu-
t r atiou is lll{'n'il'i("li. Ht,{:.UIS(' of Iht' Ill)tt'ntial dl 'pt'ndt 'lIl't' O il tln- Ir acnon unbound ill
plasma a nd ti ll' d t'I'll'IIlII' J\('(' o f half-lift' o n both clearance an d volume o f dis t ribut jou, dOSt:"
ch-pe-u demx- in tlistrihution lIlil)" II{' diffi l'li lt III idt'lI ti ~y and lJuan ti ~Y, unless plasma p ro tein
hi ll(lin~ is 1Il( 'a~ lIn"( l . Comiclt"f tilt' example of ua pm\('II.
1111' A UC of llilp nJ'(t' ll follo\\i ng si ll ~Jt, d uS('s fails to incn-asc lilll'llrl)-· with d oS(' wl n-n
d uS('s "how IhoS(' lJ\'l,imally n -comnu-ndcd (50 0 Ill~) an' gl\"t'll ( Fi~. 22-3 ). \\'itholll a ny
ot he r illfoTlllal ioll, t his nOIl!iIl('ar o b servanon migh l 1)(' t':o.:plai nt't l by ('itllt'r il d('('n 'll'it· in
hina \"ililahility o r all illl'f('a.<;t· ill t: lt'a mll<-'t~ , ill that
 COSE AN) ' WE. DEPENOfNClES '99
F
AUC - _ . Dose 4
CL

, 111' illl'Tt'aw in dl'a r.Ull,(' may 1.1' dut' to ind ul1ioll o f met aboli sm o r salu mh lt" hi lld i ll ~ 10
ph\m'l p mtt'i m . .-\\ 1l.lpmWlI is a d m ~ of low cleara nce- ( J}()';(,!t\ VC calculan-d Ireun tlala
in Fi ~ . 22~'lA \"aril's [rum n..'} to 1..'1 LAIr), the pee k concentrations ObSt"1'\1'1.1at doses of I
to" .e: ( F i.e:. 22--:1 U) p m\"idt· infonnatioll to dis l i n~ll is!l ht'tWt't'1l tln-se pussihili tit'S. If ont'
a pp rtl\i matt·s a coucent runon of I J() IIlWL wln-n mos t of a WO()' lIIg dOM' is ill tilt" body, a
\'<llllt' (If "'F o f a ppnl\ iUliitt'ly Y L c m ht' t'sti malt:d. Tlus SIIW,U \ u hnllt· sllAAlOSls sl n lll.e:
hi ndin ~ 10 plasma pm h'ins . TIlt· maxim um concentrations ohtai nt't l an- in thl' l1o gion when-
nouhm-ar h illdi ll ~ is t'\ !x'(1t'tl fo r napn ax-n, a wt'ak add that lands to albumin. \\'ilh a
molecular Wt'i.e:111 of 2:10 WIllII!t', 1110 and 20n m WL correspond to coucenrra nons o f 430
ami S70 ~ ~ l. \,.hlt's a ppm \ imati n.e: that (finO JJ ~t ) of serum allnunin. TIlis is til(" n md ilioll
in whid l jiJ is {'\!'1('1.·lt'(! 10 ilWTt';LW with bigln-r doses . T hus , wrt h minim al Inforumtion , a
probabk- sourrt - o f 1I0nlillt'arit, ·, saturable- hilld i ll~ to plasma al bumi n, ( -d1 1 he deduced.
T ht' tllt'r.lpt 'ulil- l'tlllM'tIIlt'Ul't· of dt't.·f{'il.'l'tl hi lldi ll~ to p!;L..m a pmlt'ill!i at h i ~llt'r tbily
t1I ISl ' S of a t1 m~ nf lo w l'xtr. u:t iutl r.ltin difTt'1"'S tlnu uatka lly from that of d nJ ~- i 1ltIU('("( ! ill-
l·Tt';L'>('t1 t'nry'lIlt' al1i\i t)" (autoimluctlon]. \ \1lt'1l binding decn-ases (i u Iucn-ascs ], tilt'
slt'atl"-statt' total p!;l"m;l conce-nlrutiou is not iuc reasedmueh 0 11 doubling tht· rate of ad -
ministrat ion . TI lt' sh'ady •srat r- unbou nd concent ration, howt-'\'{ 'r, doubh-s a... a l''OII'>(''IjlWIII't'
of 110 d lall ~t' inunbound d t'ar.uu'{'. TI lt- iutensitk-s of tm:il' allt l tln-rape -utu- l't"Spo:mMos an -
('\I)('1.'I("tl tn in('rt';L'>(' al"l't)ft li n~!y, In contrast , a n i I K ·rt'.L.... in ('1IZ)111(, .tl1i\i t)" would ;lfTl'l'l
!xJlh 11llixIllIlII und total concentmuons p ropo rtionally. Thus. if untninduct tou O{'('UI"'S , tJllI"
" miuor illl·rt';L'>(' ill rt'SIX lIIM' wou ld Ill' I'Xpt't.'It"'I l al hi.e:lw r ra tes o f ad ministmtio n.
Tln- t'xl'lt't1t'1.l d lall ~t' intlu- time-course of a d m g ill plas ma when p!ll..llla protein hi nd -
in.e: t'xhihih nnnl illt'ur Ill'h a\io r is eo mplt''(. C ha ngtos occur in 1)(ll:1J \'OIUllIl' of d istri bution
(C hap . 10) and d t·ar.Ull'(' (C hap. II ). TIlt' lIla~ll it lldl' uf tln- chungcs dt 'l'lt'm ls on b oth rln-
volunu- of t1isl rilJutiu ll and tilt' t' xtr1l11inll ratio of lilt' d rug. Furthermore. 1'It't .llIw volume w

A B
3000 150

?
~
100
~ 2000 150
~
~ 100
~ 1000
~
ro 50
Z

o o
o 1 3 4 o 1 3 4
Oral Oose (g) Oral Dose (g)
.·IK' 2Z-.1. 11..· .. \ ' ·c ,,{
nal' ......·n ill..,~ with th.· 'liA'''( II lindo' urAl <I......I..,t lI"t ill <1,"' 1 r rur-,rtit..; tI..,
.\t·C ;I.j>r-""'" I" "l'Im>at~' II lm ,;lmi!. \.,J, Ul l. SUlllirlt"";l> is III.. , .01 -ro,od in 1....· I" ·..~ ............Inolit.., un n ·
.01...·"'.. li..'" an' ,. "" i'l,·nl " i tl, ,·illlt ·' .. ,,,'tTl.....· in f Of an iIltn • in Cl . with ."...."1\'11-' ;11)1; ."..... A. ~...pLullt 1
in tI..· ...~t. ,.lI"r..h"· I,ilItLIlI:: l.. pL.' III'" "'1""Hinh ITIt"" I''''oI'''' >!y ""I",,,.il,,",, (I mWl, - 4.3 ~ M ,. (M,..lillc..1f... ltn
" m,l ,·I. II.. cl...pl", . ~I n . ~ .....I;",. II . Ortl'):a. E.. ;",otI~. E.: l......nllll(....t.:i'I(1i<.. ,,{rwr 'uxt"ll .... ~·n" ...... e li" .
11,...." ..... 01 l1 ,,·r.. ltl,2fi!l.--.;Z';";'. 197fil .
 ... DCY.X. A/'.D T'N,f DEPENOfNClES

of d i\l rilJIIlinll dIiUl~t.,. \\ i11l allllllln! in I)(xl)'. lIlt" (11'(·li nl· o f till:' pla'l nit I'uul"t' llf ralio ll dOt's
unl n ·lIt't1. in d irt't.1 proportjou, lilt' di sap pe-arunee of Ilm ~ from lIlt' hody. The !ifni'll.' of
Illl' "l' llIilc~ilritl ll lli<: d t'C.'IiIW in til t' concent ranon- nme ,1 11'' \'' is ,1.('11 nul a ~1.ll l lllt·a.\U n · of
the- fmc.1iu!l'IJ mit' uf di m illatioll . TIlt' (iualilaliw' ('lTl'C.1 of ...,t urd"I " bi lldi ll~ 10 plasma
or
pmh-ills fur a t1 n1~ wit h a !olllall vnlnme- distnbunon is demonstrated I ~' Ihl' ( k'(:n'asi ll~
slnr"" of ti ll' UIII.lIl1ltl n '(ollirid conce -ntration wit h tillll" 011 it <;('m ilogantilluiC' plol ( Fi~.
22--4 ) afh-r a \in~lt· 3l" 1Il~~ Lv. ,kIM' , Tht' d HTN('Il{'(.· II(,tWt't'1l tilt' dt,,(..lint' of the tolal ami
un hoUllt1 11t1w('nlrdtilJlIs ( Fi~. 12....H .) is ('\-plaim't l l'.""ti lt ' tlt"t:n·'L\I· in tilt" frdC:1ioll unbound
....ith tin ... l "'i~. 22-l Il ). 111t" a ppart'llt one-comparma-ntal natun- uf cllt· IIJt<tl l'IJIJl'('llt rcltioli
d(,t:liI... i!lo t'lpldillt'll hy \ i r1 ually <til drug in tilt' hc. I~· I .'illJ;!; bound 10 albunun.
111t· .\ C F. inhibitor traodolapnlat. formed foll(J\l,i n~ ural atl lll in i ~t ratjoll (If traudolapn l.
~I II ,"" ll~lIIlillt"a r llla...rna and tiS"lt· pmt(>in bi lltli n~. a... ,kl utlM'r a~c'nls in Ih is p ha nnow:ok"'t'
da...\ . E,idt"l("C' nf IInnlil ... aril~..iu rrandolap nlat kilwtK-s is prtAidc'll in Fi~. 22-5. IJ(ItIa ACe
( Fi~. 22 .....5 .\ ) ami plasma concentratson ( Fi ~. 22-.58 ), Pilrt K"C llarl~' t1l1rill~ tll(' terminal pllcl-"l:",
fail tn ill(·n·a\l.· ill dirt"(1 proportion to the oral tlo!it, of traudolapnl. U\'l'r til(' t"i~il: fnlcl r.ul~(·
(0..') tn HI III~) stm lit'l l. Also, ("Ulltrd!)' to tltt' (>xpt'l1c1tiulJ nf lua -ar kilwtK-S, d!lSinJ;: tLily,
.... llidl is rd.lt iwl~· frt 'C lllt'lit compan-d to tlte Iuult teruunal half-lift·, dc.... IHIt It';111 to ex-
ten..iw al'l"tllllul.t1inu ( F iJ;:. 22-'iC). 11111s. ....tlt·n a 2-m~ tiel'>(' of trcllltie llapril is ;w m inish ·rt'll
ordlly for 10 t1';I~"' . tI... accumnlanon ra tio of t ra nd!.l.tpril tl CAt'Cu/Al 'C ll . U ' Eq. 25 , C hap.
7 ) ts ollly IA!l D in 'l1 l"'i~' IK" o f concentranon-dep-nek-ut plasma protein hi ndinJ;: of
tr.ultlo laprilat Is dHIWll in Fi~. 22-SD and Table 10....... II shonkll.· noted tha t t ht' rdnltl'
flf t'IJIl('C'u l r atinn \ . tJ.,') 10 5 .,aWl..(J\"t'r wh ich tiM' frad ion un lxarnd dl;U1~t's th reefold. t1J\l.'n.
1114 ",t uf tilt' plasma trallllilnprilat concentrations ohtdillt'tl follc,.., illl: lilt" oml duSt'S uf tran -
••"bp ril l Filt. 22.....')H. C ).
1111' uh '\.t·n 'illiullli ahtJ\" ean I., mt iuna.li7.t"tl 01.\ fi,lItlw",. 11 1t' t"tn'IIlt'I)" lu\\' ptl-\ lIlit eon-
<...·nt m liu n al which sat u rable bi ndi n~ occurs ~U~I'SIs a hilltlinlt p mt l'in flf much lowl'r
t1111t1 'utratiull than albu min o r (J I-;l<:'id ~Iy(:opmlt'i n (St.... Tahl~· 10-1 I. 1111' IXII:ly o f ("itk'nN '

A B
1000 0.20

,,~ 100
o
c _E
.!::!
C
1--..----.----. ~

D
c
~
0
C
0.15
-
~ '~
0 =>
10 c 0.10
E"
~
c ~
~
'fl
Jlg
0
'-'
~
" 0.05
0.1 0
0 4 B 12 0 4 B 12
Hours Hours
. ' • . 22-1. .,,_'I ,'"'' tnt'" ,.1 . " .1",, 1 .110'l ~ c,..(onnl tu..,.." lr.d.. oc,~ ...,, 1,llmc' in >1\ "01",,,...",". AM
• >l '~' i.'. • 10-_' ,,( .111 "" f/I.( ¢- S n,;n. Su'" d ,no lC'b " ;q .lrdi ~,,(II ..· " "I...."..I......."...'lnmon
.I" n,,( II.., fint 2 1" . H. n ditT I..-tvo...-t, ,b.-.I.>C.-b,," ofll """ in ." is ~,..-.J 1':1' . r>lf*1.I.>C.-n'aor
i.. rI... fr..1 "'I ,...I ,' " lin , .,,~ a ~I ,.."( ' b.-Iomll C'>II ~' .,( ...... m Illl.."" ", '" bi ndtTfnn......
II..· ,,~ , ' ul..I ·nln.h n.. . aI .. ~' , "' ' n ' 0 ;apprn-.Ja II ("'I ~ fllf 1..,..Ln~ II "I1;'t . _ I.M ,, !lol/.
IIt I fn "" J) tw" . !lol ..-';., Sl,~u. W..(;.. S ~ltll~ . C II., 1 f,)m"t,Woni. K : t:fJ....1 ol"'moJ" ru ln
I ' .." 1 1,,1'1I: ,.., ,I... 1"...,,'..... ...i... 1te:S n( ..n"'..,nd n· f,....;d '" ",,"~..,,,, ,,,,....', ,, •. A~·...b <.1.....001 .
CHAl'TU n OC:Sf AND Twt DEPE NDE NCIES 401

po ints 10 ACE; ibt'lf ht'ili~ n -spo llSiblc·. 111is h i~Ia- ;I fTi ll i ly. IC)',"'-<.·.I!l<td ty t'IIZ)' Ill' ft-sidt's in
IMlth phsm a anti Ill!' t'l\dot l ll' lial li n i u ~s of tlw vasculatun-. Iht' latlc'r si h' IM' i ll~ mn-rpn-ted
us tisSll(' billli ing wlu-u \il'\\ l "Cl fn llll ptlsm :1 ILtIa. Truudolaprtlat , a n ,lat in,l)' polar mok -cuh-,
is n 'slril'h"Cl in its dr stributton main ly ttl c'",tral't·lInlar SpOlI't'S anti is dl'an"Cl sph ' mi l"'llI>',
lIlIlSt ly hy rellal c'\eft'tilli l. Bc'nal c'.\en 'tillil is primarily \ia glo lllc'n ilar Iiltrutlon. SCI th at n-nul
dC'aram't' shl)',\.". ('(JlJ('t'lltmlioll dt 'llt 'IUIl'I\('t· 'l,sue.'iatc'd with s<ltllmh lt' pnltt'i n h illd i ll ~. 1\1
hi~h concentration s u f trandolaprilat . which sa luralt' ..\ C f.. n -nal dl'a r.U1('t· is high anti
t,lim ilJatio n rupk l. As lilt, pIa_ s ma (l lll('t'ntmiio n falls. tln- fmd iulllMlIllid to p);lsm;1and tiS!illt'
..\ C f. ill('n'llSC'S, thc'n'hy diminishing tilt' IlnlMlu ncl pl Ml1 alJ( l lowc'ri ll~ n-ual dC'a rlllJl't·. TIlt'
tn-t I,Ai"C.1 is a 1I\ 1I(:h .. loWN c·limill<lt iu ll of mat e-rial Irmn lllc·I M)(ly. Thus. the- hiph;lsi(·(II"C:lilll·
o f phsma trandolap rilat, !it.'1.·11 ill tilt , sc ' m i lc~a ri t h Tll k pl ots ( Fi ~. 22-5 B) is dru- to conc en-
tmt im ' -i.It'pl'llllc'n t protein hi l\(li l1 ~ ami not di slri lmtioll kim-tit'S. ~otk't·_ that had o n ly om-
tlosC:' {)f dnlg IM"C'II admlnistr-n-d. ClIIt' could 1101 laa\'(' n 'at lily distill ~\lishc·d IM,tw I"C' 1\ 1'(1lI-
('t' nl mlioll-c.II·!"M.," d t," t hillt lill ~ am i tlisi rilm tiull killt't k s as lilt' c...Ill SC· o f l hl' "'PIl<tn 'n t hit" -
1)t)ll('lItia l declim- o f tilt' ptlsma dat a . Filia lly. 1111' 1.1(1 n f apprt't.·iahl .. ,K"t'lIl1lul;ttioll 011
mu ltip ll' dosill,g a rises !)t"C.... ItI SC' aftN (';1(·11 d OM' . most u f till" sph'lIIi(-aII) · a\~lil;thll' t r ando-

._--.
lapnlat is l'1illlimlh "Cl hl'!'n re rt"adling tilt' terminal p t.;lSC' . Thus. lIu lllilw<tr bind in,g to tilt'
aliiw site·, ACE:. apl)t'ar s to e-xp lain \irt uall)' all of tr.lll clolaprilat's otlt! kim 'l il' hc-I.a\ior.
A. A.lIC _ SO'IQIt oc..

.-
DoMl"'Ol

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1",
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- 0>

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c q n M
1."""'*lM1 Dost t"'ll l "
c_ .... o J'IostnI " ' - Ilo$IQ
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Ii ~ I ..
i
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.. • "
,.~

- q n M
•• , • •
..... ,-
ecw-.u_ lPIt1.1
~ ~

. '11/:. 2~ . T .... " I..' ''l,rilal , II ~' ...1;", " "'1" I. J il,· "f l r",~ I<J"prl1. ....I.il>ih ,~ ,,,l i' ~',, r ki"I'1;(' 1..·1"" ;,,,r. A.l1M' A! ·C (ll
1,, 00 h.)" f II,,· " " 1"J,. J;I., 11<. ...,.. ot i'......_ · in .Ii n"<1 P" ""o1i"" I" tI,,·. 1<..... o( lnu .. l< J...prlll7''f'T 11... d....· r... ,I(I.·'ro.s
1,,4 rn!t' If. A" ·milc'll:ouill" ,,il.·I'l.ot "f 11"""" I'L.-,"", Ir... ~ ..,]"',riL" t~ .. ,.....·"l r"lio.... "f"'. .....,J .1<...., 010.5. 1.0. 2.0. ",..I
40 mit . 1",..., ", .., Ii"'·"Ii~' ill t1...1II... c-ur..... lin ' I.... . ~1' 11~ 'I_,~I I ~' II fad " r " f 2 in till" " 'rli<~ ,lindio. , f" r.·...110(
11.. · n .. 11os.\i",I........ .nIt· L.c.-I<. o f p",p..rtit .uaI l~' wid, do • i' I';,trtit."tll... ~ ....itl..l1l ;d L.!t'r linll" . C. Acllllinl-t r..lit. , o f
2,1l0111: "f lr.tntl<";april d.til~· ("I' IUt1;t~" fail. I" 1m "" ,,, ' II '''-~n ..' " f ;loI" ·u m,,I;. lit'" .. f lr..... "->Laj 1L.1. .... \ito\t,.~1 r" nn
II,,· l' . "" 'T lt rAi<..,·l il1 " · l' n>fi'" wit !.in "c " ",nll: il1k ..-aI,,1 \h';O<~' \, ..h ' (24 II.) thai i.l'n..ht1...11 ><"tI .." t1... " .'!t h·T·
mj""I... ~ i ' ..' in 1>1" \1'''' .,"M~·n l.,.I i< ..' .......·.....1 (,JIc...i n!t II .i"I/,"· 2.11' '''!t,I<",. (.. ... B).n. H iIlJinl': ofl nmo. l< ~;.l'liLoI
I.. pla..\ II""I'"ot.>i '\\ .I ....... nt .., lint.....-il)· In d Ual (1M. f,.,..1it.., .... 10•• " ,,1h......~.....~1 willi ;TIt.'n ·a.. in ll: '~>rK....,l natit ", . (1 "'iii .
_ 2.-4 ",\I ). (Dal" in ." lind 8 rn ,m 1 ~'T ,f...' I. B., \1"" n 'T l. \ 1., R ",,~,. T" D" 1..." 1...... D., ;ar..1Slna'od>, ( : .: Tr.t"'''- J...-
I'lil: t 1,aOl,*~ >kint1k" "f.i" ",,"nr.JII<_ ill "''' ''· I..~..h l.~· ''''''Jlh ''·''', J ( ~"lit "-.t,,,:. I"I.annat'Ol .. I" p,",,- 1Q9-,l : ().tt"
inC f""" An....., I' ., W.....-, A., Enlitr.. ll. t'., \I n,, n-n \1. , Sl..r nit...." ki, J I'., ~tI ltan, E.,IlI)' '''' T.. ..nd 1..."(,,,,1. H: Ph ar-
1I,-,-, . il..01;";.. all.1 pl..."''-'-u~1l;.''' it.... IIf In...J,~al'ril . ti... rll ..·..h~ 1 aLlmin;\tmtilln . J. (:u..bn,.,.••:. 11..." "..""J ,. in
(In",". I ~~f; l) " l.. in n (n "n Ii. t ~ ·n fan l . I"·"' '' '"'' (, ,,tlIIIllllit..,,li. ,,,-)
402 DOSE AND TM DE PE N[){t\l(IES CHAPIn 2'1

CONCENTRATlON·DEPENDENT RENAllXCRITION
Ht'Hal d c,.mlll et' (~1Il \",lI'y wit h p la~ llIa IU lll't ' lll ra l io n . Hnlh filt ratio n 0111(1 n-absorptiou a n '
IIsnally p;l-s"in ' p n l{'t·......·s. li lt" rate s of whieh an ' d in '(·tly rr-lated tn ph sm;l t1J!ll't' nlra tio n.
III cout rust. adi\"c' ....-cn-tion a mi at'l in' n ·ahsorptinn an ' sa lu m h le p n ll:t 's<;t·s " i th maximu m
(·apad tit·s. This is SlllM11 ill Fi ~. 22--6, for <Ic,thl.' se-en-non. 1111' m tt· of 11111111;11" Sl,'('n 't io ll
iIWrt';l<;f'S ill di n '('l p m po rt io ll to tilt' plasma ("Ill\{'('lllratioll until tilt' t n lllsp0 rf appmadlt's
a n Ilppt'r Ii mil u lt t'n calk-d lilt' T.lI value. Const"(IHt·nt ly. dc'amlln.' hy seen-non d t'1: rt'aSt'S
;l'i plasma ('t)l\t'('ulml io ll Junc·;'....-s. T his is ollSl.'T\'l,(! for till' anrimierobial a gp ut d idoxadllin
(Fi~. :22- 7). On i ll('rt'asi l\~ 'h e do~' from I to :2 ~. t l.(' n-nal clea rance , ,l,,~'s~"tl by
..k "h\t"C. is n-dm-ed. Extran-nal e!t'ilr.UW(' is IIna ITt"t.1('{1. \ \'itll a n/u o flU)4 , t}1(' lIuholl ml
n ' na l e!t'a mlll'(' is a bo u t 26UII IIIL/ mill foll(J\\i ll~ tilt' I' I?: do~'. Tl tis va hlt' I?:n'at ly ('X{"("f."f.l'i
tlu- usual ~lo lllt' l'lI la r filtm tiull run- o f 1211 m l Jmi u. i ll( l i('at i n~ tl mt Ihis d nl ~ is (':dt'ns i\'('ly
~>('r{'h't l intu tilt' tubular IUIIII'II (see Chap. II , E limin at ion ), At t h('~' do~'s , secrenon
sllows eouce -utration d" I)(' lLdt 'II{'(' and , ;l'i a {1 J1l'il 't l llt 'II(1 ' , tln- ..\ L'e in('n ',l'il"S d ispn lj)tlr-
!iollah,ly \\1111 do~ ' . Tln- hody ('xl)t)sl1 n' to th e d l'll~ and tln- hal f-lift, a n ' t1isp m pol1 iouah,l)'
illt'n';L'iI"t1. ('o llsid t' ratio lls f(lr tln- tlll'fa l)('lltk ll'i(' o f la r~(' t!ll'il'S.
St"t.'Tt'lillll uevr-r oC:('Iln; alo ne : filt ralio n is ahm)'s a {,(llupo nl'll l , a nd p;L'isi\'(' n-uhsorpt iou
ma), or may 110 1 be. Fi j.,'lm' 22--6 also rh-mons tr an-s how lilt' mle' o f excn-tlou of a d ntl?: t ha t
Illldt 'TJ.:( It ' S filt m tio n a mi 'iI,{'Tt'l iO!l, slIdl iI.'i I)('n id llin. a lwilYs int' n 'R'iI's with pJ.lSIlHI t'(lIl{'('Il'
t ration. E\'('II t holl ~h tln- rate (If secn-tiuu appmad,('S an Ur l)('f limi t 11.(' rate o f filt rati o ll
(1ml in Ul's 10 in('n ',L"'" d in "t1ly \\i l h llllhllllmi plasma coucentranou.

t'lw:, ss-e. 11,,· r. I,· " f n·"..J .. ".. -lie." I"", ,, li"' iti""
,al,..·. t1..' Ill. ";", ,,,,, 1""'''I'''rt ••'" ( T v ). wi..·,,·., t1...
r. h· " f lihr-.lie." irK·" ·. ..... i" .li" " 1 1''''I:'''l1ie'" I" II..·
1,1. , ,,,,. ""u ·" tr.lie,,," ( ,, ,Imw:. t :" " "'''I''''''I ~-, II..· ' " h·
, of ,·,.....-lit... " f .. ,I",,, ,I."" i. !.",I.lil.,·",,1 ",..1..",·..-1,,,,1.
I,,,t ,,,,, " ·;<1",>ri,,,,1. i .., ..·;< "ill. it- 1>1..."... ''''K'''''' ~
Ir;<l it,,, _11..• irK·n ·. .. ·. I ·•. i' ' " '' i" ,lin,,'! 1"''1:'' '''
Ii"". I) m", i, ,·ill..·• ,,,,, 1." uKI i" 1,1.." , , or fu ".",.u".
(" ",I.." t 11''''''1:1''>1,1 II..· r.lll(l · "f 1'1 ",,, '.. ' K....'l r;<·
lie.""

Plasma Drug Concentration

t·lw:. 22-7. It..,,,",d .·..r-...ll"· o( elil"",....i ]]in.;<' 150

""·..,,,"..I l~ .-\to . I." n :. i' ,10,,·..·.....,,1f"IIo"",1"",
;< 2'1: Lv. ,I.",. •..J.d i.... I" II"", , ~ ",·.\t"I .rh·r . • Renal Clearance
.·'I"""·,... 'K.·
1'1:Lv . ,10",,·. 11..• I ,·I0·..... i' ' " '' ;<f .
(,,,1,..1":--,I....... Salur-..J>l.· " "T!-tie.., of ti nt", illl" T o Extrarenal Clearance
till' ,, ·nod 1,.1.,,10· ••">I..i,,, II..· ,10·...n -....• i " .. ,,,..I 100
d ,·ararll. ·. ....·;UI :t SU (h.m >(I "' WI. - 2.1
lI " l l, d >. I.. f",,,, s.."r•. Eo ll ,..I \ b llit·. II .:
Uil·I" ...... i]]i" ;u"l ,·Io"' K1l1in: 11 n""'. >I<i"' -til...
i " h,'" lll'r <I" d Ilt·" ....l i<lI~ .h . uhj.·{·h , e li"
T
11.;< n " • • >I, n,,·r.. 2t'H1'>...\l"' . 19';'n,) 50 T

o
CHAPTER n DOSE AND TM DE PENDE: NClE:> 403

Heual l'!t'ar.ll1t'l' is til(' mit' of d m ~ ('!l.:l'retioll di \idt'tl by its plasma l"(llll"('lltmtioll . :\ d m ~

Illa t b o nly filtl'l"t'tl. am ! is 1101 houut! ill plasma. has tln- s ame renal clearan ce at all ron-
cr -nrrutions. as sho wn sdlt'llliltieally in c urve :\ of Fi ~. :22-Ji. Cu rve H d t'p id s tlu- t...vnts
Iha t occur fur a t1 m g thai is adi\'t'1y st"t'rt'!t't l. I n tilt' r('W0 1luf ph~lI1a l"( llIt'l'ntmtium wdl
Iwln\\' tllost, rt'tl uin 'tl tn appmaeh saturat k m, n-nal clearance is lIi~llt'st alll ! is « 'latiH'ly
iust'usitin' to dmTlgt's in d m g coucentmtion. T Ilt' t!l('mpt' ulic concent ranons of mos t Ole-
Ihdy st'(,rt,!t't l d m gs [it, s\i t hill t his « "¢ nn . :\t hi~h('r plasma roncentratious. n-ual dt'llnUJ(."('
t!t'(Tt'a Sl's : tlu- low(' r limiting ',11m' is tllat l"( mi rillllft'ti hy bot ll fihmtiull :Uld passive n-ab-
so r ption.
TI ll' n-nal l'!t'ar.lIl l"('s of aSl"(lrhil' add. di sopyTillnitil', am i till' pron-iu sllpt.>m :o:itlt' drs-
1ll1l1:Lst' a ll ille n 'lN ' \\i l ll illtTtO,Lsing concentrations, hilt for t1 ifT(' rt.'Jlt n-ason s. Ascor bk- add
{vituuun C ) is 110 rn mlly t"(lIlSl'f'\"t't1 in lilt' hotly hy act ivt- n 'a bstl'lliioll From tilt' re na l t ulmlc,
\ \ 111'11 tju - plasma l,(IIl('('lIt ral io ll is t,\et'ssin', rlu- capacity of tilt' reabsorption nu-chauism
is (' \("('t'tlt'tl. :111.1 l ilt, vi t amin ap llt°an; ill Ia ~(' amou nt s ill tilt' urtne ( FiJ:. 22--9 ). T it.. con-
S('(IUt'lI(,(' o f uonhnear eccn-tion following «ml achnnust rat ton of \i ta nliu C is ilInsl mlt'tl h~'
till' da ta ill Talile- 22-1. Althou g:1t stiltb tim lly si ~lI ifk·.mt , unl(' that tl n- plasma roucentrutjon
tlOt'S 1101 iucn-uw III1Id i r-vr-n when 1Ilt'g:adoS('S art' gin'lI. Al1otl lt'r Ilfllllillt'ar nu-chauism
a lso l"( lItl rilnjf('s III Ihis ohwrvat ion. Tlu- hioavaila bility of the vi tamin t1l"{'n',LSl's \\i th in-
ert ';Lsill,l! tinS(' ( not Sht)\\111 ht '('alls(' it is ahsorht'tl in tilt' iutes titw hy a saturable P« )("('ss.
11u' l't llnlliTlt'(1('fTt"ti Ilf s aturable ~,L\ t mi ll!t'stillal absorptiou a nd « '11:11 tubular rt'a hSlI'lltillll
is Iha l olll~- a n 'la livt'ly small e!lallJ:I' ill tln- stt'atly-s ta tt· pt.L\IIJ:l ("()lJ('('l ltmtiull occurs. t"'-('11
when tIlt' daily u ral dnst' is illl'rt'iLst'(l g n 'ill ly,
Hat lu-r t han ' atllmh lt, n 'aIJStI'lltillll, Ilouliltt'ar hind illJ: 10 u I-;Ki t! ~I~"l,( lp mt t'i ll ('<lUst'S
n-nal dt'M;IlIl't' (b:t.St't! on tolal lUII('('ntmtion) u f t1iSllp>T.unitil o to 11(0g n 'alN at earlier unu-s
after a 1.5 -1l1w'kg: i.v. tlUSt' ( Fig:. :!:"!- IO:\ l. Unbound n -nal l'!(,;U':U1('(', till tIlt' ntllt'r hand ,
shows 110 (,\i<lt'II('(' of 11Olllillt'il rily ( Fi ~. :!:"!- IOHl. 111t" ~rn'at r-r tota l clearance l'tlilleitit'S with
a Ilil-:llt'r totul couce-nt ranon a llli a lo' \"t' r hi nd inJ: (/ " T) al earlit' r tinu-s .
T ltt, lIo lllillt'a rity In n-nal d l'a ranl,,(' of tilt' experimental p r otein d nl J: superoock- d is-
lI111t:L't' b n 'latt'tl ttl n -nal rlit'f;,htlli.'lII ( Fig. 22- 11). This protein. p rolt"ti in ' ag:ainst ('(,II
injury tlMt is tlllt ' ttl 1l\~W ,It -dt 'ri\"t "( 1 frt't, radicals or sUllt' m :<id t's, is Hlten-d and tln-n pa rtially

c
Plasma Drug Concentration Plasma Drug Concentration
H I>:. 22-'1 . 1I,-1.,'i"", loil" 1 . 1',, ~ · n '1tIM'r ndt· "f " l.l: n1i"n (,," It·ft) ur ",',uI clt-.tr.u.. 't" (u" ri(l.1) "n.l l,la" "a
" MM.·" lr.,li"" .1<, .·,,,l ' M'who·,I,,·r ,I" , .Iml: ",..It ' I):IW"lo fihraliull 'M'~' « ~u'\ .. ,",), fihrahu" ",MI ..........-ti,, " « ~ "" . li l,
"r fihratiun ",,,I " d i.........1.... ,'1" ;,11I « ~ , ,,.' c ). n M',lmR i' ,'ill,,'r 1M" 1ltlt1lMI lu I,ld\l' ''' pruh~ns. '" I" d... ~ n,1I
,"""" I..~ ' i" 11M' C' '' ''''" l r" tou '' r.Il'I:' · , 1M," "
... oose "ND 1M DE PE NDE NCIES CHAPTEi! n

n ". 22-.., . ..\ . 11.." n -"",I d.·ar....... ~· lOr ..." -",,hi<:

..... ! n·Lli,,· I" th.d lOr i""Ii" i',. ·n- ·• ' Ir~ "'.d ind ~, at pLa""...
n ....... ·"l r~h..", ....·11 ah,,,,· tI..· ,;d" I" ~ I" I.'; 1I1fVl. l~l'i.:",1 fur ,..,no.... ,bda~ !ll.."". ' 1..· ;1I.:n · · ,,,-u,n
. 1l,i..:I"'1...... ,rhio: ,.;,11'1.." " "" ·"t r.<ti..". 1.."(;<"...• tI..· rah- "r fillrail.." .·\<,~ ..I. II,,· ''''I"""i ly "f tl..· f iltl,",',.)
1' '' '''1'' '11 ""'t~ •.",;"" t u n·~h ,rt, .1,,· , 'il,.." in fn"" Ih." ." hub . 1""" ,,,..\ 1 I.i~ , .. "... ·" lr..I" "... tI..· n-"..I d. ·..r.....~·
"r .".~ Irt ...' ·.. ,.1;l1'1'"_......' hal "fin"lm. a••'IIlI ",,1 tI...t j , ,,"ly Iih,·n~1. 1',,' 1"j.,.h (....Ol.~ llr.d.."l....' ·" , pl... hl(, ..1
f, >I ~ "';,,1: i ,' "' ;";'"t""" IIf I.')IJ) I" NU l "'I: .. f ~".f,;(. a<i,1 (I ",~ 1. - S" JI M'. (.\ ,1.."(,,,1 frum KaliL EJ'.,
F n.~ I II ""' . ( ;.J . " ' KI Il " I,," . , II .: n it· "M ·h..,,,,,,, " rtl,,· ' "","TO'I,,", "r , ;t... ",i" I : I~' II", I""" .m lit ln•." J ChIlo
1"\0.. 1.. I;",';'fi~';"';'n. I·WI.l H. I" II,,· I'lL, ,, n"K~·"lr...lit'n rdn." n",,,ltt"l: rru", , lail~' "r...1 ,~ '" "f .1111" 1"11 "'~
.,".i.·..
n ""'/ d.·..r...'... ·..r ..... dt! r..w" .. rrum ,1t~ ~ "" 'I " -4 I"" ", 1/ " u" (.1 1,, 1>'1 "rtl..· .·,1"...1 1i"ulin (·" ·..r"" I(~)
ill 22· I" n.~.·." ."ltl " ,...]" ."1>'.. 1. ",I,ilt· "" ,1i'1. " \" '"li;J l~ rn~' "r ,it.""i" c. t ·I, ~1It 1 ",1 1 ., . 1n' m... ·ll h
.• 1:'''''1' "r ,,,10,,"1' , h" I....1 i" ""......I..·n" ..·" 1 "'II. ,IifT,·n·,,1 i"l..l ... lOr .......r\,i<: 11..·' ,L, . (.\ tl' l't.. 1 r"ot"
t,:;JhM·r. .\.• l l..rt""""" . I) ., .. ,,,I 11" ",;( . 1>.: STt-"'~·" I ..... h,m""'r ...,.. I I " " I~ IU~ "r ,rlo;.· .M'it l ill "'"". ,\ Ill, J.
el",. , ..Ir...12)).1tJ-..'i."hl. l~~, f

,.hl. 22-4. It.tu.yaS , It PI_•• AM..... I. A.hl Ce_ _ tratl_.I" "_Ithy

AtII.,1ts 'akl". Vari ••• D at the VI....I.. Twl•• Dally f.r , fa 4 W. .k,-
PI.ASo','... ASCOR'8IC
A.Ctl CONONli(A1'JOI'<"
!""l-'U

No ~lary <be. 6 wbje<::b

Do,Iy d.elOry '"lale cJ 50-75 mg expected Q :!:. 0 6'
') I 10 J g/doy I I wbtec ~ 15 4:!:. IOd
J 810 1') g/doy , 0 ~e<::1S IQ5:!:. ,) Q'J
"~~ v." 1.'- {S Mog<Jdow ~"'c """'"'" ........,. """01<0'I><: 00;'; <Y<i' ........ OK(.t>o< occl _ ," """"",,.,...j ~
"'""' V"Jl .)(HQ1-e.o, lQ1l4
·'!ll<:o .ilO""Qloo1"''''_''''Il~'''''''''''_
.""'" , ~ ..... 01"""""
,"""'" I",,,,,,, d ""'"'" """" 9""4' I

Ilw la l" ,Ii:t!"t1 in II,,· n-naltubular {... -lls. All li,glll' r plasma ("''' I(~ " I,lmti llll s , nu-taboli..m of tln-
lilh"n "tl d nl ~ hl '(111T1t·S " Itllm b ll' "itlt " n -suhaut ill('n',l-\(" ill n-nul cleurmu...', an o!l'il')'Yil!i1l1l
(111111ItOllly n-portcd fo r o lllt' r p mlt'ills o f (~ l tl\ ll;I rahl t' Si7!' . ~ olt · that 111I' ap p,lrt 'll l IIp pl ' r
limil o f n 'llill d(,i1 r.U1(~ " (·10 m l. / Illilifj{l k ~) is Ie, .. than Iht · ~1()II1t" nl la r filtration rate, a
p mbabl,' ('(lII'i1'lI"t" llt"'t · (If rill r.llioll o f IlIi.. p n>lt'i n bt'i ll}{ illm tn pl d t· 11('('a ll'il' o f its la~l'
1IlI IIt '('"br ,i:tA' (\ 1.\ \ '. = .1 :2.(11 11 ) ~l ll lllt· ) . :\ItIUlll!-:h 1111 s!I("t'ifi(' ('llt -OlT ill IIlo1t'('1I1 M Wt' i ~h t
run II(' ~H' Il . filtration of p nllt'illS ahll\(' 3U.lIUO Wmo ll' falls niT mpnllv \\ i l h ill("rt',LS ill~
muk-cular ,i:tA·. :\ 1,,1\ '1 ' ";'H.lIIIO WlIlo ll·. u n ly a sma ll fr.1l1i o ll is filtl'rl "tlt''\("l 'pt in ~'flll lt'n l ia r
. li'>l ·'L'iI· (SI'! ' C hap. II. Elnuinariou. p . I ";'S).
CHAPTH 21 oose A1'.xJ TM DE PEf',,()fN(lES 'O.

A B
80 2 240
~
~
§.
~60 •• ~
y
180
§. ~

~
• ~
• • O'!
.
y
c 40
~ • ~ 120
~

<'i • c~
-a • a:
c 20 ~
60
~
,
c
'" D
0
•• •
0
C
=> 0 • •
0 200 400 600 0 200 400 600
Minutes Minutes
t'". t Z- l O. .-\. n..· n..0.01 d.·....... u · "f t1''' '1~T'''''''''' i" ,," tn.h" .I"..J .,, 10;'''1 .1......... d ....,~ .. "11}, I", ..· ..r'. ·r ..
o.i'~ ' 1.5-,,<W11o: i .'. •\< H. 11,,1"' 1I,,1 n·,0.01 d.· , ·. 'N, d..• "tI"'r 1...,,01. •\<. ... ""1 1 ,..· .... I" d ....,I:l · ""., II,,·
(l ......... , li ,,( Ii",,· 1,,· 1, 11..· i"ilo.ol pL-."... n l ·"' r..li.." . 'u' n ' i" ' h,' """1:" ..f :2 I" 4 mWl _ n....· I, ~ ;a\
n • •n '"lr i... " .. n ' "'1""1 1,,, p ""lun' ,....,I" ..·..r ,", ..1",( I" u ,·......1 ~1..'1"'I(<1 " . II 1>1'1 1(<111 III "hid. Ih i. ,lnl l:
prim..'; ~ lli,..l. in 1'4."", I • (;1"'1" W. l)i,I'; h" li. ".) II mj',lL - :2~ ",\ 1\. \ \ I". lif 1 fno'" ( ;;". " " i" i . 1.; ,\1,.
s.. .,'. S.E.. Tu" ..'r· T..n ,,~ ,. 1.; ,. ......1 li4,,-I, ~ ... Tj ;., n ... ..-Ir,...1 (If ... Iu....hlr 1",... b"l: I.. 1>4,,,,,, ,,,",1(,.;,,, 'N' II...
pi nn.... "'i'.. l k·lm'l. ·rti<... ,i ,1'' ''1",nlnit \<·, J 11l;<n ,l;or• •~i , ..-!:, 1i",.>J,;onn.. 1(~ 1- 14, I ~, I

06 • t·I" . tZ- l l . \I " n·,...1d ,·.r..,u · " f "".

...", lli''''''1h" ", , SI'I,,·n,"" I.· ' 1i'''IIII....... ill ·
• <-n'."'" . 1hi"I..·• pL.,,,... ,u......"r...;,.." ..r.
• h·r ..n i,v, ,I....· ..f"'"' ",~'kl: i" '.;1:1'1 . ,,1......1. ,
n", ''''1''' ';'''' '''1;<] ,In'l: i. fill,'n ..1in tl..·It!<..
0.4 ""'011"...... 1part;"I~' ",,"al. ,IiIll..I I~' ,,,I..,.
I.r ,...11, . .-\1 I,id..'r pL.", ... 'l""""lnaI""".
,I..· r..,, · "i fi hmh.." 1.II.., ..J"l,t:o "i ll..·
• ,"I.,L,r ..·n. t" ..I
", 1 ". -!:.I . JlI>!' d ...
,In'l: ( I ",~'I , • IIIn l .. \I I. ( \I ,.. hfi.l l (no",
0.2 T....." c . ( ;n I' ,. ( 10011" ..1. Ii , ,.. l lIr..t,'r.
I) ( :.: 11......" n l ",o-t" .. " f n "'. .....,,t 10" .
"..." " '1""-"";'1.' 'i1."'''I....· ill I M ·..JII,~' "J.
• ",,1,"(·" , e l", 1·I...r"';M.,l, 11"" ., .'j,(j" I.J--..
7:211. IW I .)
0
0 250 500 750
Plasma Human suoeroxoe
DismutaseConcentration (mO!L)

HI'Iml d l';u<lIJl"l' m ay a 1"' 1 , !low (')IJ("utratioll dq )j'lltit 'lI(" \\ 111'11 t ilt' d nl~ ( I) p n ..
d lll"l"S dt;lII~I"S in p ll autl ih tubular rt'ah'i(l'llti oll i ~ p ll -tlt'!)j'lIdt'IlI, t · . ~ . , salit~ lah' ; (2) i~
;1 diun-tic ;tllli n -nal Il<l-~ ~ i \(' dt';u,U1("t' i\ How -d ('!)j'lll lt'll l. t· .~ .. t llt,,( lpl lylliT w; er (.1) ea ll\t'S
!It'pllmto\idty, ("~ " a ll alllillo).~l~ '("t lSitl(· , Tlu- lII('"{·!I iUlblll ' o f t il(' tl~t t\\"tl t1nt ~~ a rt' ;tho
tilllt·-tl(1)t'm lt·lIl. 11lt'{lpllyllitll' pr oduces t1illrt""is !;t'IOll aftN its administration, hilt I l l i ~ ,·f,
f('"t1, and ("t lllSl"( !IU'1l11y us n-ua] dt';U'iUlt" . dl '"('n';L'it· \\i th tiun-, Ti lt, 1Il'pllnJlu\ k l'ff,'t.1 of
... DOSE AND lI."AE DEP£NDEr-.c",S CHAl'TfIl '1'2

;lI lliIl U~:I~ 1.' IS idt·s . 011 lilt' ollll'r hand . dt,,-t"!ops wu h ( k~ · 'lIItl d u ral iull uf ( ' \I'I( I\l l rt' to tilt"
( I m~.

CAPACITY·lIMITID MITABOLISM
I't' rhap' Ih(· 1I1C ,,1 drama tic 11t~ ·-(I(·pt·m l{,ll ' kim-tic mechanism is that IIf ClI1Ji,rit y. /imit("(/
mf'laJ,..,J iml . a (·har.u:h- ri, tit· ~"pi{"".tI u f (' Il1)lnalic n~dl.1ionli. Rt'(Ol.II (mill C hill}. II (F.q. I I)
,lid!

Vm ' eu 5
Km ... Cu

Vm
6
/(m ... eu

11K' "'lllial and therapeutic ('UIl ~'f IIlI'Il(" S of \l id lad is-~I {'Il tt-1l kinetics an' 1M' '''' loxp Jo rt'tl
\\; Ih hm (·,.lIup lt-s, akullnl ;,uKI phenytoin.

Akohol
:\t do·••" t1"lI;lll~' ('u nsnlll('(I. tilt ' nn-tabolism of alcohol is ('ap;K.i ~·. li m i ll-(1. r\ h hflll ~h me-

l" bnli ZI..1 by bnth ,Ikulllli dt·hydn~t' Ila..;t· a m i l)1od m llllt' P4.'50..2EI, lh t' (·liminatioll ki-
n..ti l'S of "kuhn! h,lS 11('('11 appm dmalt"t! b~' a ~l idlad is - ~ lt' n h'lI llIu l..l o f a ~ill ~ll' t'HZ)11lt",
11.i....illl plificoc i ki.wti(· IIlllclc·1 i ~ ~ 1I 1 Kl."{ IIU·IIt1y p resented.
111l' m'l\ iTIIIIIIl rail' u f ''It'f;llx ll i~lll . Vm. 1.1 11I1 till' !\l id .;ll' li.. constan t, Km , an ' apprnxi-
Illatd~' 10 ~h r and 100 mloiJ-.. n.·..pt ~1: i \l·ly, 111(' phanll;.( " ll()~i(· drc '(1~ of ak n llnl. which
dill·.. IIllt hi ntl til ph ..mu p mki ns .I)("{-'o llll· app'lIl'nt when till' pl'L'In" ('Ulln'lItra tion i.. a bout
:!O() IllWI.. (..JIl(... -ntruuons ahll\'(' SUOI) m w L an ' potl'lIti,tlly It'll. al . Thus, the n lTlt.'t·nt raticlll
r.1II ~C · in wh id. akuhClI l"(I'I1.. its phanlla(" ltc ~"il" effec t s is w..l l aho\"(' its Km,
Tahle 22-.'5 show.. tln- m k 11lah'( l mh oo f metab olism and d c·;mlllt.'t· of ak'n ll,,1 a.. a func-
tion o f c11l' (..IlJ( .. -nr ra tton at tile' nwtalxllic site. :"\oh' Iha t ran- o f md al xllisCIl o f alc"llIol is
c''''il ' Tl t i a ll~' r-on..taut, ze-r o-ort h-r. and d cKl.· tn \ '", t llnJll~hClIII rln- r.III.1-':l· o f (..lIIt...-ntmtton..
a"'>( )('iatc't! \\;111 ad i\"ily. :\l'<-" In.liTl ~I)'. dl'arallt.'t· decn-ases at hi.l-': II ('Hlln'Tltralio ll... At low
(1J1l1,,·lltml illll". tlu- intrinsic dear.U lt.'t· ( \ '",/ KIII ) approaches I(MI Lzhr o r 1.6 Lznnn , a v alue

,.1t••22-5. Ce..e........... ef M ......II Cl_ _.... ef Ale.....

•• • ••INtI... ., the c.ne.,,"""'." at the M e fI..
Cor£ ( Nl U .I QN
AI sm:
.... " 7000 QQ 14
5000 Q8 20
3000 Q7 32
1000 Q 1 QI
50) 83 17
100 67 33
100 SO SO
SO 33 67
10 O QI QI
'9 _ 01 _ ~ . ' ~ c». .. . Coil \ ~. 10 g/'" • .,. 100 "'<).'1.
'C ~ ~
CHAPTf fl22 DOSE M'-lO rw.e DEP£NDEN()ES ..,
in l'X<:t'SS u f I\l'pa lil' blood lIow. TIllis. ut n 'l')' low ('UIl('t'lltra tiol\s. tln- t' ~t md ioll runo is
su ffidl·ntly high so thai tln- rate of rm-taboltsm is partially limill'l! by Iwpalk 11I·rfllSioll.
Under tln-se ('u ud itiol\Soml hioavaila bilily is ('xl)I't.1('1 110 1)1' n'lII\('('11.
The ('1l11st'llllt·IU1.·S o f zero-order elimination can hI' d r..ll11atil'. TIll' usnal -si71' d rink, ·I,'S
111 1.. o f -Il)ll vtv whiskey contains about IS 1lI1.. or 1-1 g, of alcohol. nri nk in ~ Illis quantitv
of alcohol r-nch hour l'x('I'I'Ils thl' eliminating ('al);.ld ty of 111I' IMMly. Co n"' '1 IIlt·utly. al(ullOI
accumulates uu til ulttman-lv ('il!tt't coma o r death tnterwues .
Ak'Oho l dislributes ('\lml~' t h mll~holl l total IMMly wan-r: its \n lu uw of t1ist rilmt ioll is
Ihe n ·fon ' -12 L, Al'l·'Onlingly. app m'li matd y 201.1 g of alcohol an ' m...... h-d ill tilt' I M Il I~' to
a(,hit'\"(' a ("IlIl(, r-ntranon. allllllt ,')Ul)() IIIWI.. thai can pnllillt...• (11m" o r, ol't';lsionally, t1l'ath .
But, sin(1.· llw m il' of ingestion , 1-1 Wh r. t·.'l(1.'1'1ls 11ll' mh' o f nn-taboltsm. 10 wl lr, by ull l~'
-I W'llr . this rate o f d rinking mu st Ix' maiutained for at II'ilst 2 da ys (a Inial of -I.')drinks] to
accumulate 2()() g of "I(u hul. T his dl'gn...· of accruul cnnoccnr \\i ll lin :) IIr (21.1 d rillks) wln-n
four d rinks are ("IlIISllIIWd ('\'l'I')' llfmr, lx-cau se thi s rate o f ingestion , ,'>6 W'll r, l'x('I'I'Ih 111I'
maximum lIwlaholie (oupad ~' by -16 w1lr.
If tln- mte of ingestio n is n-duced tu one-half d rink (nr ': W11r), 111('11 , ....it ll rt'slx'(1 In tlu-
('fT('l1 of alcohol. mn- ca n dri nk \\i lh virt ual impunily ;L\ Ill)\\" slJ()\\lI. By t1I,f;nilion , of stt-al !~'
stat e. nih' of l'Iim;natitln matche s mil' n f administ mtillll (or Input ). R",

Vm ' CUll
R• ~ 7
Km ... CUu

or un n.·a rn.m ~l·lllt ·ut

Cu.. - 8

Using tlu- prl '\iollsly ~\'(,Il values for Km am i " ", am i au It \'11Im' of ': Wllr, till' plal l'au
concenr r anon o f al("Ilhol is 2.10 IllWI.. wlJidl pnlllu('('1! o llly a ma ry;nal l·ITI'l.1. .
Hl'lll'l.'l 011 1111' calcularions alllin ', Chn lllitoully illl hihin~ one-half a d rink IIf whi sk,'Y1)I'r
hour pmdlll,('s hUlt· or uo d Tt"l.1 . hut lakill~ mu- dri nk pl' r lronr 1"It,("IlllJ('S It"l hal . , 111'n ' m il
Ix' uti stam Lan l t111S';I~I' n-WIllI'1I IfI malntaln rlu- t' ITI't.1.s o f alcohol. ~ l a in tt ·!MIl I1.· of t' ITI'l.'t
require s titmtion of t1usa~l' 10 rlu- t'ITt'('l ilst,lf.
T Ill' l'(lII\l·fllll·ll(1.· of ("1lpadty-limitt'll uwt alMllism 011 tl l(' till\l'-i,'tlIlN ' of a d n '!-t ill tilt'
IXlll}' wln-n inp lil mil' is d lan~I "'! is also dt' lllllllslmh...1 \\i lh ak1.11Iol. \ \ 1u 'lI ak"llhol is ad.
ministt-n'll IlJ m ill afn-r i ll~t'still ~ W11!t'r, light en-am. or 11 ~l ll (,( lSt · 'io lutiou (!':if) w"2-1f) m l.) ,
tln- plasma coneentrunon-tinn- pmfilt'S difT('r pmfollmlly (F ig. 22- 12). Co mpan 'll to wan-r,
aduumst rat ion o f li!-,:Ill ('n ',1lI1 and 3.1'-" glu('(lSt" fluls tltat dd "y ~,lstrit' t'm pt~ illg, Ill\\l 'r
bot h AUe allll !lI'ilk couceut ration and ilwn ·llst· ti uu- 10 reach the p -ak. ' 1Il'st' ohst,!y ations
t"1111 Ill' ('xplail\('11 by lilt' lIt'a dy 71·rt!-Hn IN ml'tahnl islllof ak u llo l. To l·mph'ls;:11' 111(' poi nt.
ll\SUlIW that bot h l'1iminal iou an d input M (' stri{'ll}' jO'.{·rn -o n lt'r, ll' S!tIM1l in Fig. 22- 13 .
1>1'l'n',l,iug till' inp ut mh·. fur a ~ \'t'll lotal doS(' admill;sh '(('11, 100H'f'S ,,\ Fe am !!lI'ak ('( )II -
('('lIlmtiou 1l\ ....l ·1I ll' in('n',I""S tilt' j'l('ak timl', C II'arly, IIml hina\1lilah ilily ill tilt' pn'w m1.·
of 71' rt!-tl rd ('r (,limiualioll alit! \'Iriahl,· inpul mlt ·s l';UlllOI I'l(' il''''OSs('l1hy l'lmn' ntional an 'a
mlio UI('t1111l!S.

Phenytoin
nlt'nJl'I('nti(' p mhll'm s t'nl"lllllllt'rl'l! \\i lh t"1lp,It;~·-l i m i ll ...! nlt't al lllliMIl ,In' d ,ls\ i('ally I'X-
('mplifit'l! hy p lll'nyt llin , T}v;m l "m aw l Kill \, llll('s IIf this d m~ an' S()(I IIIWtl;ay anti OA
mgll .. alt hou ~1t tltt' \';Illltos val')' \\i tldy. TIlt' valut' of Kill is USll;tlly l'Xpn.·sst...1 in INIll S uf
40' DOS{ AND TIME: DEPENDENCIES CHAP1U 22

BOO

~
E
c
600
0
.~

E~
u
c
0 400
'-'
0;
~
0

"ro
E
~
.ss
c,
200

0
0 2 3 4 5 6 7
Hours
nil: _ 22- 12. :\ ,Iwn·......· i ll th.- :01 ,'11'1;"" ! ;llt- lOr .. k~" ..... p"..lun.J t~ ~I< ...i,,~ ~.hit· " 1n I'I~i l~ (,."..... ,.....k
lUIK~·" Ir.dl"n\ '" I1 I.·\{ 'C I" ,.... -n."' ;u,,1 ti",,·,..",;..·1, th" I"'a!< In i' ll·,.·......-. 11 " , ..fT' '''1 ' Iiff..... ' m ill 110" , "\1""1.1•..1
of li",'.. ",Io·. 1o;i".-Ik-. 10:-' tI..· , • ""'1 ,.."'." ."'.... in .-4.t'C. l1,i••" ....•....OIli.." b ..\ p IOl.i, 1 lor .. l,,,..., .. ,, t ml o' of
,·Iimillali.." ;d ;11 m'.. ' all 1\ ""~lI lr.. li<.." . .., i11l1, lnaI...I ....~ ... "'"ti.....IJ:., in Fill:. 2l- 13.....10..1" 4.'> m!. o(\:l.')'l " 1...... .1
in lit) ,til . of "''''')(I'
j ilin' , \\;0., ""lmini.,.." ...1 IU min after 2o¥l lllL " f ldl' .. " h', Ie); 2-4l1 ,,,I , of hll:ht (.,....... ( .);
' ... 24U ",I . " f a 3.1~ )til..' ...· 'I<.I" IIc", 1.' ()
"' WI• • ::u.n I.l ~l l. (1i 1,_1, (rnm ,lat;/, o f s.... Ir,...m. A-J.. \ \ 'jl].:,hU' ''l,
I' " . S..l",... , E.. W•.;.II.·, . Il J . ;u ..1 W"'I:'''''. J l:.: F.ul .·ff....1 , "''''''1>1i"n ..,..l nM1.u.. oIi'''' "f akl .... oI. Rl"-
llrinh l l l~' I'mn u..'iI .." fru 'n Ju" n1i1l of ~ I IIJiI-' un Akul "oI. \'01. 37. 1'1" 11lr.-1 21-t, Ilr.fi, C"'1':'Tld ,I I,:,' J..umal
"f SI"d.......] :\ 10.,01 " ,1. h M·.. R"I ~'n l ~."",. ur :\ 10.. 01..01 SltltlH.. . ~ .....' Bmn.wkl. ~ J (J';!JIO .)

•' i lt. 22 - 13 . ,h a tl U' ''·' I,U'n.'C' of ,('.,,·o n l,·• 1000

.·li"'i'....l iI..,. II..· 1,L.., n,., " .....l ·lIl rnlil.. 1' .cI II..· .·,..1
A
,,{ a .'ill-Io:, , ~ ..... " f a .\m" I~' 1..01". i" ;' l 1i.. " lM ..,.,,1
....,. I"", ·,..t!.· i"f",iI,... of I _ (lil, 2- lC). ..,..I :}. II) ,
.,;
I.. ,I" r..Iii"" an ', I" il...Iiff,·n ·nl fn ,m ,h. ",· "11.."(1...1 S BOO
""11, fi...H.n~ · r lil"'I"",,, n..·..".... u.. h' tI... I....~· ..1
C
g
Ih. · .·,..1of .·.It·h i" fll'io.., i.. II..· c1iff"n" MT 1..1"' . ..·n
,Ie",· .1, .. 1 .." ...." ,1 ~"" ,I"rinl>: Ih.· illf" . ..,n 1...",..1. ~ 600
~
( ;,.." . ..\...·,,11, ·. II... .' ........"1,.,"....' at tI..· .·,..1" f .....~, u
c
" f II.., ;" (".io",, i. ,10,- loa"". ... Ih.., ."1....1."(I;d ,I"" 0
u 400
I" ,..· f"I ~",,; ,,1t tI..· i.". 1..01", ' ~"" . ~,>I •. Ih.ll ,I..·
'~"" 'r II..· " '1'''1 ,....... II..· , 1tI.. 1~ · r i. ..\ I ·C .....1 110..
~"",. , i' p'·.. l ......M..·nlr..l io.". n ..· tinM' ,.. I" ''''' i . ... f
....11.... -. i'...-n-........ !. Fllrtl"·n ", ,rc'. if II,,' ,Ie....· 1....1
-
g
~

0
ro
E 200
I....·u 1I1(n.... 1 , ........ .')·1,. 1" '" " '1. '.t'.. al III ~tr .
~
~
0:
'''' 11'''1",... ,1,1 haU' " ",ld"..1ill!" ,1a',,\ 1I" 'n' ",. ..,Id
h..... I....·" ,.. . .-\I "C ill Ihi' h~T"otl "·l io ...I ' ·""" " I'It·. 0
0 2 3 4 5
Hours
 ~E AND1M DfPfNDfN::t5 ...
total. r athe r than uul xnutd, enux-utranou. Sim't'/1I is t)11il'ally 11. 1, Ille appan' nl Km for
tot al conc x-ntration, K/II' , is equal tu -I mg/L,
Pl ale au, I't'rha ps tilt' mus l st ri k i n~ n )IJst"( ltIt'Ill't' of tilt' kindk'S of this dnJ~ is 1111"
n ,lal innshi p nhS('f'\'I,() between s lt'ad~" s lah' plasma conceut mtton und m it' of ad minist ra -
tion , ,1-'1; shown in Fig. 22- )..1 . .-\ ~n'atly tlisp m pu rt ioll;IIt' illl'n ';I-<,(' in ('tlllt't'nimiioll is oj,-
S('ryt'l l in, ;tllli ;thu\'(', lilt' Iherupeuticcom-ent runon Tilllgt' , 10 It, 20 IllWI~ As a re sult . tilt'
di lTt'n 'lIt't' Ilt'h \·t"t'n till' d aily dust' ~h i llg inelTt'(:t in' Illt'm!lt'lIlit.: couce-ntruhous, h-ss thau
J() IIIWL, an d Ihal p md lldng pOll'lIliall y tox il' I"'( JII1"'("lIlmliollS, ahm'(' 20 IllWL, is lIarrow,
TIlt' ""S('I"\·t'(l lucn-ase in t'tJ!lI"'( 'n l ratinn 1~1II IJl' t' xplai rll'd by n'amlllgt'lIlt' nl of E(I. ~.

TI lt' ('tJUS("tjllt' nl't's o f \l it'hat'!is· \I t' IlIt'n mdaholislll n-sult when either the dt'Si n "ll s!t'atly·
stafto 1I 11hu llmi (1J1l(1'nITiltioll is a boo\'t, Ksn (Km' fi,r tut,,1 ('tlnl't'llt ntliun) or tlu- mit' uf
mlllli nisi nilio ll n-qui re-d 10 adlit'\"(" tln-se- l'Olll't'utral iu lls app m;ll'ht,s \ '111 .
Bt"(';IIISt' of ils kiuetk-s, unly slllilll d .,mgt'S ill plll'll~1nill input t'allS('(1. fu r example. hy a
d .;\nge ill s elt form (ad d an d sodium salt an' u S( '( 1) o r ill hiu;'I\'.I.ilah ility can pn"llIl,,{' n.lu-
!in ,ly la ~t' (:ha llgt's ill lilt' steady-snue conccurrunon. Tu illmlmlt' this poi nt , ('tJ!lsitIN a
mal e patu-ut « tt h K/II' and "ii \'allit's uf :l mw L ;111(1 ·125 llIWduy, n 'slll"(iin'!y, OIl\(1 wl.n
has an ;I\l 'm.gt' sh 'ady,stal t' l'tllll't'lI l r;lti"n of 12 IIIWI. " I.t'll taki ng 2nu Ill~ umlly I'\l'')' 12
hr. 0 11 s\\i td lill~ from his current dU"'I~I' form (hina\';til:thilit\" :: Il./iS ) to mn- wi th ;\
Y,
hin;\\';lila bility of (1.9.5, it is seen, bv Sl'tting R , :: F , I)lt in Ell . that Ill(' a\'('m~t' sit-ad\'-
I;'
stalt' l1JllI't'lli m lillli is t'\I)l"(,!t"l1 to' illl'Tt',I-'i(' 2') TIlWI.. TilliS, a minnr d t;lIl)!;t' in h in;I\·ail.
abilit)' (U.S.5 In n .9o'» ) (,lU S('S a major <:I.allgt' (12 to 25 ) in tlu- s h"ad~'-s lal l' t'tIlll't'n l m!i" !1
when Ihl' dosin g r.lf(' app mad w s tlu- \ '/11 \';IIIIt'.
T illlt,' 10 Pllllt'au , B t "('llll S(' o f l':tp;.l('il ~·-lilllih"(l IIwtah"lislll , lilt' nnw III n ';,(t'h Sftoiltl~·
stalt' \1lnt 'S wi l h li lt' ran- o f ,ulm inisi mtiull. Figll Tt- 22- 1,') shows lilt' ap pmil<:h In plntenu
du rin g (';,wh uf fuur dosing mit's, whi d l hlt'n';l-st' hy small lncn-meuts from :lon III -12.5
Ill Wt b~-', ill a !l<lIit' nl wil l. tH'ie:t1"'II am i Km' vahn-s . ;o\1l!t, thai tlu- !illlt ' to O'"dl HO"l uf
plateuu illl'n',lSt'S pn ~n's sin'ly wi th Il.t' mit' of admini slmliolt. TIlt'S(' d i.sPnJIJl)rtillua ft'
dla ngt 'S in Ilw stt'ady. slah ' t'1II1't' ntratiulI and tl u- li llll' 11" llIin '(l tn n'al'i . them an' 1II'ljor
probh-rns ill uptiTllall~' dosing plu-nvtnin und illlt' llln 'li ll)::: its l'tJlIl't'nl r.,tinns. 1':\'('11 1 111I11 .~1.

m'

Vm
23 4 567 8 9
Daily Dose (mg!'kg)
"0 005E A.NO TM D£PfNOENCfS CHA.PTU n

Fi R. 2 :Z- 1 ~. F"IJ..... i nj( ",ll1Ii nj\lr..· Rate 01 Plateau

Ii"" 11.'-, ,,,f".i,,n iJ ,imOl I.. h·d ~ "f Administration Concentration
I'IN"I~1"j" ..I , u " l a" t r..h .. "r :)I ~ I. ~
25 (mgtday)
.1 ~u. 4un . an,1 42.') Illlttel..v. lht· 0 f-
'~
r io..", .. ",,,,-..,,1,..1;,,,, "PI"""'-'"'' 425
20
".·;o<h··'t"I' >, ..10..", "f fi, ,*.3. I ll . ;",,1
22.- :"'K/L. ..· . I" ·.· l "·,· l ~- 1,'(.lnr,'t!
lo,..·. I. ~, ~ m,h ' .... . tI,,· '1 '~"' ''· .\I ..lt·
"
1l
~
8_ 15 400 f-
.,''' ·'' 1r..li n ,, _ < li'I''' 'I'' 'rli'''' ''h' I~' 5 ~
;,1( "'.. 1. hili '" i' t1 Ii",. , ""I"m..1 °E
,.."1,"'.... 4, tiN ' pl.ll ll . 11..· ..,........ ~ - 10 350
~ >-
;,..1..,..1" Ilw h".., "'I"in..1 til ",,,d , ~
c, 300
!Jll't " f ,I..· I'l.o"."" ,..I,.... 11,,· f"l. ee >-
J.....; ,,~ ,,,,r""""" r ,-".),...,. "',-n- ",,'(I- E 5
~
-1l11WI ~ \ "", . 5U II1IW'l..y:.' ·...ill
10;" , ' , ee
1. 11 ", ~ I . - 4 .lI 11 \ I I. I K<1",.lun"J
I~ p,'r1lli,,;, ~I "r ." ,hli , I..." tI... lr;MlI '" 0 '-
r...... Win' .-r, \I .E" ..".1 T,....·,. T.:\ .. 0 5 10 15 20 25 ~

"10,-"., . ",,,. e l."I' _2.~ . in :\ ppli,-,I Days

l'I. ;o, ,,,..,", ,k;,,.·li.·, : l' d .,..i!' I.·. "f
11"" "' "',,1;" n r,,~ \I",n lt '" " ~ :1,,1
.~h h"n . "hl,,1 I,:, W K E\;tll\. JJ
St~"·" I ~. ",0<1W J I k". l'u"h.I..~ 1
I,:,' '\ I 'I.lio ~ 1 ·n..·...I" ·uli 11..,.• ~I" >-
k..,..•• W.... loi"1{1.." . IW,Z. )

. '1 11:' 22- 16. 0 " .I,,"''fl·.. 'i,,~ tI..· ,Lily,!" · f"",,
2.';(1 I" ;2{lIl mWd,,~ . Ih.,' pi...,,,,.. 1,1.. ·,,~t"; 11 ' ·n·
Imh" " (" l>laim..1 t1ai l~' ;"'1 I..·f" ..· tI... ",,,rninlo:
,1".... 1 ,1"..,1111,'" ...... ·I~· 1",,,,,,1 .. ,..... . '''''"'~' , I.." ...
.\"lI" · 11..,1 .. ~ l'l " ..I".i in tI ..· ,I.til~' .1"..... 1t· I.
I" 'jt l'l ' 'fl·a"· in tl..· ·lIlr..lio.11 ..I , ,, ~'
,I..'" \11..· ·"I...l it..' 'Ol .. I" II I ..fl..r lla\' 2.1 ) 11
"'Wi . - -I UIt \l l . \ 11,.11'>1"" f"",, n.....I",,,..W ,II ..
VII. :1..-1'.. T<o;<\ . J. .r.. l'II I i<·~ . W.. ;Iud I'",,..•. II I '
11 " '''~1''' " : ·n..· ,.....'..1".. 1' ....1:-..•1..'" 1""""''''''''''''
( ;1111. 11..." "... " l1" ·T.• J.~ 1oi22--l\2.'i. lIN 11'1'0 >-
<1,..... 1"" th I,,·t"'i" itll' ..r C .\·. \ 1,.. 1>;.-.)
o 5 10 15 20
Days AfterDose Change

rlu- " ppnMdl I" pl'lh·a ll is usu ally sUIIlt'what filliekt'r nn rt '(ludll~ cl,,'«·s thau n il illl·n·il.-sill~
Ilw III. tt can still talw <I IO Ii~ Iinl(' , 'I.-S ShIM1., ill Fi ~. 22- 16.
I\C'(>;IIL'«' ck-arunce, ami IlI'lIl't· half·lift' . an.' flllll1iul\S (If th t· ptl.-~Ill<l conccntrution. Ilw
Illt·.lIlill!-:S (If tht'''''' pa ram et ers are- losl when (';lpati ty-limitt '(l lIlt' la!lo lislII (l('t.·urs . For t!lis
reason. tllt''«' para lllt' lt' rs shu uld not lit· 11'«'(1 for pn'(l i(:ti ll~ o r s l lll l llla ri7j n ~ till' killt'li t'S o f
d m~s ~ 1 1I ",; tl ~ thi s kind of 11t·!m' ; or. Tht· pant/lIt'll'n of c:liniet' an' IhoS(' o f tilt' appmp riatt ·
lIo11lillt'a r IlIIKII·1(Km alld \'111 for ~l id ..U' l i s- ~ lt· lIl l'n kim-tics am i \ ').
A Ilt"rn l ion~ in ~ lt'I " hf)lism . Anot her tlll' r.lpt·utit>;llly impo rtant f.wl·t u f lilt" kinetics of
p llt'Il)1uin is ahe-n..l mt'taholistll hmu ~ht "hout hy utl w r c1ml-ts ant i d iSt·a.st.· slalt·s. Eil llt"r
Kill ' or \ '111 (',1lI 11<•• aln-n-d. h ili l i lt' t·fTI'(1 U11 plasma ('( lIlt 't'l l t ra l io li is diffcn-ut . Frnm Etl'
!J it cau IK' <;('(' 1\ that the p!ll'1l)1oill ('tlll('t.·ntration OIl sll·.lIly state is d in.'t:t1y p ropo rti on'll tn
K/II' . Thus, a condi tion such a.~ <-'t llllpt'iitin' inhi bition u f nu-tabolism. wh it'h i.lTl't.1s tilt'
Kill ' vulue-, pmduet·s ('tl rrt'sl )f ltltl i ll ~ d l a n~t·s in t1tl~ st('ady-slatl' p ht," )'toi n n mn ·lIlratiolt.
 DOSE AND 1M DEPENDENCES 4"
For t·xalllp lt·, wln-n d llwtidi lll' lnhiluts plwlJ~1 o ilJ Ilwtil holi:;Ill, tlw n ·hy i llt'n',l\ i ll~ Km ' From
-I III6 IllWI., tlu- sh ·a tly-sfalt· unbound and total p llt'lly1o ill t1ll1t't'lIlmliollS an' t'xl)l'(1t"l110
illl'n'il"'-' by 50'1 ux well.
l u contrust . t'itllt'r a n hwn·a.'W· in "m,bnlU.ltht about hy t' n0 11ll' inductiou. nra <I t'(·n·a.....•
ill """ t'illl'\l"li by' tilt' pn ''\I'IIt't' u fl wJlatic drrhus is. h t·XI)t"l.1t"ll to pn M.lllt't· a d hpmportillTlill
l,hall.ltt· in tilt' stt.ady·stalt- p1WIl~1 0ill concentration. 11 lis is '\I"l' n by l akin~ ti l(' mlio of tl,,·
Iwn dilTen'llt eeuce-utr ation s. C" ...r ,lilt! C" ...2 ( Ell' 9 ), Ihat n-sult Imm till' uunl n-n-d . \ '/fl l '
and altered. \ '111 1' ' 11111t·S. n -slll"l.1iH'ly,

10

Fo r exampk-. wln-n 11" "" 31K) IllWtL1Y, \ '/Il l "" ,')(K1 mW(b y. ami \ ''''1 = -100 IIIW(by, ti lt'
un l M.JlIII<I l'(J!l(1'lll mtio ll at :;It'iltl~' stalt· is duuhll"ll. CUa,l IC" ..,I = 2, Jf \ ""l h fi(K l lllWtLlY.
t ht' ratio is 1),6i', Thus , a 211"l dt "l.· n·il'W· in \ 'm t1ulIhll'S lilt- sll'atly-s la h' 11111("l' nl raliull;
WlIt' Tt',l\ a 21)',f incn-aw ill \ '1/1 n -duce-s tilt" sh ·<I, h·-slalt· 11 1l1t1·ntr. ltln lJ bv 3.1%, :"olt· tha t
a "Ill uf 31lll mw(Lay Tt'sll lts ill a roncentmtion ailpnlill'hill~ infinily. iu,; l lhat with a \ '",
hdow 31XI IIIWt!ay'. sh·ady stalt' can nevt-r 1M.' ,u'hit·H"l1. 111(' inpul raft · " 1luld 111l'1I ar.\1IY""
exo-cd " ", . alltl EIJs. .'5 In 10 would !lut b,· applimhlt"
AIt'tlhul am] p llt'lIy1oin rt'()r\' '\I'nl t'xtn'lIl1:' 1'il.'i(·S ill Iha t almm l all tilt' dimillatiull of t·iu·1I
dm~ IIl'1 10 hy 11 sin!-:It· s atu mbk- pa tlt\\1IY. ~I l l n' l'tlllllllllllly, 11 t1nJ ~ is IIlt'l al .0Ii7.l.'l1hY'\l'\ 1·r.tl
paill ways , a m i un l~' 0IlC' or 1\\ 11 of tln-m app mad ws saturanou. 111C'1I, saturatiou h;l~ It'Ss
t·lTt,1 o n total ch-arane-. TI lt' r-stent of tilt' t·lTt"l.1 dt'jlt'lltl" U II fill . tilt' ff'ild ioll uf t1 rtl~
di mill lllt"li by till' salll mhll' I);ltll\\1IYatlow d rtl~ t~ llIl't·nt f1lt i l m s . (lilly if fm is 11..'5 , nr ",rn ·alt'r.
under lIumatllf'ilt il1 ~ (ulldi tioll" is tot al d t·<tf'illll't· ma lt'ri lilly ltlT" ,lt"ll hy .Siltllf'i ltinn of tilt'
piltlm-ay, E\.;llIlplt·s of dm W' ill tltis t~.I.le.ltu l)· indmlt· pmpf1l11olol.lht"llph yllillt·. ant! sillil",'lit,
iU; ' 1.

TIME · DEPENDENT DISPOSITION

111t'st udy o f d l<lll!-:t·S in n 'spoll "'" III t!m !-: aclmiuivtration or kim 'l ic'S\\i lll ti Ill!' uf cby·. IlIUlltlt.
or ~l'ar is a n un-a (:aUt"ll c1mmll/, /w nluln,J,,:w . Tln- pharllliU'tlkindil' l~lI l1 j)f'l lt' nl is ti ll ll"
I1t71(" 1(/1'I.1 ki'lI'lin: or t·/m moIJ/lfl n lll/l 'Hki m·tin: . Ca rtMllIiV.l.·p illt· SlllM'" uuu- dt'jlt 'm lt'1ll1' ill
Its t!ispositi o n (Cha p. 2..1. p. -130). The <ll"l.·n·,!."l· in ils pl.-ilk 11111l't 'nl ralioll 0 11 Tt'!wlilin ' oral
administration ind i('illt·s tlaill t'i llll.'r ural bic lil\1tilah ility d t"l.'n·,!.\t ·s o r d t'iU"U I1.1· ilwn·,!.....·s \\i tll
time. 11lt' lallt'r h,li; 11I"l'n sh(l\\lI 10 expluiu ti lt' oh....-rv..mon l'itllSt"l1 hy' l'ilrl liUl\'V.l.·p int· ill-
tluling its (1\\11 nu-tabohsm. 111is t",'o illt/'Il'ti" " is al<;tl d ust'- a nd (111l{1'lllraliu ll-c1t·III 'm lt'lll.
a p",pl'rty common 10 Ill<illy ti lllt'-t lt·pl.·llI.lt·llt pnll' ·SSl·S.
Autoinductiou has a llllllll )f.'f o f IllI.'ral)f."ulil· 11mSt"l11l1.'lIt1-'S. It a lTl."l:t s till.' tiun-to ill,lail.'\ I.·
Sh 'iUly stilh' alll.l lilllits 11lll." Sa hililYtO Il'i(' infonniltioll fn llll a sill.ltl,· t.!1l'i(·11lp n "llil1 kint'l ks
af!l.'r rt·IM.·il!l."l1tlUM':; Of l'(lIll irmOIl:; atlminist r,d ioli . Furtlll.' rllllln -. i1l1lay hI.' a.\-.l Il'i<I!I."l!' \itl l
tilt' ind nd ioll of llwl al Mllism (S<lllll.· t'lIl.p llat k IMtll\\'iIY) ofl u ad m inis!t' n "ll d Ol ~s " pn Mllld ll!-:
a d m~ illlt'f'itd ion ,
:\ltllUlI!-:h t·nt.ylllt· im lut1ioll is I)f.'rhaps tilt' lllosl l'tlmmOll 1'1111-.1' of tillw.tlt·!)(·ndt' nt ki·
lll.'lk s, IllI.' n · <I n ' 1Il,lIly' utl ll.'r n W;UllS for tllis 1)f·lla, i nr , Fur t·.\;lIlIpll.', tlinmal , ·"ria tio ns in
n 'lIal fnnl'l ioll , Urillt' p ll , " l,add !-:lyt1'p Ttltt'i n t'(I1Il1'n lr. ltioTl , ~il\t mi Tl h 's ti nal phy-,; i olt ~ ·
(fI.MM.1 ilnd t!rink ), alltl l,lrtli<\(' olllpul all Ol'(:ur, C llrt llli(" "lTt'l1s of a t1 01 ~ 011 its 11\\11 n 'llill
a nd IIt"llillil' dimillalioll ha n ' al-.l' 1)("11 SI."l'Il, ,!.\ pn'\ ioll sly IlII.·nt iullI."ll.
AlIl inoJ,::I~'1 )Sid('s l'llIl pmtlll(1' n 'Il;(1ttJ\ idty ' \i tl l d m lllil' ad m inistfaliuli. Bt"l';I.II'\1·lht·M·
,U1tihiol i<'!; an' prilJl;lrily 1.·limill <lh "ll hy n ·nal t' l.:l'rI.'liOlI. <l I.lill1 i ll i , l. i ll ~ n.'I1 <11 fUlld io ll ' \itl l
ti lllt' may 1111N ' Kft'alN c1 m~ a('('lIl1lllla!iu n ;llId IllI.'rt·fo rt· mort · t o,i d l ~" TIlt'rt· is dl. ·arl~· il
412 DOS( AND TlME DEPfNOENCIES Cl-tAPTH :n

1Il"t'11 to moni tor t1wmpy and 10 timit til t' d u rat ioll o f therapy. ('S!ll.'<:ially ill p al it 'lI lS who
already 1101\1.' comp romised renal Inucfiou.
An example of diu rnal d langt'S ill d nl g absorptmu and di spositi on is ShO\\11in Fig. 22- 1'j .
~1t'( li all da ta an.' ..1.0\\11 (lll~'au'i(' of skt...s"('(! dt stnbuuou of "llut·s ) fil l" I'ight suhj('(1s whll
n-cebr-d an oral SO-lllg d uS(' o f n ·r.tpami l at various times du ring till' day. Xote that ad-
mnusrr atkm in tilt' ("""t'ning p roduce-s a 10\\'('1" pea k d m g conreutration and . ,LS such . may
p roduco It·ss effect th an d Ol'S admi uistruti on in thl' lIlomi l1 ~.
F OIM! is a major l'il1lst' of diu rnal variat ions . Gastric ('m pt~ill g is slowed or d elayed hy
food ( S(~(' Fig. 9--7). ofte ll n 'sulting in a dt '('n ·a.<;l,· in the- peak couceutrutiou alii] un incn-ase
ill tlU' tinlt' of its occum-uce follo\\i ll ~ a S i ll~ll' dn'\(',

NONLINEAR METABOLITE FORMATION OR EliMINATION

Xonhnear fonnatt ou or e1imhmt iu ll o f a IIwt alKllitt· is o f therupeuttc Intere st wln-n il uc-
11J11Uts for ~)Il1I' or all of elt lu-r thl' t1ll' rapl' lltk rt' SrOlJ ~' , u r to\idty, or !lolh. Th e conse-
lillt'nl'("!> of such nonliuearitn-s depend 0 11 till' c..lU st' an d thl' sill' of cecum-nee. At tilt' end
o f Chap. 2 1, lilt' mt io of A UG values for IIlt'laIK)lill' ami d nJ~ wus ('xplon'tl ; l-S a Il W ;lIl S o f
t"''alnaling: chan~l's in drug metnbolisru from oue oc castou In anot her. 111l' nuios l..1lI also
he used to ;l~Sl'SS !'toun'('s of doSl' dt 'lx 'lIdt'n l't'.
Tabk- 22--6 lists kim-tic chan~l 's r-qx-ctod for a dr ug that fnom 1\ .11 !'t('tIIlI'lltial llll' tah..
olilt·s follu\\ing a single i.v. dllS(·. Using 11ll' p rind plt,s gin'n in Chap. 2 1, Iht, {1J1lSl'tlllt'n{'('s
o f capacuy-lnnued llw tahol ism at l';leh of th t' silt's ill th e metabolic schenu- ( '; lII lx- ;IN·s'>('tI.
Fur a compound \\; 111 nonl ilJ('ar metabolis m. A CG illl'n 'i\.,\(·s with n-spe ct 10 the doSl' ad ..
minis n-n-d , till' A UG o r the p md uli ur th l' nonlinear p;,thw ay decn-ases \\i tIJ n 'sjX't"t to
till' Aue o r its 1'T("l·lInoor. rr tlte silt· of 1I0nlint 'ilrily in\llkes lIlt' first or IlIn't· conv-cuttw
steps. till' rauo o r an -as of till' last 1\\1) pmd uds remain s constant . thuugl. ho lh an-as lIIay
1)(· dt'('n·a.'\('(l with n 'spt'(i to thl' dllS(' gi\"('II,

F1,it. l!:Z- 11. )l,1,..li"n pL.\", ,, ,,'r,,· 60

I'"mil t""'u ·lllr"li..n ·!illll' prufill.. f"r
'1-1.>1'1 0"";'''10. .....-1, !tiwn .. oi ,,~11·
"ltl-I1IJ.: hJ>Ii.. " f ,I",fo: "I tI..· f, ~ Ir""i n~
h".. 'S : ·H MI '\ .M , ~ . . ), "~ K I ,\. M. (OJ,
,.. . ..1 (Dl: 40) P,M (L!.); "~ Kl P,'l ,
40
1. ', ",..I mitlnid'l '.• '. F"",I "''''\
"'i ll.l..·III :2 hr I>,·f"n · ttl :2 I.r "ft"r
,Ir,,!: " ,Imini- Ira t in n. ". f",.. 1 10
1<,..""" In "fT...1 w ....l'.unil "1,,,"1>-
II".. , T" minimi",· " , I.·I,,~· in .... ."r,-
"l.....J I....,,,it. 0,,1.;'''10 1'• .1.:. II..· tab.. 20
II·" ",I,i1,· .1;u..Ii,,~ "".1 n ·",ai" . ..1 OIl
f"r ].'!i min, 11... 101M1ic's lO r II..• ,Imjl.
"I'f"'a" In dliUIl«· "ith tI..· Ii " ..• ,,{
;oolmini'Ir..l1,,,, ,1" rlnJ.: tI..· ,1..\'. F...~
Inn " tI..·r II....., fo u l ",..I r-" It;n' "'''Y
I..· n~I" ''''l I.It·. (".jl... d""llo:'~ in 1..·- o
1'"lk 1>1.....1 11",,· (...· u l' '' mil l,,,, a
hijl.h IWp" lic ,·.Ir.ll·!inn ratio). en- o 2 4 6 8
l)o"". • 1 i\i~' . <or I....". ·in 1,;,.. IIn~ (I Hours after Dosing
rnjl.fl•• 2.2 Io1 \1 J. (t'mlll IlLo.. K K.,
l...tI",nl, ..... S .. a,,,1 1I,·ul)'. J......: In-
11,.."....• " fIi,,"·,,{ ;oo h" iniolr" lit.n ' ''I
....r..l'.. mil 1,1".rrn ~ .ld ' "·lkO . cn« .
Phu ", ,,,",,!. TI,,·r H :36 6 _370 .
1m .)
CHAPTER22 005£ AND l'J.tif OEPENOENCIES

TIll' ~l'TIt'n.1 1 tendencies for dlilll~es in steady-s ta te ccn centrutlous foll (l\\i n~ <:h m nil'
dosill~ art' III(' S:UlW as Ihnsl' for ACC aftN a stngk- dOSl', Here. however, till' compound
( t1 nl~ or ll1('tilholitl' ) with ('IIl:ldly· limik d nwtabolislll lIlay 1I0t reach stemly stall' if it is
fornn-d at a mit' that ('x{,('l'lls us \ '111.
Dow-dr-pcudcncc- is l·.'I)('(,lt'll in till' t!t'gn"l-' of unromductfou fur dmgs that IIndl' ~o
th is lx-havior. Such is ob sl'l"\"('ll with carb amazepmc. As shown in F i~. 22- 181\. the sleady-
slatc' concentrutiou of ca rb amazepnu- fails to increase ill clin 'Cl p roportion 10 daily dosl'
(C ••.", 1( 1)/~) c!t'c:n'ilw s). Furthermore, till' rutin of the steady-slate co ncentrations o f the
IIll'lah' llitt' l' IrIl:llllil7.t'pi lll'- 1n.tl -epoxtde ami l'arhalllai'.(·p illt' illCn 'il.'i(' with clost, ( Fi ~.
22- ISHl. These J'l'SIlItS c1l'IllUIlSlmle nonhnearitv in rln- fun ml!iull of Iltl' ITll'lilbo]ilt', Till'
din'l1iollS of tht' dlall~c's sll~c'sl thai fonnali01; clearance of tl lC' c'pcI'(id r- is increase-d.

RECOGNITION Of NONLINIARITIIS
~ Iln l illt ':arili c's
an' nftt 'll appa n 'lll ill graphic and tubular prvseutations flf d ata . TIlt' inter-
pn-tat iou o f such kim'lil' bc'hil\in r oftell requires il me thodfcal analysis of I he Iufonnatlon.
T his analysis may !lc' accomplisln-d lIsin~ tlu- foll()nill~ steps:
I. COlllpan' tlu- ohsc'n:aticlll 10 thai expect ed for linear kinet ics .
2. ItI(·nli(\" the kindic parillndt'rts) that appc'a rts) to he ahen'(! and tho direction of Ih('
dl<U1!-{l"
3. Den-rmhn- till' primary phan nacokmeuc p<tr,U1WIt' rtS) CL II • CLII , \ ' , ka. ;lml F Ihilt
apl)('ilr to he ilffc"l.1c"l.l. Also l" ·llillatl' ifIII is nln-n-d.
~ . Co nsill.' r tln- II\c"l.·hani sm(s) cons istent \\i lla tilt' chan~es Clhst'n·ed .

Urinary Re<overy
;\lIl1lill";lIi ti.', an' nfkll fi rst id " lItil"iC"l.1 Fnnn fl'l'()\l'n (If .Img <I111lllldaho lih-s ill uri ne.
Thi, i\ tin' caw ti ,r \;11i(,\li.. add. ;1.\ \1.0\\1\ ill '1';11.11' 2:2-7, '

Analysis
dt'pc·ndc'lln .· in salicylit-ad .! is " (lpan'lIt fnllll (·han~r-s in tilt' frill1icm of a
Sit '}' 1. I ),,!'ot.
, i ll~lt' nml du \{'
rt"l."II\"('n'l! as 1IIldlan~l't1 dm~ and a.s the nw laholiles, salit-, llIrlc add and
j!;hll'unmid.. l"lluj u.ll:att's. \\'il h lim-ar kindil's , till ' fml1ioll of each (,-ulIpclllncl n '(""l'n"l
n-matuc rln- "'III1C' rC'j!;anlll'ss o f cloSt"

T."'.22-6. CoIMe4I __ c•• ef c.ptteltr-U.ltMI Pr.c._.I_ the hq-'i.1

M .......n... ef _ Drvl 01.... I_ • 11...1. De..
su: A!.Cl...,1 A!.Cl",;\
' CO'' 0011 --.;z- A!.Cl'" ,1
D _M , .... M} .... ~,
~ ~

I
2 D =-oM , .... ....,., .... t- I ~

I
3 D _ M, =- ....,., .... ~ t I
I
4 D _M 1........,., =:> ~ ~ r
5
I
,
D _M I _~ _

;'.... .... e-...",~ 1..",,_ I doc_"" ",,~"'_

t- ~

-
. ... c<JpDl:,.... .... 1Od """,*"".",, oJ ~~ ~
;1 "' '''''''= 1O<l ~ "....""''''' ...... ol_ "o,o,,~"''''~doo.o ~ . _~ •• _to<l
... D05l: AND TOW DEPENDENClE5 CHAPTH 12

t' ;!t. Z2- lll . .-\. Tilt, , ....d.\·." ",,·

unK~·lI lr.ati"l1 .. f ,,"",.."....,.1,;'..' f..ul. A
40
I.. irK·n ·"...· in .lin 'l.1 1'" 'lM.rtinn 'n •
•10.- .L.il~- ,10...... . ,...i<I..,..~. "f nn"I"..·.,
killo.1i<. 8 . 11,,' r-~ti.. " f lh" (~ ..K.·n ·
li""
I .... r tI ..· " ..1.. 1..~ih· . . ... ,h;lm..·
••• •
7.·l'i '..·. IIl.l l ..' lC oJ.ic lc·, ;1.1.. 1,..rt...rn..•
1<'1';"" inn ,'a. ,- wnh t1 " . iI1 1ol. rate.
11.....· "I...·n... l..nl. u..I1,..,h· that ,-i.
• • •
tl" 'r II..· d .·;I.... ,II..' nf fenu..oli< ,to in· •
'·n·"...... "r ,10., d.-ar",,,. " .. f .·l j ",i' ~, · •
t i" " <lr tilt' "[>"0;.1.- ,1"('''';0\,-, a t
I,j~ r .I". in!: r.. l<." , n..· fumlt· r. ..
,,"' ,...,..'(' "r ,.....·...1"1"·"...·,,, au· •
'"i,..I0 " 1;"" "f tIIo.1;d,,~it.· f"n""Ii"".
i. lI ..· ....l 'lalldli.. u. t:...: h I" lill l illldh
fo:r..pJ.. ;. th. , "'.·..u .,f ,L.t.. rrum ;;
rat iO- lit< . (Carh" I1l "7t"I' i''''; I "'WI.
o +----~-~--~
,. 4.2 II \l , u rl... ,,];./t'!'i ,... ro.n - o 400 800 1200
" 1',,, ;<1,-: I H1 l(/ L ,. 4 .0 jl.~1 ) Dosing Rate (mglday)
v..I ~ I" .·,1(mm K ", l ri "~ "" a , T.» ..
Sin"'.... 1_:\ . H"m ' "," GI.. a'KI (:0 11'-
k,.... V..\ .: :\n' oi'KI".1i<malKI 'h·ao. ~', B
..t~l.· pl o;ann;o<".li'K1il:" of ..-..r!wm a-
'~l>il K· ;I.IKI it. "'~joll' m<1"I.>li" ,"". Hr.
0.25
J. ( :l i ll . l·h ~ r l1t a.·" I .. 3.3:6 11- 6 1.,),
•
IUlJ'2 .f
0.20 • • • • •
•
• •
0.15 •
0.10 •
0.05

o +----~-~--~
o 400 800 1200
Daily Carbamazepine
DoS<! (my)

T 2 2-7. UrI_ry . _ ..,. .. Salicyl ic Aclt••H." M Pen...

. . . 11. ._. Onll Dese-

cos """"< !'....uCyu...ec ...,=

"""" ee-exc

""767 "'"3 '00

"""'0" '"
102 83 17
5 70
1533
3000
17
14
59
50
""
30
CHAPTER 22

SII'V~ 2 10 .J. l1w int'rt'lN'(1 (ll:'I't-"'lIl n-coven-d as Ulll'hall~('(1 tlm~ U ll illt'n',l\in~ dust,
coukl he es pl.uned h~' au mcn-ev-d hiua\"ailahilit)', an iIK·rt."ll'il.'(! renal ck-arance . or a 1'; 1-
padly limilation in its lIlt'laholism . This is seen fmm tlu' relatiollships Ar.. / Dust, = fi" f
allli ft' '"" CI' 1\ I(CI'1I + CI',\'II)' Without Inrtln-r information, these- possihilitit"S can no t be
di still ~lli sht'll . TI,(, dt'('n"IS('(1 rt'('1M'I} of Iln- major metabolite-, salie) 'luril' add, and tilt'
m'arl )" compk-n- total n 'lUH 'I) ' (as dm~ and metabolit es ) at all of tilt" ("N'S sll~('SI Ihat
illt'n',l-'>('(I bi(Ja\"llitl"ilil~- Illil)" nul hi' tll(' explanutjon (st·(, Chap.:21 l. Inl'n 'ast'(! hio<lmilahility
\\l ",ltI inlTI',\-'>(' mdaholit(, rt'('(A·t 'ry a <; \\'(,11 , wiJkh was 1101 the t Hd-,>(' .

( oncentration-Time Profile
Figllfo' 2:2- I~I is a SI 'lllih "~,lIit llllli (' plol " f plasma salie) [h- add t'lllll'l· lIl r"li. '" \si lll lillU' an N
a sim,:I.· :1-1,: o ral elm" .

Analysis
SII'1l I . Till' slo p(' of the d t'l·linl' is W"all'f at low than al hi~h couceutratlons. \\"11t'1l
lnu-ar killl'l it'S o p('mtt's. rln-re is either 110 c ha ngl' in slope o r a W"<l!t'r slolx' al t'a rly nun-s
whilt ' d islrih.,lioll is t )("l'lIrrill~ (Chap. 19. Di strilllltitJII Kint'lit-s).
SII '11 2. Tlu- half-lift' ,,1'OI"k m us tinu- pa.Sst'S or ,tS conceutmtiou decliues,
Sll'l) 3 . It appl'ars that t'itllt'r C I . iUt'f{';L'i('S or " tll't.'rt 'll-Sl:'S wnb tillll' or ....i th fiJliu~
concent ration.
SI17/1. From tilt' tlI,st' andmaximum concentration [around 20() II1WLJ am i tilt' conciu-
sion h;lSl:'t.! till urinal)"dat a (a nd ind.'!")(·ndt'11t i.v. dala ) that salil')'lic add is lotally ah~orlH:'tl
aftN ora l admiuist(;ltinn . tht, volu nu- Ilf dislrihuliOlI is es tunun-d to ht, about 15 to. Iit:'ill~
Sf l ~lIlal1 , " is unl iL:l'1y Itl ck-cn ',l\l" much \si l h either tilut' or dl "l· n'a...ill~ couccntrution. AT~
increaw in CI. wnh tilll(' or at II"n'r « mcentranon s would oc cur if elimiuatiou of SiUil"f lit·
udt! is ea pad ty. limilt't l. Tht' data in Tahll' 22-. im lit';ltl' that s ahcylk- uchl is ('xlemi; "l'Iy

.1",. 2t-19. s.- ",ilt~ l l"nit· I'lul o{

tI """.."", t, ltlt:t"1llnditltl ul"~i<.,.ii<· a"'itl
200 in " I'jO'l:t fulk.....; n~ a ~in~lc, ur.,] .1.....
"f :l ~ o( ....huen ~it:yLt't' ( I "'WI. -
7.21l ~1). (Adapt O'lI fmlll d..t.. in s,.,Lo...'-"i .
lUI.. B" lIman. J-1~ . anti 1>,)'. T-J.: Th·
t'1T''(1 of l",oHunllltol.'T11'';'" ",,-1un tl...
"'t1..IIt>!i. ", " 'ItI .-un·Ii"n "f lit:y6 1t·, J
I.••h. e li". M O'II.. 33;1 39:l-1 ~) I . 19-1-'1 ,)

10 +--~-~-_~-~-~ ~
o 5 10 15 20 25 30 35
Hours
4 16 DOSE AND 1M DE PENDE NCIES CHAPTEP. 22

converted to several metabolites. However, the pronounced increase in fraction excreted

as unchanged salicylic add with Increasing dose (Table 22-7) imp lies that saturulnlitv of a
major me tabolic pat hway is likely at the 3-g dose level.

Protein Binding Dolo

TIle tncorpo ranon of billdill~ da ta further clari flcs llll' nature of nonlim-anries pn'S(·nt. as
shown in Fig. 22-20.

0.25 A 0.25

'"
E
0

OJ 0.20 • 0
~

•u 0.20
c

•"
C

<'J 0.15
u
ec
•
• 0
0
0
0 "
0
~
c
~
c
~
e
u 0.15 u,
3- 0.10 :2:
e
;;;
~
~
•
c
" •
0
~
c
0.05 • • 0.10
~

z 0

0
0 10 20 30 40 50 60 Cu
0 106 179 220 250 m mc
Salicylic Acid Concentration (mgll)
20 B
C
•u
e
•• •• •
..
15
"'-
~o ~. • •• • •
'u ~ • ~ •
• •• • ••• • •••
~ § 10 ••• • •
"'E
.8~
;;;
co 5

o +----~---~---~
o 20 40 60
Unbound SalicylicAcidConcentration
(mgll)

Fi~. 22-20. ." . n....clc~"r-. . lll"(' "l ",,1",,11,,1dnl~ Ie...,........... 1Ii',,' ). d,,·((>nniTK... l uroo:Jc.r It .-...J;.·-ltal(,,,,,",,lil i,,,,... .. ,,,I
dO(· ((.."fi.." n" 1..,,,,) in pbsm.. (0) '''I)' i m"t"T'WJ:.· \\~'h ....-. .·11 ..ch.... it< li ~lic." lic acill C'OOC'l"!,Ir:thnn is i'KTr:l....J.
11K' <.Vm.-sl'.....Ji n:l;loIaI pLo.~'fl;l ('On('ll'ntr4linns ill"(' "" ("" ri"'I""''' on t1 n.....·;or K-ale of tiK' u"ho.md t1n lJ!: c<ln·
ttntr.ll;o,., (I ">WI• • 7.2 ""I). lRt"lIr:tWll (rom FIl Bl.IU·:'. TWl.'1'. T,;":.. and " Idmoo . K.L: Salk.,td"·l"'ilr... ~
Tbe rt"SIllt of I'rott"in hintlino;t and mt-tahol i~rn. {.1in. Phamlarol. Tber.. 26~'>9, l~. R..-protl...ed with £"'1"
",i~"" of C.\'. "I~·. J B. ""·tol.al ck·J.~of salic)iic add, d.-tt-nnilK'd 1I1K"''1'~t'"Ji(~·-stalt"l-ondi lions. n'm:ains
....'«'flIWI~· co"slanl \\; thi n tI" , r4"'...... of tiK-rJ.pt"ll ic coo"c:t·" tr..li...",; a fort uit'''" ("On<l"<I' lt'lloCr of tI..· .-..so.'flti:all~·
....I"i,·aI<...,1 01,,,1tlf'P'"iu:l: dT'''l1S of s:ttllr:thlt, pbs'fl;l (lRIII-i" hi n.li'lX :mel J:llllr.d.a.· mo.-taholhm (l mWi• • •. 2
Ji ~ II.
CHAP1H n DOSE AND TM D€PfNOENCfES 417

Analysis
St/'I' I. As Oh.....·fY("i1 in Fi~. 22 -20 A.fll I IlCn.·;L>;I.~ wi th iUl'n ',L\ing: eoncentrution in tlu-
anl irllt"llInal ic t11t·r.lj'M"util· fOlIlj!;l" 100 to 30n mg/L. imlimlillj!; lIon lillt"a rit}" of salicyliC' add
hi lllli llg: ttl plasma proteins. :'\onlilll'luity ill Cl" , is al.. . . unooverecl, As slltJ'\\11 ill F i.l!;. 22-
;20 B, "<llil'\ '!il' 1Idd has 11 Illw dear:lnl't· t'\ l 'U <II Illw ("tlll('l'lltrdtiolls, As such, C I..II should
n..m ain n;nslalll if ebuuuanon pnK.'l·s.......s <In' Iln alTt'l1t"i1 h) ' tilt' couceutrutjon (dust') til'
sa lil'\·Iil' adl!.
Sfl"/'~ 2....1. 'nit' panI1l1 t·!t'rJ<; alTt'('h"i! a n' idt'ntili t"il ill this ca.....·.fll an d Cl u,
Sf"I' -I, '111t' mechanisms itl\'nl\1'<1a p pt'ar to ht· s at urable bimling: to phsm a proteins ami
sonn- form of eapadty·lim ilt"i! elimiuatiou. F ro m tln- ad ditional inforlllatioll in T a bl(' 22-
.. anti Fi l.:. 22 -19, the l'<ll><ldt)' lilllitatillll mus t lit' wi t h mt'l aholi slll .
I ll t(" rt's l i n ~ly, to ta l dt·ltr:Ull't' is rd:tlin-Iy constant tllro ll gh ollt tlu- tln-rape-uttc mnj!;t· of
s;11il'~ Ire add ((.'" hdwl't'li 10 ami fiO IllWU, This is a l'lllM'tltlt' lIt't· of til l' u p pm illj!; ten-
d l'lld t's of Iht · twu forms of Ilolllilll',arity . Cll·antlll"t-· dl'(: rt'3.'it·S \\it l. l'J!l(,('ll tmtioll lx-cau .......
of L"dpadty.limilt"il mdallt,lism . Satur:thlc' bindin g . 011 th e ot h...r ha nd, tends to illl'rt':LSl'
drilr.un,· al l.i~llt'r l'lIi("ulmtilJlls, CI. "" fll ,cr.." , The (It"l'ft',L"l' in lInllt)llllll ck-arunce,
,I,,· ('(lIN'llllf'n(,' of sat llf:lhi lit)" in two major metabolic pat h \\~lp of salil')'lic acid tfonuauon
of saltcyhmc add and salil~'1 phenolic ~l11e\lronitl t' ) leads to a t lbpmportiol1alt> increuse in
1lI11ltllllld coucemrunon ",it l. illl·rt·asi ll ~ dosin~ r ate ( F ig:. 22-2 1), Further illfonlliltioll 1111
the spt'('ific nonlillt'ar lIlt'lalltllil- pathways rcqulrcs isolatillj!; th e nll'taIMllit' )"l<ltllways. 111is
lias la-r-n ;tl,,,mplisht'tl hy l'flm ll<lriU!{ till' mit'S or urinal')' ewreuon of t",lCh lllt'talMllitt· to
ti lt' .1I110 UIlI of salil~'Iil- add in ti lt· body. a procedure a nalogous to t he dt"lt' n n illatiu n of
n-nal dc'ar.tllu· . '111t" uu-thod is applit1lhl.. if thl' r.tlt' of excn-tion uf Illl' tahulitt· t'flll:lls Its
ra n- of (Urinal ion , , LS is tilt' l'.N· for salil)'lit· add afh' r a si n~lt' doS(' ami for a ll d m w; Ilm lt'f
stt·;U!v-Sl;I!t· l'lIItiitinllS.

"i~. 22-2 1, TIM ' 'I";M ~'-'ol"lt' IIII I""IIKI n OlK" U,

40 Im liuu uf \;\Ii.:ylk ;Mitl ill III"",,,.. ( 11I. 'a ll ~ S l) l i,, ·
(n''''''"' .li'I>n'l" >rtio "wI'·~' wil', 1.1... ,1c"1l1f/: roll "~ "f
"' r iri n .'u r 1ri n i , (,<llnr 1<'l1' ly ('<lIl\'l'rtt'l l 10 II",
n"~,,,," .....J rnt't"I".tilf'. ... Iio.,.i ir iIcicI. TI,,· ,b.pl'Ol"""
tit " l"h' ;ll(n ·...' " n·II, '1~ 11K' "'hmd 'ility of 1\\., " f
salit.,li<.' ad,ls " "'jolt' rall....";l~~ nf d i rni lwlit.... f....,
mal if", uf sal;,;,~ 1,IM " K.tit· ~lll(;'rt: nlio lc· ...,,1 "" it., .
lu rK:- ",,;. 1 (I "'WI, - 7.2101 \ 1). (H' 'l1r1o\11 fmm
Tn"...r. T.~ . , T"I1~· Ull . llI ). _S . , illKI RitW 'II11il1', S.:
Lint··ar ' "I . l" lll!in.·ar 1d1l.1io.~. In T('1....~ ill 11"",
n""'''; 'I;';.,.] St.;...,........ ~:.I'I I I" , n. H n~" M" ..... 1 1·.
SI" i ,,-.,. S t....· r"n. t:t" r. 1\Pl1. PI' · ,' l- 17,)

o~='----r--~-~
o 1 2 3
Dosing Rate (mglhrlkg)
<II oose mD TWf DEPE NDENC IES

THERAPEUTIC COHSEQUENCII
111(" t llt' l'd l'wlltic ('O IlSl;-'(IIlPIl{"('S nf dCl~.-<lt.pt'lJ(lt·1I 1 IdlJ('ties an ' (x'rh aps la-st considered
unde r steady-state <:omlitions. Here d nst· dt '!k-'lldt 'lll't' in rat e-limp profile of a bs0l"Jl{julJ h
of little or no ('tlll S{'( ! II( ' Il ('(' u nlt'ss hiO<lvailahility h' ~1t' lI t ) is also aln-n-d. Alt t ' nllio ll!i i ll
hi();'l\uitthilit)" are import ant in that unbound concennunon alld ;1111011111 i ll tht· I KXl y al
Sh-" Kly sl alt· Illay dian}!;,' d ispmlx lrtion'll('!y on ch;l n~ nv: dose . Coudltfons tlml <:,UN ' <kIst·
dependence ill hinils-.u lahil ity may also produce Increased \'a riability in this paraun-tr-r at
tilt' sm llt' t!1I'-t-', Fur exa m ple, {'Ullsidt'r two drugs. 11 dis solutio n rate-limited one, su d l ,lS
pist'l )fu!sin. 31KI Ollt' th ai is 1 1 i !!:h1~' r-xtracted on pa-S.Sillg across tilt' v:a.~t rni Tl t l'st i llal ll\l' lll­
hram-s III' through tIl(' live-r, sll {.. h 'L~ alpn-uulol. Chall~l's in gast ric l' m p~i ng: and in othN
ph)'siolo¢ C' factors {~<1II pr oduce l a ~{' va muions ill tln- hioavaitab itity of tln-se- d nt~s . TIlt'
I'lTt'(.'t of rap id g;L~t ri{' ('lllpl)i ng lIlay la- a d(,<.'n ';L'it· in h ioil\'ailahility of g ris('o flll\i n IX'('aIlM'
ofl t'ss time for mixing ami d issolution hut <111 illcft·il.'it' ill biu';.I\'ailahility n[ alpn-nolol "c'(";mo;.( ·
of Slltli fOlhih ~· in intl' stinal andhepatic mctaboltsm.
C lilliedlly. the IIIOSt d nu lliltic _~U ll n'(' of dust' dq x'mlt' lll,(:' is l";l(lat'1 ty-limitl'd uwtaholislll.
O nl)· smal l changes In hi oa"lIi lahil i~' lIlay p rothlt'(:' largt' (-!J;l11gt'S ill tilt' steady-stilh' con -
centrat ton. Under tilt'S(' conditkms, l'.u t'ful titrat ion o f all illlli\idllal jliltil'llfs dmoilgl' n --
tillirellwnt is IU'('{I('(I, especially if thr- d nl g has a narrow tlll' rapt'uti<- illl!");. Mon >(l\"t' r, Ihis
!i(llIn'l' o f d' lSl'-dl·lll'nJt'lll'1.:" also p r oduces latg'· inh'rp;.llit' lit \'ariahllit)' in sll'atly-slatt· CO il-
centrauon. as observed for p henytoin in Fig. 1-5.
Tunc-ck-pe -ndcut kineti cs is pe rhaps best t)Vifil'l! by auloilldlld ion . Allutl wr muS(' is
decreased renal fum-tu m on cnntimu-d admi nistration of a lIt'phmluxi<.· d nt g:. If tiM' d nt g is
prima rily n·nal1y r-liminah-d, till' tln-rapeutie {UIlSt'l llleU{'1.:" of the IaUf'r (·lltlSt' is clear and
nppnsitt>to th at of antoi nducnon.
In p;('Ill'ral, if two drugs art' ('(l' liv"I" lll in "II rt' Sjk'lt S eU'1.:")'t for (JIJ(' Sl ll l\\i ll~ ('itlll'r a
dose- nr time-depeudeut kiur-nc bchavior. then till' OIl(' d IO\\i ng linear killdk'Sis till' d mp;
of chnk" .

STUDY PROBLEMS

(Answers 10 Siudy Problems ore in AppendiX II.)

I . Gn·lr- the- numlx-rts} (If th e 0 11{' or more C(II"nx t answ ers to each of rln- fnllo\\; lIg
lllultiplt>-dllliw 111It'stilJlLS. Brit·lly di Sl.'llS.~ 11.0 <;(' an swers that Illlly 1)(' amhigllom (sit-
uation s in w"klt til(' snu r-ment lll,,~- Ix' l n lt' or fal<;(· ).
a. Capad l~·- l i l ui h'( l TlIt'hlholislll of a t1 m~ is .Ls."C )l·iah 'lI ....,I !t:
I. A h-ss th an p ropo rtional incn-ase in Ill(' l'h ·;l(ly-stalt. pl iL~ lIIa coneentmnon Oil
incn'asinp; lilt' 1111.11 tlai l~' dow.
2. An ap pa rell t half·life liliit ts longer at low thun al hij.!;h coucentrunons.
3 . A dt'(:rl'aw ill the rat!' of mcraboltsm ill' the amount IIf d mg ill tilt' hlM ly is in-
cn-ased.
-t . All of the above.
5 . 1'0111' of tlu- aIMJ\'t'.
h. A mean steady-state plasma co ncentration nb taint'(! afl('r .10 (Ins('s rhut is mu ch
Ili1-:lwr thall tha i predidro fro m the \'alue of deitnlllt'(' oht.ti!lt'l,! afte r a ~i llp;l l' do"l"
sllAAt'sls Ihat:
1. Ind ud ioll has ()l·t:urn 'll.
2. TIll' \ lllulTll' of distri huti on has d,'(·rt'.l'l'll.
3. A lllt'talMJlile Illay be .".'t ing as all inhihitor of dmg d imilliltin ll.
-t . 1'\OTW of tlw "htl\t·.
 DOS{ ANO lWi OE PEf\()f NCIES ...
c-, Til,' fullil\\ill ~ slt·ally-slatl· plasma dnlg concentrations have b-en ohst''''''I't1 ill a
\ lIhjl't i foll (J\\ill~ various ('Oll\ ta nt datly o r.tl llnsag('S:
OC'I5N::; UI! STLlDYSl ol'E f'lAS,\,....
1"'9/cn,1 CONCfN1lATlCJN ""9/U

500 45
1000 56
1500 62

TIll' S(' dal a an ' cmsts teut \\i lh ;Int i may IX' explann-d hy:
1. Il l't·rl'll-'>l.'tll ,io;lnlilabilil , ·
2. 11l(:n ·;t.....'t1 ch-anurce
3. I)t'('n 'ast'tl pl.tsnm pruteiu hindin,g
-t. IIlt'n ·;t.....'t1 volume uf distn bunon
011 ill t'n·;tsill~ tilt' d(J\ill ~ r ate.
d. "nit' lotall'utllllialin' amounts of dmg l'tlllt'l'!t't i in lil(' urine withi n 41; hours (es-
.....·1I1iall)" , \1',,) follcl\\i ll~ various single ora l dost'S of a d r ug. ad m inistt'rl'tl un st'l);,lrdtl'
occaxkms. an' '0 110\\11 Ix·III\\·.

50 11
100 28
200 90

Tlu-.....· da ta an ' ("IlIlsh tt '1I1 with and ilia)" lx' ('~lllai lJ('tl by:
I. Satllral)II' adin' transpm1 in Iln- wall o f rlu- ga.~truin test illal tract
2. Satumbk- fin;t-I);,l\s metabolism
3. Sal urahl(, active renal tubular seen-non
·L Siltumhlt· ad i\'(' n 'II,11 tubular reabsorption
2. Dt·fillt, ., atum hll' fi nt-pa.\., hl7latic nu ·tah..,[L,III, and dl"SCrihl' how this lk )Sl'-(lt'pI'JI(It'nt
kint't ic hl·h"\i,,r l1111 lx' St.'t.'11 ufh-r oral admimstrattou \\ithollt ohS( '(\in~ it afiN an
t'fllli\"alt'nt i.v. bolus dcr.'l'.
3 . Tilt ' ste ady"stah' p l:t~lIIa coucent runon of phenylbutazone n -Iatin"10 li lt' dose- admin-
istN t>i,1 t1t'(·n·;l....."I,1 wln-n !!in 'n omlly at anti-inRaJlllllatof)' dose'S of 200 to -too IIlgiday
( F i~. 22-22). Ti lt' dr ug is primarily hound to albumin.
<I. Draw a lint' 011 both ~raphs of Fig. 22 - 22 (bottom of p . 420 ) shn\\i n~ till' relation-
sh ips I'Xjx'('h'( l when kim-ties art' linear.
h . Suggt'st ,III t'xplanatinn fnr rlu- ohst· (\·atiolls. IQn 'u till' additinllal iuformatnm tha t
ollly lIt ~li,gihl« amounts of pht 'n}'lhutll1J)'ll' app"'" r in uri ne and ft'l't's at all c1os('S
t·'(;lmillt,(1.
-t. For f'tIl·" of tilt' " Ihles O il til(' top of p. 420 , imlicate all of tilt' possihilities in till'
fol1l l\\ill j! list that lIIi~ht ('.\ plain rlu- dose-dependent kinetics 0"\(·(\"('(1 for t'ae1l dnl,g.

USI of Explanations
1. Salurahl,,· Ilt'palil- metabolism
11. Satllrahlt· renaltubular reabsorption
II I. Satll mhlt· n-ual i\{'!in' ..... -cn-ttou
1\'. Satllrahlt:· plasma pmtein bindin,g wi th extraction ratio appnlal.·lJing Ollt' in OfWillS of
r-lirninatio n
\'. Saturable pl,tSlIlil protein hinding with extract ion rat io appn);,td ling zero in or1?:ans o f
r-lbuin atiun
\ '1. Salnr.lht{· nu-tabolism during first P;l\S of d rug through till' int estines or tilt' li\"er
\ '11. Sat urahh- ~;t\tmi ll h'stinal t rallspmt
 420 CHAPTH 22

a.
'.ltl.22-8.
Singlececl do!.e (mgl 300 000 QOO
A ' f!JQ uode< blood COllCef\l\'O loon-f1me Cu/'V'e
(mg-n./ll 3 10 10

h.
T.II•• 22-9.
ROle 01 ' v i!'lfu~ Img/h'l 5 10 15
2 65 14

e.
,.111.22-10. O. .c..ptll'tM." Dnt.
Songle iv. <be (mg! 50 100 200 400
lr.. T>OI blood COOCefllfOloon (mg/1l I I 20 43 87
Asoo uncle! blood concenkahOM,me curve
11Tl9''',/ll 20 55 160 4 10

A B

'c"
~

'"
0
0.5 '1>. 5
.;;; .§.
0 c
.5!

';;;"
c
.s 0.4 iic
~
~
c
4

'"
~
~
c 0.3 ~
0
'-'
3
0
'-'
~ ~
c~
- 0
c

EI
O~ ~
~
EI~ >.
.E 0.2 c 2
~
~
-s, c,
c
~ ~
~ c
c, ~

~
0
E 0.1 ~
c 1
~
=>
"
c, ~
~

~
~
~

o -l---_-_-~
~
0
100 200 300 400 100 200 300 400
Phenylbutazone DosingRate Phenylbutazone Dosing Rate
(mglday) (mglday)
Fill:' 22-22 . C..... bl i<..,~ ..1 I'L.h..." fu, 1"..·..
~1 1 ", t ....."..·. t:,,·nl. " . '...' """,il""...
l ln 1""" '" '' '" ~"ll; i"n ..·.u inll:
,!.oily ,10",.. (21M) l" 4lM l ",~I: ,-",-I, ,I..... "''''' mainlam.·.J fur it ""nbnll"' !lf 3 ".~·b. l)j~.·d an' tl Illt;d !'la.m;/,
" """'" lrodi< "•. ,,,,,,,,;din ..I ,,, tho· (lai ~' d,.... ",h", ni'''"n,t! (AI, ......1,10., ul1l"..u,,1" """" nlroltir", (8) III pLol' ~""_ t:a.J.
,-=-,"'..1 " >rn...p ""L, In da la (""II""."["<11o'nt t I m~1. - 3 .2 11 \ 1). (R . .. lr..",., fmm I h d>;am. C .• A..n ....~ . I~J. . IInh.
P,p •• 1.~1 ,,'h . \t .. 01' '' \ fl, "'....,,,!. ~l . : t\ d Hu" iI: . ~ ..... r.ulJ:inlt ~""I:o' of ,I... I'llilflT,a(u!<lntofit... uf rl "',,~f"UI&L01'" in
rl"''' llldl" ,, 1;,n l" ; ' I<: Il; 'fit 'l 'h, Ii r. J. ( :1111, 1 1I;1,n nd(~ ~ .. 12 :113-1 Z!l. 1!1'I1. fl'1," ldI K~ " ;tI' I" 'nll ln it ll' " I'1iL..·h "'l
~i<'n li lK' PlI hl it·..li" ",, ,)
CHAPTER 22 DOSE AND TIME DEPENDENCIES 421

5. The re latio nship between ~llleost' urinary excretion rate and its p lasm a concent ration
in a ]wa lthy individual is dtsplaved ill Tahle 2:2:-11. Prepare a ~rap h of glll(1)se renal
cle-unmce in millilitt' rs per minute as a Function of its p lasma cono-ntrauou . and hri ('fl~ '
exp lain 11ll' observation.
Table 22-11 . Glucose Excrelioll Rale 01 Yarious Plasma Glucose COllcenlrallons
Excrelion role
lmg/mml 5 66 151 256 400 520 631
PIo!>lTlO 9~
conc enlrolion
Iglll 2.00 3.0 1 3.Q8 5.03 6 .05 7.08 7 9'1

6. 111l' data in Table :22:-12: we re ob se rved for disopyramtde ( ~ l. \\'. = 3.19.5 ldlllotc ) in
two different subjects. each rccetctng various rates o f i.v. infusion . Apprmim,ltely 5.Yl-
of d isopym mid(' , a Il<LSie dmg; that hinds to a I-add ~1~"('llpmt(·ill. is llnnll:llly excreted
IIll(:!J,lIIg('(1 in urine. 1111." re mainde r is metabolized.
Ba-"t't! on th(· Infonnanon above. give two possi ble explananous for the dose-
dependence of disopcramidc clear ance.
Tobie 22~ 12.

JJ 0.03Q 0.70
0.077 11 5
0.154 2,01
0. 300 2 48
B.H. 0.0 8 0.82
0.16 1.30
0. 32 2 30
0. 64 200
1.05
I.Q4
4.'"
5.56

r. T ahl(' 2:2- 13 is lntcndr-d to summarize the dire-ction o f d lan g:e cxpocn-d in th e d ispo -
sition para meters and in total and unbound steady-state blcod couccnt ration s of a d mg:.
rdat in' to the rute of is. administration , WIW ll the re is a dosr- d('IX'mlellcy in absorp-
tion, distribution, or pli millil tioll. Complete the tabk- hy indkatinl-: j for increase, !
for ck-cn-asc-, or H fo r little or no change .
Table 22~13. Disposilion Kln ellcs alld Tolal alld Ullboulld Sleady-Slale Blood
Drug Concenlrallons CIS CI fundlon of Dose_Dependelicy 111 Each of Several Sources
Followlllg Oral alld I.y. Adm lll lsirallolis
OIRECIIONOf
C H ANGE~
CONCENlPAr!ON_ I'
SOURCEOF DOS.!
'"'"
INC ,eASED
TOIAL
I~IE OF AO\A/NIS1~liONl
DE PE NDENCY DAlYOOSE TOIAI UN8Ol.l'lD
Orol Administrotion
BiooIIoilobiliJy ! H
Absorplion (O le conSlOnt ! H

Introvenous
Admini5lroti on
froction unbound in blood
Loo.v eoccnce « sc drug r r
High eJ<lrocl ion ro lio dr...g r r
froclion unbour'ld in lissue r H
NoetoOOlic c1eor once r r
Renal deoooce ! !
~_-p.d"""do_detov- ........
>n,."""d~ .. <;I ........ _ bIood....o.-
"1'- o-.ge...ar-"", CIfId ..eo-! blood '*"9 ~ oelche 10'" ~ 01 " * " -
 [)(JSE AND Tw,f OEPl:NO[NCIES CH,A.PTH22

S. Four mcchautsms that pr cdocc dns(·,tl('IX'I\{!t' llt kim 'lil'S h ~t't lll' r wit h sup pleme nta l
information ohl aill("l.l under lim-ar conditfons. an- lish "l.l lx-low. ( :ra phil'ally show, on
Ill(' plots requested. Ih(· kine-tic ('()II."I."l.IIIt'Il(,('S of each of t1\('S(, mechanisms. Draw 11
,~"litl ljlU' for thr- oh.... -rvntion (·xpt"l.'t("l.1 when tl u- ktnet k-s an ' linear am i a da~/I/'d lim'
for tilt' siluat ion ill which dose-dependent h(·ha,;or occurs. Oem-rul tr-ndcncu-s. ruther
IIMIl SIX"l..'i fk fUlIl'tiona litit·s, un - Sl)uV;ht .

a . Satllmbl(· Hrst-p uss llu·ta!'o lislll (oral ad ministration of a DoS('

- - \ 'S . Dose
sinv;ll' dost' ) At'C
h. Salumhll' n-abs orptton in tilt' n-nal tubuk- ( f' '" 0 .9 : fi' ,k
----"'- \'S. DoS(~
= 0.5: dm~ W\l'n as si n~I(· ural dow) ,H.fC
c. Cap;\{i ty-lilnilt"l.l nw taIMllislll (fi ' = OJ)l . dOlV; illfllS!"l.! in- G•• \.,;. Infu sion rat e
travl' llous ly al a cons tan t mle)
d . S;atllmblt' h indill V; to plasma p m tl'illS (sinv;!l' ora l <10.....-] CII \ "S. G
9. Tlu- da ta in Fi~. 22- 7 for dicloxaedlin we-rt- presented wuhout a,sSl)(.;ah"l.l plasma protclu
hin<linv; in formation (110 1 pm \id("l.1 in tilt' urtid(·). 111t' n-nal clearance of the <lnl g. as
.lss('Ss("l.1 frmn Af'.)AVC. t1t"l.·n·.l..... -d 011 ill(.'n ·a.s illV; Ih(· dllS(' from Itn 2 g, Dicloxacdlin.
a weak add "itll a 1Il01(,(11Iar w('ighl of 4711 WlIlol(·. is (·xll'llSivd y hound to albumin
(f ll = ll.()'i al 10 Illw'l .) and pmdul,('s a poak couceut ration of <IlMlllt fil l IllWi. uftt'f' o m!
administrat ion of 2 ~. Could saillrabl(· hilld ill~ to a pl;lsllIa pmteiu explain til(' dl"{'n 'm,e
iu /k./lU:C ,,; th tln- la~t'f' dose?
10. Tahll' 22- J4 lists plasma le-pa riu at't h ; t)' d t'h'rm im "l.l hy til(' amount of !Jt'x,ad iul('thrine
h mlll idt' n-qctn-d to neut rallzehepariu at1i\; t)' using thromluu.tnduced (,(la.l"llalion .tS
an e ndpo int.

T.W. 2~14• ......... ActIYIty 1 . " - - SI. .lel.• . •• lectI_ .. 25 .... 75

U.ltI/k,., H..,.rt.............. Dec I•• H. .hII, .... lftCf·

"'" ,...
Hf P.o.l:N "'ClMTY
= ....,.. rs
10 "
0313 b
15 0 872
20 0238
30 0175
40 0106
4' 0591
60 0.06< 0 420
Q() 0249
120 022 8
ISO 0 161
180 0083
~tr,.,,~ , I O W~ KM and K~,1l1l Hopao "' ".-:.-""'ObyilwooO''''''''''"''''''=>:h On ~ "-' .31 104·
11 3 lQ81
·k"""'l-"''''''''I .....
' I'ooto ~ It. dodocto<_

a. 1'101 b oth .....-ts o f uctivity-tinu- data 011 til(' sann- S(' lllil(~mit lllnil' gra ph .
h , Do tln- data .s \I ~esl dose-dr-pe-ndent kim-tk- h(·ha\;or? If so. whk h ph ,lOl1at, )kilwtk
par,ulleh' rs aplx';1f' to 1M' alT('('t("l.I?
c . Could till' kinetic bd la\;oT 1M' explailll"l.l I,:,' (·ulJ<ldty -lim itt"l.l elimination of til('
~ lid mel b -~ I ('n tt'n t)lx'? Brielly discuss.
d . Hepa rin is a natu ral Ilt't en~em"l.l1l s lllul'(Ipo!ysa(dlaridl' (,(lllsbti ll~ o f polym eric
un its o f di lT('n'nt ehaln II'ngt ll am i clu-mn-al composition with molecular \\l.·i~h ts
O W TU22
'"
r.U1¢Il~ fm m 3,()()O to 40,Ol.XI Wlllole . could the mm lilll'ar kine-tic IM'!m, i or 1M' ex -
p laillt"tl by tln- shn ulta neous :L'iSlly of tuult iple o .UUpOlll·IIIS? Hrit"ily discuss.
II , Usill~ tht' data in Tahle 12....s (problem 5 of C hap. 12 Siudy l'w hlt' lns ) tl ~t'lI WT wtth
illfonll atinu in Fi~ . 22-2.1. an sw er lilt" foll u",ill ~ ' llIt·stiollS.
a. Brit'f1y t'xp lain why tln- uppen-nt A VC o f ( + )-nwthylplwtlidatt· is ahout 10 to :211
tirm-s II i ~I It' T thanthat for tilt' ( - )-iso Jlw r ( Fi~. 22-2.1.-\) fllllo,\ill ~ a 30 -mg ural , loS('
of m" ' lIIllll', Is )lIUT explanat ion consiste-nt with Iht' similar IMlf·Jin 's of tilt, Iwtl
iSl)IIl('rs?
h . Is Yllur ex pl.mation in "a" l11l1sblt' llt "'i lh tilt' "hst·I"\'{'lI I;ll·k u f 'l <tifft'n 'm1' ill tht ·
.-\VC vahn-s n f Iht' rilalin k add met abolites of til(' n -spc'(.1iw iSllllWrs?
e . TIw ritahnic .Ki d IIlt'lahlllitt·s appt·ar to dt '(.·lillt, "'ilh tilt' saU1I' half-lift· liS till' ( + )
anti ( -) Isomers flf Ill('th ylpl wnidatt· afte r th t' 30" 1II~ dust,. 1I0w \\l mld )UII lK1.1 HlIlt
for thi s ohso"I"\'at i,m?
II. Explain why' 1111' pl'l\ ma lU IIl1'ntmti llllllf ( - )..rilalink ;Ki d ap pt' ars til III:' about 21 )ll
higllt'Tin til(' first 2 hr th an ( + ). rilalinic ad t!.
c. In F i~. 22-2.1U. the- .. \ t'C of ( + )-nw lh,.lp ll('u id.a h' inl'f{',l'it"'i d isp Ttlportioll ally' "'ilh
dose of l'oIl't.' lIlalt' o\'('r till' I'dll~e 10 to 40 1Il ~. lI ow do yUIi ex plain tilis 1Ippa n ·" t
lIonliIIparil,.?

A B
1000 120
e
:; 100 .~
a c
c~

t
~
10
~

~ 'S
"'.-.. 40
~

"- ~
c
BO

<3
•~ ..
'0

il
0.1 ~ u
=>

0.01 0
0 2 3 4 5 6 7 0 10 20 30 40
Hours Dose 01 Racemate (mo)

. 111:_ 22-t3. ." . n l<' '''''-'"1<1

(~ "l<"·lllr..t it.... .. f ( ... )-m... I'~~I>I,,'n io L.l .. Ie), (- }-n...lh:-1I't lllL.I'· (0) &". 1 II..-i'
rnpc-ctl\~ ""o("h..I" .... li n ('<,Io"r ), ( ... }-n , ..Jin ie: ad, 1CA.), lUMl (- ). 1i1..Jin ic ad.1(6l .. ft,·,, nr.4l ...I",i n j\t,ahun
of 30 ~ of r........mic mo1 t,~fpl ict.I .. II~,ln.-hI.. n,l.-lo a " ~\Inlt~r 8 . n M' " ·Latln",h, p hrfv, ·n th.· .U·C III( )..
n," h~fpl M'T> icL.' .. ;Ul.1,10..... f"lk 'n~ .1 ",lrninhtndl< >I' ..( 10. 211. :10. an.1411 "'I: flf 110.- r. , ' m ;<lo· 10 tI 111<·
..>I,,",....,. (M ,.. II>~pl...ni<LoI..' 1 mloil 4,3 .... \ 1; rilalinic ..n.i; I mWI. .. 4 I I'M I (A,Laph..1fn.." A,-,:>""~' T..
" otald. II.. s.twl. T.. s.w.L., L "'>0<1.0 ."..;U)(I I ~. T.: :"inulin•.,., kill.1i<, "f lhn.... 1I1<1h~tph•."k...' .. . ·"".IIIi.."'.·n
in a I~"I witb n.on""1»';.' a>1<1in tx-.hh>' .....""1....1'. Eur. J. e lm, 11 wr m• • .oI •• -4 "';~ . 1!H3.J
 TURNOVER CONCEPTS

OBJECTIVES
The reader will be able 10;
1 Define turnover and I\JmClYer «ne and the following poromelers: IvfIlC7Vef lime, fractional
I\Jrl'lO'Mf rare, and mean rMidence hm&.
2 Deseemre Iulnovel porcrresers and turnover rote 01 0 CIOe"CompOftmenl, lirsl'Ol'def s~tem
when inpul 01 elimination is completely blocked.
3 KnOW" the limiloliOns01 0 Single!lme-pamldetermination in the inlerpretolion of linetic events
when the tufllCMll' of 0 syslem iscseed
4 Delerm,ne turnovel roteand mean residencelime of0 ecce 01 df\Jg in 0 multoeomportmenlol
syslem in which elimination OCCUIS on/y hom thecentral sampling comportment, wt.en dolO
oher 0 s,ogle bolus dose are prOVided.
5. Qvonllfy the reiohOflshlp between tumover roteol on endogenous sobscrce and !he plasma
ccoceoncuce 01 on inhibilot of iTS production. given oppl'optiole dolo_
e ESflmolEl creounme clecrcrce Irom two loeI'um creonn-oe ccocemrorces obtained uw nco-
sJeody-slote conditions

CONCEPT Of TURNOVER
\-t lllYdnl h":'i Old 1,,· il rr(·'(:ti ll~ t ill" C'UlIl't' n tml io Tl of a nUrlllal ( cndl JV;(' n()Ii_~) ( "II11,t ih wlI f u f till'
IIndy. EXilmp lt's art' o ral a nli<:o aj.,'tllan ts . wlJil'h lowl"r p lasm a coucent ratious o f certain d o l-
ti n~ fact o rs by i n lli bi t i ll~ thei r synt hcsts. a nd u ricosu ric egems. which !O\ \!N till" plasma
l'(Jll('lm lml ioll of uric add h y i lll'n'iL'ii ll ~ its renal deanUll1', SOUIl" t'mlogt'llulIS l'(llI1ptJIIIJ(Ls
a n ' also u "\I'l 1ttl a.<;"\I'SS \,lnO US IMIlI) ' [uuetious. Thus, creatiui ne is commonly II_ I t o assess
n -nal Iunct ton , ant i h ilimh in is 11"\1"<.1 10 iL<;st'SS hepalil' Inncn on . A{,-'(m ling ly , III 1M' uhlt, to
n-lute st' ns ih ly lilt' pha r macokincncs of a dmg 10 its p harlllilt.'(ll(>W{' t' fTt"'{1 when all t'mlog-
t' II0US compound is imlll"'('l 1 or t o Interpret t ilt, {1l1ltl' u t m t io ll of a n t'Il( IOgt'IIUIL<; {'O Ill IX IU ll d
to ll\ "\I'SS IMMly funct ion. till' kinet ics o f th e (' Il(IO~~e llollS compound must lx, understood
111t' amounts of lIIilll)" IMMly consti tuents remai n filirly cons ta nt with rinu-. 11 1is does 11111
mean . 1111\\"\'('(, that t1wy art' in a static state. 1r1(1I'1'i1, the-y an' ofh ' u ht'ing replaced or
s~ll l l l('s i ...t'(1 a l a rapid nih'; th ey lIrt' sahl to 1)(' - Iu m in g over. T ilt" {'(IlI{,\'p t o f t"mot'~',. can
M

1M' a pplil'11 11I ph..ma prote-in s, t'll Z)l l1t'S, ho r mones , dt"<.1 ml~1 ('s , wa te r, aud in fad to vi r -
tuall v evr'rv su hs la n{'\' in the IM Mk 111t, term turnoeer, lI' I'", ," t'r . <I' M'S nn l illl lit'l.t1t, hn\\,
m pi:Uy til(" n 'm"" 'll p ro(.'t 'SS (M.1.'tI~, It o n ly indicates t ilt' natun- o f tilt.' pnM.'t'ss,
Turnacer i"'111k... tlwt a ..." /Mtm W(' i... (Jt . .tn ltty state. Thus. lilt' m it' o f n -mwal t'i lllaL~
tlu- rat r- of d im illa tio n . nlis rate, t he turnover rote , d fM.' S no l fll lly ( '( )Jl\'l')' Ille speed o f t h e
p n M.'('ss . T o dn tha t. tilt' t urnove r r ate mustl x- re latr-d to tln- amount o f su bst a nce present .
fn 'l l'lt' n lly c..dh-d tilt' plllli .~b·, 11 11' ra tio o f tl.t' turno ver rat e. R 10 tilt' pool sir:a-, A n' is
"

.,.
{'l.llIt't ! tlu' f roctl(llwl tu n ltl{:('" m h', k tl ilil is,
"
CHAPTER23 TUi!NOYU CO'-iCEI'T5 4"

A second useful pamll]('tN fOT IIll·<t\uring tumowr is t" "lan '" ti" lI'. t,. It is t he' tilll!'
n-qnm-d to renew the amoun t in til(' pool. COlllp!('k n-m -wal aet ually n-quin-s 1II 1 infinite
penod of lim e , Ix"<."lII ~· newl y l' n ll' ri n~ subs tance l'OlItilllluusly uuws \\i tt. Ihal Olln'OIdy in
till' pool. TUnlO\"C.'T tune can he· n·adily t1dhwc:l. hOW('WT. by tile' lime n "(luin'll 10 bring;
inlo tl.t ' pool tilt' amount Ihat is ill it, therefore.

,, -""
A
R, 2

Consc.... l llell t l~·. tln- rdationship 11"" 1\\'1'1'11 tumo...e r tune a nd Fracttonal tu rno ver run - is

1
',- r, 3

111t' Input may lx- t' itlw T S~ll l l lt'l k o r ill\llh-t· II trunsfer of sllh..IOIIIl't· into til\' poo l [n uu
d~·\\'lw n·. o r 110111. A g;( ul t·xam plt· is tot al hotl y »un-r. whidl is holh imbi!x'l! am i S) 1I -
Ihesi7j"(l ln ' catabolt..m of flMMh t ufTs.
Fig;u n ' '21-1 sd l('nmtil~dlly sllows lilt' IU nlo\"C.·T of water ill rlu- IMMly, Using; 111I' l b la in
till' flg uro am i Eqs. 1 to :l , til(' fnUO\\illg;an'rag;I' t umovr-r value-s for \\~I IN ar t" uhtaim....[:

Turnover rote .. 2 ,5 l {or kgl/ day

Frac tional
turnover rate
Turnover time '" 17 days

AhlJou g;h tln- turno ver rate (2,.> kWtLl) ') is a la rg;I' value, till' <Il1ual tu rnove-r o f I M "I~' wate-r
is tlu ilt· slow as re·f1t"<.·lt'll hy tln- Imcnonal turnover Tille (fi%lt lay) nr turnover tinl(' (17
<ltys ), C lea rly. these- two p;lralll('tt·~ dmTiI<1l'ri 7.t· tu rnover lx-tn-r than tu rnov er run- alone.
111t' ou tput I ml~' invo h l · ~'\'(' ral pat ll\\~d~'S . For IxMly wan-r. urinary a nd fl'(',11 e-xcn-tkm,
perspiration. a nd n 'sp ir;ltiun a n' tilt' major m utes o f los s. In .1 hOI. dry tll·st·Tt clnuatc, lilt'
!ll~ t two pat hways, espt'li ally perspiration. llIay Incn-aw tlTmllati(~llIy, Illlukt, mu st tlu-u Ix'
tucn-ased to {"()IIIIlt:'usale fO T inert·'l'if.'l! loss. 111e poo l size n-muius t·sst· ntially constan t,
1I1t1lulIg;1t turno ver run- lIl a~" bt· iue rt·'j.<;("(l tll 21 l..IdOly un dt 'r tll{'....· exrn-nu- ("Illltiitiull s. In
t his situation, fmdimmlt u nlo\"{'r T:llt· am i IUnI()\'('T finn- o r wat er IM'l"lllllt·lJ.5 da~' - I a nd 2

Water Intake

-~
Foodand Drink
(2-3 Uday)
Total
Body Water

(42l1
... Water l oss

Urine,
Perspiration,
Respiration, etc,
(2-3 Uda,1
426 MNOVER CONCEP15 CHAPTH 2J

dar s, R.·sIX't-1i\"l'1~·. The poo l Si7,t· of Illany IXKly constuuents is kept constan t by Ii-edback
cont rol nn-clnuusms that main tain houu-ostasls.
III cont rast to th ese substances. till' pool Si7.l' , m tlwr th an fm d iu nal turno ver mtl' or
h IOlO\'t'T time, o f man, -ot he r consntuen ts (:h all~es wle-u tht' tu rnover rate is a ItNI"tI. T his
A.·sults in a <:hanJ?:(' in lilt' conce nt....i.Iion of t!ll' su bstance. Sdl"t11'1,! examples of till'S!:' sit-
uations in whidl tu ruoc er is altered aft' listed in Table 2.l - 1. TI\l'S(' indudt· ind uction of
cytochrome- " "50 iS0Z)o1lWS by phenobarbital, (:han~t's ill pla.s ma cn-a tluine ill acnn- n -uul
Impai rment. and chan~t·s in plasma concentration of dolt i ll~ factors Oil adnunistmttou of
(11"'.11 allti (·oa~ll l'lII ts .
T urnover ('Olll"t'p ts ha\'t' a wide nmgl' of applieations. Befon- l'llllsidl'n ng particula r
applica tions, tilt" similarity hl'tWt't'1l turnover lunl"t'pls an d I IIIN ' that apply 10 coustunt-
run- infus iou should ht, 1I0 1("{1. Co ns ide r, for exa mple , FAj. I. The iUlaloguus l'(lllation Iol-
1{J\\i ng constant rate lnfuston is k "" R./A ... T hus , Iracticnalturuover rate. 1.;" is S~lIOIl~lIl(lll.S
\\i d l dimilla lioll rat cccnste nt for a Ollt'-<."tJmpa rt llwll t model. Also, pool si7.1,· is S~llU ll~'II1UUS
with amount in hlXly OIl sleady stall' . A major dtsttncttou between the- 1\\11 concepts l'!l:ists
wi th I"t.-spt'(:t 10 the initial condition. In tu rnover. tilt, Iujtial conduion is one of sll'ady state .
Wil h constant mit' infusion, it is not: ini tiall)', no d m g is in tilt" I)( xl~" :\o,"i ths la nd illg this
and ot her difference s. such as ft't'tlhill'k (,(lIIl nJI, man )' o f tlu- <"tIll('t'pIS of l"tlllslillll mil'
Input h a\'(' application ill t urnover .

TURNOVER UNOER BLOCKING CONDITIONS

11ll' turnover pamllll'h' n; of a S)~ l e lll lIIily lx' O" lilirwd if 1\\11 o f lilt, foll(J\\ing th n "{' art'
measured: tUOJ(J\'l'r rate, amount in the [lIxJI. and Imctioual tu rnow-r mit', :\(111(' can lx'
obtalned fro m measurement o f steady-state plasma roncent runon alone. 111l' tu rnover ra te
(':.11I be measun-d ill some eircumstauce s. e .g., tilt' didly n-nalcxcn-tton of cre-ariuine, hil i

,~

""""'. """"'. """"'.

,w<

J. Change in Pool Size '"'"

" '"'"
" "'"
lncreo~ pool size tececsed s.,."rt.es;$ N/C lndvet>on 01 a cytthrome
[or concenltOlionl or input PASO isozyme by
phenoborbi lQl
Dececsed abi lity N/ C I' t PIo$lflO creon-nee in OC'UJe
10 e!,m,nole reoollunchan
,mpa irmen t
Decreased pool size N/ C N/ C Decrecse ,n cooceeecbco
(or cooceoececol 01 eEKlO,n elon."'9
facto<! aile< oral
anlicoog ulonl$
lncr eo~ abi lity 10 N/ C t 1 Decreosed renol tubolo,
el,m,note reo b$Ol'pIion 01 ~m
vfle acid by a
VfleOWlK:ogenl
or No Change in Pool Size
II. Little
tooecsed outp.rt [or locrecsed inpul t t 1 loc-ec sed WOIe'f
e!imirolion l eonwm plion in hell

Decrecsed OOlpuf [or Decrecsed input 1 1 t

- "-'
Sod'vm ,n uuoeon a
e!imiroloonl ~k d >el

"-~
""Ie _ .... 01 ..., c!'ooge
' 1 • do<:_
( HAl'lU 23 4"
a~ai n . oilie r pa ramt'h 'T!i n -main unknown. Except IhnJIIgt. th e II ~' (If tracer amounts of
isol opi mlly lallt'l c'll sllhslm ll't's. which can 1)(' measured im !l'pt' ndc'nlly. frad iun al lllOluvc'r
rai l' can I...· nu-asu n-c l only hy Jx ,rturhing sh 'ady stall' ,
Til :ipprc't,'iah · l!1t' (UIiS('l j!lt'lI('l'S of a1ll'ring fnu.1i01I:\I tUOIoH'r rate. l1l11sidc'r the even ts
ill Fig. 2.1--2 (uppl.'r ~mph ) ill which t'l im illMion is im llll."liialely alll.l l·ulllpll.·tt'ly blud,c'll
anti input is nualn-n-d. TIll." rate at which tl1l.' SIl!lst.tIIl'l" ael1 nllulah 'Stlt·pt'lIIts O il its nonnal
turtn m-r. '111t' lin lt' n-qui n -d for a doubling o r th e amount initially prt'S{'nt. A ... is tln-
t umowr tinn-. hv dd initillll . Sim ibrl\". if concenrranon is IIW llSUrt't1. turno v er tunc is tbnt
n -quin-d for till.' ~1J1l('t'lIlmlil m to dlll li,lt' tln- stt'ady.sla te \11111t>. Thls Ia.st statement ussumes
tllal lIlt' sysh' m ad s .tS a siTlglc' l"lllnp.trt lllt' llt within tilt' thne Frame o f tilt' 1lll'a. .u rC'II1I'lIls.
To dt ·!t"nllilll· tUOIO\'l'r ra te. tilt' steady-slah' amount in tilt" 1......1)' IIlIlSt 1)(' known or tln-
convr-rsc.
TI1I' l't)llS('l !lIl'lK't'S of illlllll't li'lle l)' and com pletely hlolling inp ut under condit ions in
wllil'b t'l im illa!iull is fi rst-o rder, and IlllalTc'l1I'l1. and Iilc' hody acts as if il wen- 11 singl..,
l11lllpartlllt' nl an' t1epidl'd in Fi~. 2.3-2 (IO\\'t'r Wa p h). 111t> simanon is eqmvalent 10 stu l).
pill ~ a coustant -mn- inlntH'lIuus (i.v.) infusion o f t.lmg: al ~h·atl~· sta tc'. Ht't"i,1I (C ha p . 7) Ihal
till' .m lllllnl in 111I' IlIMly (nr pl'Lsma l'tlll('t' nim tio n ) tlu-n f.ul~ c'xpol1(,lltially hy olle half (';ldl
hllif-Iift" HI-call also tha t tilt' Imctionn l rate of eliminatiou is the- ehmtnanon nth' (1J1l..taut
k, a m i ; LS ' , = Ilk,. it r(JlIll\~~ tlrat :

5 F1!1t. 23-2. [''''..... ~rt7I >h . n .., p'.. .t Un' illt....-~

Ii,..·,,":-' illo lill..• .. t....., (..I am_ l .·hl"in.odi.."
,. n .. nplo ~· hlo........1 ;AI .. I i"I..,1 r..t.. ",main. nn·
.~ 4 t ·....,'!:' ..!. Th· . 10'1'" i. tI..· '''';11:' '''''' I" n........ ".t. ·.
•
'"
"0
0
A. ,'l .. It ,. 1......... ..""'1>1'. n .., r-oo! .i,.. ,I...-n"ll-_ " ilh
tin ......1..'fI ( . 1 am",,') illp" t to t.""pIo-t..~· 1"' .......1.
0-
3 ----,--- • n... tl. .. t i"r K l"tJ"....n tl.ol ..l ..... fin.t..."..I.,. t·lind .
~ , ,
, , llollion ~I .. I OtM·o<' ."I>;&rlltM·nt di'lfrihulil., p''ftain.
~ , ,
;s: 2
~
~
.;;;
" t, .' TI..., r~l .. t'Ol,'otM,,1fo" II ,1.1t inr (110'('1' of m ilo~-
ari tlulliol' pl.. t ) i. II... f -til"wI IlInMM " ...d In l..ot l,
Kn'I"" , I"".t oj"" U '''p"......1...-wr...10 tI t.,.;liti~
,...J,.... lUKI tlnM" i. ...·L.I,..I IO tl..• '''';fo:ln;d 11I nKM"
"0
0 1 • I1UM" ,
0-
k( -t 0
0
0 1 2 3 4 5
Time/(Turnover Time)
1 •
R, -+ 0
;;
.~
0.8
'"
"0
a'.
~ 0,6
:s
~ 0.4
~
.;;;

~ 0.2
o L- -...;:::::=,.
~

o 1 2 3 4 5
TimeJ(Turnover Time)
42 8 TURNOVE R CONCEPTS CHAPTER23

1 1
I, = ~ = "0""'.6"9"3"/0-"-/2 1.44· '1/2 4

or

To illustrate the consequence of blocking synthesis, consider the effect of the oral an-
ticoagulant warfarin on prothrombin complex activit y. Prothrombin complex activity re-
fleets the activity of the four vitamin Kj-dcpcndcn t clotting factors whose syntheses are
inhibited by warfarin. On administering of a blocking dose of warfarin. this complex de-
dines monoexponentially with a half-life of 1.5 hr, as shown in Fig . 23-3. He lice , its turnover
time is 21.6 hr. T he cOllSequence of blocking degradation is different as illustrated with
creatinine. Creatinine is totall y excreted unchanged. Aceonlingly, as shown in Fig, 23-4,
serum creatinine is expected to lise linearly. not exponentially. wir]r time in a patient with
acute oliguria, due to virtually no residual renal function . Notice that the actual rate of lise
(de ldt) is about ,3.:5 mg/d l. zday (0.3 1 m\l/day), from which the turnover of creatinine can
be calculated as follows:
Equation 6 expresses the interrelationships between turnover time, rate of rise of plasma
creatinine on blocking its eliminat ion. and other parameters.

f =
A
:....:u =
v · ell .s; 6
, R, V· dC/dt dC/dt

Clearly. to define the normal turnover of creatinine, both its volume of distribution (V)
am] normal plasma coucentratlon (C.",.) are needed. Although neither value is known for
the pat ient , tho usual values, which do not vary \\idc1y among normal healthy individuals,
are likely to apply. The volume 01" distribution of cre atinine IS 42 1.170 kg, because it

100
A B

10
o 12 24 36 48
Hours 0.75 1.5 3.0
Dose (mg/kg)
Fig. 2:J-3. A . A bloekinfl dose of wurfarfu. 1.5 mglkfl orally us til(' sodi um salt. caus ed the pmthmmhin t, ,,nple,
aethity to d"dint' cxponcutlallv over tilt' first 4S h r ufh-r adminis tration to a subject. H, As expected. high"r (",~,I
and i.\'.) d{)se~ of warfarin produc ed no furtherchange in the rate of dcclmcof the complex adhit y. us dl'lermin ed
by till' al·ti'; ty rem aining at .3(1 hr. Ukdrawil from :\ag",hima. B.. (l"lkilly. B.A.. and l A" )", G.: Ktnc-tk-s of
pha rnl,,,,,logie "IT,,,,t in man : TIlt' antil""gnlant action " f war farin. <:Iin. I'harmald. Til"r. , 1IJ,22~"3-'5. l\)(i9.)
CHAM El! 23 429

t1 htlihut('s illto to!al lMKly wate-r and is ulllMmnd within till' I M MI~" A typical plasma ( '011( ,\'11 -
tration is 0.9 mg/d L (O.UIi 11\ \1). Hence the IUn10\ 't'r rate of cn-atinim-, R" is 1500 109!
(by, am i tlu- turnover tum- is 6 hr (0.9 mgltlL /((3 ,5 IIlgltlL/day ) . ( I da~·f2.l, hT))].

ESTABlISHMENT Of A NEW \lEADY STATE

l ush'ill! of tilt' I\\U 1'\ ln' l1It' ('<l.St'S uf l,(lll1plt'!t· blockade consklen-d above, inpu t or d imi-
nat ion is IIsually o nly pa rtially affect ed. Q uau nt auon of SUdl a situation is dillk'ul t. \\11t'1l
l'itllt'T thl' in put rate or fraeti nua! turnover ra te is illllllt'tliatdy slufn-d to a new constant
\·alm' . it take s tinw for tlu- IMM)I Si7.(' to n-ach a ut-w slead)' stall' andtherefon- to Tt'lIt"l'l
tilt' sllift in turnover. a.s Illustr ated below .

Turnoyer Rate Altered ta a New Constant Value

C ha ll.!!:t's ill IMM)! s;;{.(·\\i lll time nil iUl'Tt·<l.sinv;or d''l·n''lsin~ inpu t ( t u rnover rate ) by a [tetor
of fonr an' ShO\\1I, Tt'Spt'i:tin'!y, by tilt' solid lint's in Fi~. 23-5 . TIle new stt·ady stall's n-flect
d l;lIl.!!:" s ill turnover rate-. ~ol i,'t' that , a... tilt' e lim ination half-lif(· is unalte red . tht, tilllt· to
ft '''l ,11 lilt' IlI'W \ tt'ady stun- is till' same. This is seen hy the ti me n-qutrcd tc n-ach one-half
tilt' way ttl tilt' new stt·ady state. lndr-ed, this sta tcn wut is true irwspt't·ti\"t· of tilt' extent IIf
dLan ~t' ill turnover rate, as shm\1l in tilt' uppt'r gT"dph of Fig. 23--5. Had lilt' turnover tilll!'
1M.'t'n I hom , tln-n it \\llll ld haw taken -12 mill (0 .003' t,) to ('(' . 1('1. this point : if it had lx-en
I week. tlu-n it would ha w taken about ,Ii days . This lack of d l an~t· in tilt, timt' 10 ~o From
run- st,'ady state 10 another d i s tin~u isllt's altered turnover ran- fmlll a.lh'Tt't1 frM.1 iona l tu m -
over- rate.
OUt' common example of altt"n.'tl turnover rate is "n~1 1 1t' Induction. w llt'rt'hy a com-
po und (ti lt' illtlul1'T) ineTt',N 's tilt' syn thesis ....d(· of a d n l~-Ill,'t aI M )li lj ll~ ('117:)111('. 111t' n -sult
is all iUCTt';IS!' in tht' I)lM)1 sin' o f the t'n Z)111f'. which in tum is nor mally TI'H('l1('t1 by a
pmlMlr1iu nal ill(.'n ·,l\l.· in tilt' \ 'm , ami In-nee mtrtustc clearance. of a suhs tratt' . TIlt' hnlf-
liw s o f tim.!!: n 1l't aI M )li zi ll ~ ('nZ)111''';; \111)" from hours to days so tha i the Iull e fTt't.1 nf in -
dlll"!ioll lIlay 1I0t II(' S('t' li for sonu- tilll" afh-r an i ntilld ll ~ a~('n t is admlnisn-n-d. Ot:('tl~iOIl -

12 I'll(. 23 _ .... ,\ <" ,,1.. u · n..1 h il" ..·

"dU"OS th . , " 'nlln lU'I(~·"lr.. ti<MI of
"n'alinillt' 10 ri ..' ..I a ,unolan l rod .,
,,( 3.5 mW,llj ,L.y (I mfo:ll . - ","
:::;- 9 11 \1).

~
.s
~
~
·E
'~ 6
~

ts
E
e~
00 3

o +---~-~--~-~
- 1 012 3
Days Into AcuteOliguria
 CHAl'lU23

n~. !3-.\. ( ·,.,wr /......,011 1'o.4 lU.- in':"'" ." to a New Stu State
....., flO'" '1..· ,lrijcin;ol f...... l
1111..... ) lum ·
"" r l.. 4id h,...) in''''' ." M' f' .Ir. A fuurfuld
,In In f..t • .....J lu · r ; ..,.. , ~ h.....)
(1'''' ,I..· , 1 h, he...,"",,". 'I 1:a1ro four 3
h"," "" I" I .... _ ' otrah·.ot.d.. ' in
.~ .. " I. I~ ".. t;nq>h 1', . 4 .. ,,"" ,hn-a..-o In a '~,'"
, f,.,"h ,I I ,'"(I , ... """,,,.) lurllU\'l'1" 2
f'at Irt I lid J. , I~ a f. t .., (I f"", -\ tau,· i f decreased by a
f..101 1TW.Tn. In fr.fIt....J lurllU\~r ralr (ItlppIrd factor of lour
b....' ~ n pn "It,,'n II ,_ "'~ oUt r llll
(~ ..,, \; he.......... t ~ is 1'1"".........1four
I ' ...... _IO? r'"P"o. o L-_ _- __ - _~

01 23<15
TimeI(lnit&al Turnover TIme)
1.0
j
g 0.75
..
~

i§OSO
R, incteasecl by a
lactor 01lour
$: '
~
~ 0.25
Ntw Steady Stale
i , decreased by a lilctor of lour
o
o 1 2 3 <I 5
Timelllnrtial Turnover Time)

t ·llt . t,:J-fi. Cart...,n.u.o1.IM· "IMI.·r· 16

1:'''''' .."I ,.. ,.I,Jct..... ... ""'10... "......1 M' ~
II..• ' ....nllllllll. pU. ".....
\.1. ... ........ 1.... ,Lr... 7. "'.
""'M"....I.. ,"
1.'). ' 1'0. 2:2.
s
c
14

..,..I 2.1 ,i ..n ..n l ,;",11,1'.....".... " '!t.

i"..." ,i 1'0 "'~" I..L·" 1>;0' ...,,1';'''1
~E 12

~
,....~ . •1.....,.· 1" tI,,· n" ,mi"lI.f"r 22 (,,,, . 10
)Ol""1Ilh~ I"'~'I , !'n"ilt11or1J I....... .d Ofl
l i"" l..·,..... · ph"""""""h"" l(' ,1..1.., w
c 8
.. hl..i'....I I.rr.i"u. I~· in II... ... hjr-t1 a \
~
.....11.......1,... ' hr ..... ""'pt..,,, ltuol n"
1I"1,,,t,, ,,, '",..,ro. ..... .......... loy tI...
6
\
11',,,,,,,, ',. . . , ' .....!Mtif.... . ..ummlt 11 4 • • \
an .."I•• ", I,JctIl'" _,,1.,1 fur """"'.... <l •
"'..'r p"..•. in ...I,kl, , I,r I.. no... ·r ' •E 2
II",.. ,i l l... afTr<t rtl .......,....... is ;q>- •
pn"-l",...r'" ~ .....~'1 . &rr h"iIt,",rtll>;o if L- - ..... hl,- ~

Ibe- IfJIfi .."'>mi l..... (I "'1'1 . - " .2 0

1'\1 1 ( ( :.. ~-nC'1 19761 >;0' In.. .\ mrri·
un I'har mal'r uli .. al .-\.."ri.Ii,,".
c:I,,,tnJ I'fo.r. ---.ol.ll>rlh c.--..,,,•
0 2 4 6 8
...,. 15 17 19 21 23

• ..d Appl,,","I~ ..... s..."OI,,1 .:.1"..."

Rr pn nlM " "11. ror, .niu io n nf Ih..
,' n..-riN." I-'tum _ ?tt, ....1 ," " " ;iI>
'.....1
CHAPH R13 TURNOVERCONCEPTS <"
ally, u t1m~ iml u{'('s its 1)\\lI Il1daholi zill~ t'II7.)11ll'S, md oi'ul/l(1;'III, a,-~ iII11stmh'l1 wit h
{';lrha mazl' pi rw (Fi~. 21-6). As {..I ll hI' seen. it takes approximately 3 \\'('t' ks to adlit'\"t' t he
full t'lTt't1 of antoinduenon of th is a ntit' pilt'pl ic d m g, i n dit.-ati n~ that tilt' t urnover tilllt, o f
tilt" afTt'(1 t't l t'II0 1m' is ahollt 5 (lays. I nterpretatfon of t he exact dru g conceumuton- nme
re-latiunship is ('(llIlpl il'llh'( l hy th t> ~r.u lt'ti llaturt' o f tilt> Induction pN/('('ss, l"~ till' t1t/!:rt't' o f
induction d l llll~t'S (,(lIltiTl' lo us ly \\i tb t1m~ concent ration.

Fractional Turnover Rote Aherecl to a Hew Constant Valve

T ilt' (' IIJ'i.{'tj!It'!l('(OS o f (·han¢ll ~ elimiuat iou r.ltt' constaut (frad i(1II011 turnover mh' ) a rt' '1Ililt·
d ilTt'n'llt From dlan Ki n~ input (t UOl(l\'-N ) rate. T Ilt' difTert'lll,(' is shown hy tilt' stip pledlines
in Fi ~_ 2).....'). It ( ';11I ht, St'(' !1 t ha t a fourfold dt't'n';lw in tilt' elimination mil' consta nt quad-
mplt,s pool siz(' , hut it takes four times ; tS 101l ~ to reach III(' sa me new stt'a tly sta te as it did
afte-r '111ad m plill,l!; turnover rate. A fourfold Inc rease ill e1imimltioll rate (1J1lS t,Ul t, un tilt'
ot llt'r hand , n-duo-s pool siZt' byu £1t1ur of fou r. and tilt' 1\('\\' stt'ad)' state is n 'adlt'l1 much
mort' 'l llil'l.Iy than by rlu- fornu-r nn-chuntsm.
1111' pri lldplt' is illus l r.lt('(1 h)' cn-atinim- . If n-nal fUlld ioll dmps inllllt'tiia tely to a value
that is 50 , 3.1 , 2'5, or 211'l u f normal. tilt' plasrou c n -ati nine coucentrunon rtsos to a IIt'W
stt'ad y sta tt' thai is 2, 3, -l. or ,S tunes tilt' normal value, n 'spt 't.'tivt'iy, a.~ Sl UM 'll in tilt' l'l\\'t' r

R,IRAinitial) ..ilt. 2.1-1. l',,,...,. ~ml'h , n Il ' rutl \i ll' " in·
5 err- ",..1 fm m .",,' III m.· hn,,'S its corilQnal ,;d,,,'
5
..1" (at ••tmw) tI", t"mco",r itK'...•..."''S1,:\' ti ll' fiOti '"

"~ 4 I\ IR, (..,wall. n lt' hnw i1ll1!r·lif." IlIfTII" .. t li n,.. ) In

VI 4 ;1.1'1 '"_ '" ....d , r.....· '1<'",ly ";1.1.. i. II ",.. , I ,...u r
i!.rt11>h , n... "PIm_'" (11 11... TIl"'" . 1 1).- 01;1.1., h p.....
3 1r"'l(I..I ..1"... (al am...' ..) lhr, fr...i'llnal t" ""M' r r;l.h'
3 ,1."("11.;1.. ... 1':\· II... filctnr k, lk,(lnllla/). \\1..." II,,·
~ 2
,"',"', nf k, ;l.1'1'"_·I,,'S ...·m (stiPl'Ir..1 lUld . •" ....f:.'
lit;l.l.. i. I""'" ;ll~,it"."l l1,.. pmllln!:(..1 ;if'''"''''''
""
•8i 2 II,,· I" · '1<'...10.-, . l;<!t' fur tI", "tI"'r ('OI"lilil"" nUl l",
III

t"\I, J 1':\· il... (Ill'" (h;l.lf.\ifd ....I"I.. ..J 10 n·...·!.

8 • ti ll' 1'. . >1 ilir half...~, h,""'...... II,,· jnitial lU,,1final
e- , ;d,H'S.

O
0 2 4 6 8 10
TimeJ(lnitial Turnover Time)
,
,,
5 k, /kclinilial) 0.20
, 0
~ 4 ,, , 025 -
,
~ ,, , 0.33
~
3
,,,
.s ,, 0.50
,,
~
2
,
8 •
e-
O i-
0 2 4 6 8 10.
TimeJ(lnitial Turnover Time)
432 TURNOVER CONCEPTS CHAPTER23

graph of Fig. 2.3---.-7. T he new steady-state concentration is directly proportional to the

turnover time. The turnover time and the half-life o f cn-atiuiue elim ination at various
degrees of 1"(' 1111] function are shown i ll Table 23---2.
The time required for a plasma creatinine concentration to reflect a ch ange ill renal
fun ction can !Jp greatly prolonged wtrh severe renal funct ion impairment. Interp retation
of a plasma creatinine \',I]UC i ll a clinical sitnation is the-refore dependen t Oil the acuteness
of the change in renal function and 011 the degree 10 which renal functi on is impa ired.
Furthermore, ill bedridden or nnly partially ambulatory patients with severe ren al dys -
Function , the muscle mass is I)pically decreased, lead ing to a reduced production rate of
cn-atinine and a rise of only ahont I to 3 mgldL (O.Og to 0.27 1l1~1 )/day in plasma creat inine
1)('I:\H'cn hc modfulysts treatments (used to remove uccumulutcd polar substances, see Chap,
24, Dia lysis),
Distinction [x-twecn decreased turnover rate and Increased fract ional turnover rate is
similar wtrh the analysis uhove, but here pool size decre-ases. as shown in Fig. 23--H. T he
time required to approach the new steady state is th e same when production rate is de -
creased (upper graph), but is shortt-ned when fractional turnover rate is increased (lower
graph), The rate of attainment o f the new steady stat e is related to Its 1H'W value; the lower
the value, the more quickly it is ach ieH'd, as ShO\\11 in the [ower graph of the figure.
The rate of decline in pool stze , on decreasing turnover rate, ts limited by the fractional
turnover rate itself. T he decline in dotting factors . on administering warfarin, serves as a
good example. This sy.~te\ll is c-xamim-d in greater detail. as it is representative of many
other such systems in the body.

INTERPRETATION OF NON STEADY-STATE OBSE RVATI ON S

Frequently, it is necessary to Interpret data under nonstcady-statc conditions. This arises
following the acute administration of endogcnous drugs and when one of the turnover
paranll'tf'rs is acutely perturbed.

Administration of Endogenous Drug

Some marketed dlllgS are endogenous to the hody, Examples are testosterone and L-thy-
roxinc. The number of such dlllgs is increasing rap idly with developments in biotedlllolof.,'Y
that cnuble the expression and production of recombinant human polypeptides and pro-
te ins, such as folltclc-stunulattng hormone and erythropoietin. \\'ith lllallY of these , a basal
conce-ntration in plasma exists that must lie taken into account when attempting to tk-Hm-
the pharmacokinetics of the administl'l"ed compound. The approach that follo\\'s is suc -
cessful when the basal turnover rate is nnan(~cted by tho additional material. Sometimes,
this is not so because of feedback control systems that adjust the endogenons turnover rate
to maintain homeostasis.

Ta ble 23-2. Calculated Turnover Time and Half-Life of Creatinine when Renal
Function is Decreased
RENAl f UNCTION
(PEKENTOF TU RNOVE~ 1M HALF-liFE
·NOPMO.['1" [hd [hr)

100 6 4
50 12 8
33 18 12
25 24 17
20 30 21
10 60 42
CHAPTH 23 TlIPNOVfR CONCEPTS

Fi ~m. · 2..1 -9.-\ !\!lows the serum ccnceutranous o f ('l')1!lmpo idin afk r i.v. holli s udnun-
ixtratiou of ('I"XM'li n alfa, a n-c ombiuaut human eryt h ropoietin. and pla(, ·ho , ~ot i(,' 11ll'
tlt'<."a y of " l')1hmpo it'lill lo its llJ.l'ial \11111t' , Tln- ',(plation dt' fiJl i n~ tilt' eonce-ntrunon dllrin!-:
Ilu- decav, C (l ), is lilt' su m Of t\\1' concentrations. III(' basal e uuvn tratiou am i that R\sndatt'tl
wi th th ,: ho lus dose-, (;'. 01... . 111(' difT(·rt'Il(,(· h<'t\\ '("('n CIt) 0I1lt1 11lt' hasal n l1l('t.'lltralioll is
St't'1l to l)t· app mxi ruatc....l hy a IlItJl] u('xl"XlIl('nlial t.... [uation. dlarad t·ri...t .... 1by (;1001.. . (t1llit!ll'L )
= IliOn ( . - 0 IZr . with tim e in !I0llN ( Fi!-:. 21-9Hl , 111e n m t'sl)tllldi ll!-: pita rmanlkil\t'lic pa ·
rameh-rs an' \' = -I L!7U k~; CI. = n.5 L/l, r!70 k~ and ' liZ = .'i s hr.

Estimation of Creatinine Oeorance in Acute Renollmpairment

In patk-uts with a('ull ' rt-nal dysfuncnon. it is 1I0t al\\11~"S pos sih lt, o r p rad icill to \\1ut for
tilt' serum crea tinine to rise to a IIt'W slt':uly stall' tn e stimatt' ('n'atill ilJ(' ch-ara no- Irom
serum creatinine, part il"ularly wlu-n n -nal Iuuct ion ht...., "'It'!\ cr-rylow and cn-utinim- half-
life ht'l'tllllt·S ('t lrrt'sl"XIJl( li ll~ly \"t· l')· lon~ . Crt'atinille dt'a r.ll\('t' ( . 11I still he t'sli lllah'(l, how-
ever, fm m two (Hr 1II0rt') serurn cn-ari nnn- \.,hlt's O lt rln- appnJ<,('h to plalt·all . 111l' p rind plt·
la-lund Iht' metho d is tilt' sanu- it" that IISt'(1 whr-u ('t m s idt'ri n~ till' rise (or fall) ill p(;t,ma
(, m"'ll tmtiu u nil ,l!;lIill,l!; fm m II Iit' slt'a dy state tn anot her ru\ltJ\\in)l; a dlilll~t' in its mil' nf
cousta ut input (C hap. 6 ). ~ all lt'ly . it\ depi(1t,,1 ill Fi ~. 2.1 - 10, tltat th e oh'it'm ,,1cre-atinhn-
("tlll(,'u lmtinn is th t' sum o f two coucentrattons: ( I) tha t iL~ Sf)(;alt,, 1 with what n -nuun s in

RIIA, (initial) t"iR,.2.'J..-1j. 1.,',Jrr J!! 'rl/'h , 1.,. >1 ;.i...• ' ''''Tl·;t" " til
1 ;t n. ....' 'h'"" I~.. ;.tal.· lh,,' t ..m"I,, ~ ..h I" tI.., f...1".
1.0 H,IR. (i" ilmh. 1-.:- "t,id, 11M" tun""" r nil.· ,It··
0.8 '·n·"....~ . TI..· ,....... 'h ·;ot l~.. ;.'"h· i. ;tl'l,"_-f,,"t l "'ill,
~ 0.8 II,,' " , n it' 1"" l f-li f., ",I,,'n (", "••tlw ) inpul
,·n ·iL"' ~. I~ "n'r ~nl/'I" 1'. ..>1 , i...· ..I..., ,.."Tl·
,I.·.
""
0.6
~~ 0.6 ",1" ·11 Illt "m "., j f....1it""'"' tun""..r ",to· i".·n·
1-.:- ,I..· f...1,,,I;,/" , (l"ili4/l.I",t ,I..· tin'" (l,;</f·I,f,')
~

0.4 to ... t,M "" tI.., ,......' ' h·",h· , t;t lt" i' , I" ",,"nt"tl
o
~0.4 0.2
as
~ 0.2 .0

1.25

1.67

2.5

5
10

1
Timel(lnil ial Turnover Time)
 T!JiNO....U CONCfPTS CHAPTH 13

A B
1~ ]
c
~
~ -
1~ J
,""
E- 1000 •• - ""
~:>
u _ 1000 ••
" :>
Jl- •• all.
u ••
•
.
CC
'.;:> .2 E!J •
'~ ~
o c
100
j ••
•••
. =
"
<O S!
• • • .e- ~
2 ~

.
100 ••
••

r
- B
~ C "1;1
•
0 0 0
:;'0
W u 10 00000000
&- 0 -
10 •••
"
~u
0
:;.
w
0 12 2' 36 '8 0 12 2. 36 '8
Hours Hours

. -llt. 2.1-9. A , St'nlln " 1)1 h"~ k ll(1j n (~ 'I"'~ 'lr.d k", ",.h lilll'· I'~~ I. ~ I"·m;" 'l{..rill,,nl<.. l~ ali.·, tv 1.>1,,< ;klm;n·
i." r"i"n ,,( '1kk1in a1 ra ( IIMI Illliblllt) ( ) ;<)kl pt.r..·dk) (0 ). H. wllIil<'I:-'rilhmi'" 1'1". nr II..· .IifT,·n....~· I.'t\o~~ ·n
tI... . ·l)d m , . oIo.1in (" nn·n tr.dk.., arkr tl .., ,10- "f ' 1••1;n .oJra a". 1 I".·
I......J ,.a1,... ( Ill Ilnih/l.l . tA.·II a' 110.·
;l\.. r'"ll'· ".w II.., po·ri<..1 n( 'il"'!:- (,>11
""1111{ tI ", ..., "".,. \I....n ,L.t.. rnr 21 , ,,ltjt'o1' . (Fmm 11..1,..·,,, C.E..
M ....,... . M .. 1.:11I"-. S.A.. Sd",.., !.·" . J. R.. WII' a" ..),.' . \ 1.. S"ld... J To, ..,,,I Ah ral..." ,. I'.A.: O""I...r..li" . I'I m ....
l"I* h,,1k-S ;<),,1 flI",,"'lill' ...!:-ll.ll11it-S ur .,.__ 1in ..1(a ..",I 11"'1i" I..·t.., e lm. 11I1lru"", ,j n ...r .. ,511,7( ~2-71 Z. IW I.)

th e lI(k ly f m lll tilt.' lime o f tht· first uhscrv a tion amI (2 ) rlu- ri s i n~ conce-nt ranou that is due
10 l I lt" con nnual p n l(! lI l 1inn o f cn-atlntne. That is. the serum r-reatinnn - .'o lJ('1 ·n l ra lio ll 111
a llY tinu- a fter t I is gi\"l'1l by

q~ - q ' l[e - lid}' + . R, _ II _ e -'ld)'j

CLc~dl
Concenlralion associated with Corcennonon associated with
who t re moins of creatin ine in continual productio n o f creatinine 7
body from lime o f firsl 01 turnover rote R,
cbservc non

w Iw rt· C (t I) is ti ll" coneent rution 'II lillIt" I' C I. ( ·tl(d ) is tllt' l'n'itlillil w d t·" mm'l· ill tln- p.,lit·n l

. '". 2.1 - 10 . \\ 1M.., ,..."a1 (,,,..1'''01 I. 6

(l. 'll h · J,".·ri<,....lt.., ti nl nr clt·ar
("f1· .. j", .
Il..'t halrl~' (;Jb In a ,........ ,-...I.... C 1't ,tt(d ). s,...
rum lTl·ati ni l ... tI..-n rh. 'S 'u".-..nI a lit.....
, I.--h· " ..tr ir n ·na! (uII<1 i<n, " '''''';11<" ",.
'1.."1" AI ;u '~' Ii " ..· tl. I~"' ..I.. l'll'\.......lhT. •
f l , h.trn-...l t. II,,· {'f..k'I.. lt....I..'" n~' I. · .....
~re !.'tl ;n II..· " II" ,,( 1I",t re'maininl/: (rm"
: l\ (l -e O(~M)
tI.... am•• "" h . 11 1..~, a' ',.
C(l l ~ - l, ") . ' .
"..' ,b '< llldl

C(~I
a,K1tha. ;lUI

{If l 'n ·..ttnit

I
(I.. ~h
" ',h II.., nklli"",,] 1"1"'1
ill .~.Ior ). .... - ."
". :
I

• ". .- - - - - - - C(111e llO

__
11,_ 11 _ .. _ l .... ·'I. • " .
Cl '(;tt(· [l ,•
" •
•
•

"fw'll" *(.[ ) • C:1'(.~.fYl· ;<)..1tt, b tI tllm- o

,lI.-..r
ralt· ,of crr.olinill.·. .. ~.kh is !:' ' r;J~· o 12 2. 36 '8
,,""IIt're.... In ." ••. ,..,w1 U"I"lin ''' ·lIl,
Hours
CHAPTH 23 n.)iNCM ~ CONCEPTS ."

wit h n-ual flllll1 ioll i mpaimu-nt . an d kid ) is ti ll' u) m 'spom!inj.{ t'lilll in"lion mh ' l''U n~ l a n l.
:\ s sho wn in :\Plx 'ndi :\ I-II , a n t'~l i lllah' of CI ' c H(d ) t1111 al<;(1 II(' ohlilillt't l Imm rmu-eutra-
lions al ttnu-s I . aml ' 2 ' L\ follows.

2R,
B
[q,,) + q', i1

whe n ' (;(' 2) is ti ll' l'n'ati "hw com-entra tion al tin' St"(1 J1l tl o b....·rvut ion a nti III i ~ tln- limt '
inh '''Ylll ll('IWt't '1l nb~'''YOIlions , i.e .. 12 - I l'
:\ltlllluV;h \ ' a nd Il" tln- turnove r unu- (p n M.lllctiu ll ra le ) u f l'n'ati nint', ar e no t Illoll ~b l
10 dl'lII!-(t. in ucun- n-nal i lllp;.li n"t'llt.I I( ' ill ~ ;a fUll(1ion o f 10la l lM. xly wan-r a m l llllht,lt, lIl;L"~
n~l't 'l1 iyt'l~', I Ilt' Spt't;WC value.. in 11u- iml i\itlllal pa l il'n l a n ' ~" ' lt' mlly nul kno wn . 1111' vahn-
of \ ' is taken 10 hI' total body water, ,!!;i\"l'1I hy fiO'! IxM.!y wl'iV;lll in a n ol llt' l'\\i St, uo n nal
subj''l1 , 111(' vahu- of H, dl'lx'lltl~ O il "(xly wl'iV;ht, av;l', V;t-ml" r, am i wlu-t lu-r ti lt' pa lit'lll is
emaciated. ,l-S t1ist.'uss('t! in Chup. 16 , Di se a.\ l·. Ih Sl't! O il the n ,latinllshi ps ~\l 'n in Table
1fi-2 fill' ad ult pat ients who ;m' uol t'lllad alt't! or OII('SI',

(IdO - Age (yeorslJ x we ight Ikg)

Males: R, (mg/ day) • 9
5

11 40 - Age (yeorsll x weight (kg1

Female s: R, lmg/day) = 10
5 .9

To ilIllsl m h' IIII' ua-tho d. (11l1sidt 'r Ihl' tlal" in Fi ~, 2.1-W uhlaint' d ill a 20 -yl'a r-olcl
60- ~~ malt' paucnt \\i l h ucute n-ual fUII(.1ioll impairment . 111(' serum concenr ranon s an-
1.9 IIlWtlL ami -1.1 IIlWtlL mt';'l-s un 't1 2-1 hr ap art , 111t, t"\II('(.,It'd ,""hit's of \ ' alit) n, ( Efl' 91
a n' 36 L ami U-IO IIIWday or 60 mW1l r, n 'sl)('t.1i\'(,ly. s ll h~ l i l ll l i ll~ Ih, 'St, \'alm's a nd IhoSt,
o f (;n,,,tiniJw conce-ntrunon (t·:sp n'S.... -d in IIlJ,iL. 10 r-usun- 1"l!u;llily o f IIllits ) into E(I' S,
gin's 11 CI. C H (If (UJ Lill I', or (,') ml./min .
EI!uatinll S shoilltl he applit"l) jlldido usty. I\ pa rt fm m l ilt' pr obh-ms of l'sIi1l1;llinj,t n, ami
\ ' ill r-tuucian-d allllull('Sl' palil·llls . then- a n ' also i s''II I'~ ~ u m J1l1lt Ii Ilg: ti lt' (1m(1'nl ml ioll
datu. The 1llt'1I1I M.1 p nJ\i dl's a !)(M.Jr 1'~ lilll ah' of cn-atnum- d t'a r:IIl(1' when Ihl' d ilTt>rt'Ill1.·
11('IWt"('1I Iht' 1\\11 Illt';.Lsu n 'l1lt' lIls is S111;.111 (a nd tilt" ;l-s<;(I(;i;llt't l Iwn." lIlag:,· error is lalJ!;t' )'
unle-s s, of t~ lUrst' , Illt,y n 'pn -St'nl lilt" ~lt'ady.slalt' value. 111l' li ~t' lihOl KI u f Ih is ~ i lll ati oll eun
~,·1lt· mlly II(' d' ''llu('t''ll from l ilt' Y" lul's an d lilt' hull' c!ifft' n 'Il('('! I('lwt't' n them . Fur exa mpk-,
if 1\\'0 \~ll ut·~ taken 2-1 hr OI!Mrt <l rt':) alltl ,l .:} mWtlI .. n 's!)('t'lin ·ly, Iht,y an'li~dy 10 n 'p n 'St'llt
Ihl' slead\'-slalt' vahu-, ill which (';.LSI' C I.cH(d ) (1Ul II(' t'slimah"li di n -ct lv, CI.("H (d l = n,1
C.., TIl t' <n ';L\t ming: is ;.LS follows. " 'itll a no rmal se rum cn-atinim- of "~Ill tltl I lllJ,id l., a
~leady.~l alt' (' llll't'lll mtinll o f " Ixnl l :1 lIlWc!L would (1 J rn'~ pol1tl In a pp rtl\illlah ·I~· :J(l'l of
uo nual n-nnl fllllt1icm ( Ell. 16--12 ), wit h all t'\I)('l1t'tl ('n" llinillt, Il<llf-lift, o f 12 h I' (T ahl,'
2.1 -2 ). Tilt, 24 -h r lnn-rvul l x-tweeu lilt- I\\ U f1 lt'a.s un'IIl" 1l1s \\ulllti thcn-fon- rt'(lI'('St'1l1 «p-
pm :si lll<llt'l y 2Imlf-li\'('s, t' lI(lll~b h ult' for t ht, (, m('t'lIl ralioll 10 han' a pp madlt'tl slt'ady ~t a h' .
~ I o n"l l'"('r, hat! n -nal fllnt1 ion Il("t'li mlld l IOWt' f, 11ll' riSt' ill St'n llll ('n 'at ini lll' t1\"{'r 24 hI'
\\l lUlti ha\'(· I)("('1I IIIl1l'h v;n'alt'f thau 111..1 nhSt·rYt'tl.
:\ partit'ulotr p m h lt'm in tilt' app lil'aliun of Ell. S ari ~t ' S wllt' ll ('n'ali nillt' d l'ar,lIlt1' is n 't)"
lo w a mi a t It';.Ist Hilt' of Iht' 1llI';lSl ln'llIt' nls i~ f;.l f fm lll slt-a,l\- sla lt' . TI lt' ,·,I n 'mt' is lilt"
stlualioll of Illt';I-Slln'IIlI'llls la~t' n SlM. lll aftN ai mus l lolal rl'IMI ~ ll tl ltlll\\1 I , C n ·" tini lll' d"a r-
ant~- , alt lloH~h ull\i ulI.sly Inw , i ~ \'l'ry ptx lrly l'~tifll alt "l l. ;'l S lilt' ~ltll)(' til' lilt' 1,1lll1.' nl mlioll-
timl' rt>lal iomhip is tllt'll a pprtl\ imall·ly R,/\ ' ( Fi~. 21-11. AISt), wlll'1l n'llal fU 1Il1io ll a p-
pma d l" s 11' m , 11ll' Il()nnally j ll\j ~lli fkatl l lumn ·tlal (111111)( UWIlI 1 " '(~lm t's a sllll..taillial fllllt"
43. ru~R CONCEPTS CHAPTEr 23

tion of cn-uttubu- eh-arance . such that t-reatiuim- ch-arance is no longer soldY;l meusu re of
n-nal fUII(:ticm.
F inally, Implicit in the- metlux] is tlmt tilt" t"stiumh' of creatinine dl';lI'lllll,,(" applies at all
times within the penod of measun-nu-nt. OI,,;ulIs]y. e xtrapolation to other tt mes is dan-
ge Rms \\'IWII renal fun ction is uns table.

Anticoagulant Effect of Warfarin

I II ("OI n 11l011 willI ot he r l' ml0J.:{·lIoHs substuno-s. the amount o f e:tch d otti ng fac to r in tln-
hod y, A. is a n-snlt of 11 d illi'n'\l('(' lx-twccn its rate of syuthcs ts. U" ". ami dc'gradation, k{
X . \ . AmI. at any 111( 11)('111, whet her at steady sta te or not , .

dA
dl
R.,., k" A 11

Role of change Rote of Rote of

of clotting factor synthe sis degrad ation

whe n ' k, is tln- tlt'gradation rate constant (fract ional turnover ratt·) of tlu- dott in ~ factor.
:'\orl1lally. tIlt, system is at steady stall', rf,\Idl = 0, with s~llt lJes is lIlall'lJinv; degradati on,
I lowewr, ill tIll' prl'S('nl'l' of wa rfarin, the synt ll{'sis L\ inlJihiled without alTI'd ing " /' TIll'
(·lotting lildor cnuceutrut iou (o r amou nt) the-n falL\ at a rate that dqll'llds 0 11 hot h tIl<'
degre(' of inhihition of sYlllh esis and "'0
Eitlu-r a sl t'ildy-.~ t ale or a noustcndy-st.uc-ap pro aeh can be Ilst'(l 10 aSSt's.~ the more din-ct
re latiollship lx-twccu S~ll l h('sis r ate and plasma «nrfurin conce-ntmtion. Ead l ap proac h IJ ,L~
its own uu-rits. \ \ 'ith tht' steady-slaft> approach Ill(' entire dotting syslt'm is aIlO\\"("'<l to
rr-ach a Il I'W sh' ady state in till' pn'S('lIl'C of a constant concentratjou of warfarin, 11l('1l "
Olil" again ,"Vrft = 0 , Sll that " •• = R....,1k, and. 'L~ k/ is unaIT(·(:ted by warfarin, the steady-
state amount is dirt'dly proportional III n"n' TIlt" pr ocedure is th e n re peatod for different
plan-au conceutmtions of warfarin In elucidate till' n -Iatioush ip IX' h,\"('(' 1I n"nan d pl'L~ lll a
wnrfariu concentmtlon. :\lt h(Ju~h this approach" ppl'ars simple , the re is a prat1:iml problem.
Hecal l that tilt" time req utrcd to g(l from one plan-au 10 anot her depends so lely 0 11 Ihe
r-liminution 11;\1I~ li fe of the substance. As the degradation half-life of the d otti ng factors
alTeded b~' warfarin \',ny From hou rs to days, with an a\'("ril~c dTecti\"e half-life (for pro-
thr ombin comple-x acti\"ity) of uhout I day, it takt',~ lU'arly a wee-k to reach each new steady
stat e. Sueh a study tln-refon- tukcs as long as a month 10 compk-te.
The lIonslt'ad y. state ap proach. wliich IN 'S data nbtatncd fi )lIowi n ~ a S i ll~II' bolu s dose,
is more rapid but re q uires an estimate of I.,. Th is value- { ':1lI Ix' obtalncd hy ~i,i n~ a dose
of wa rfarin thai ('(Itllpl('fely bloc ks s~ll t l l('sis initially (H",. = 0). The prothrom bin complex
ad hity Ilu-u falls expoll(' lItially (l-::t l' I I ). so that a st'miliJgilritlnnil" plot of till" prothromhin
complex adhity agains t tinu- ";\'l'S a straight lill(" with a slope of k, ( F i~. 2.'l-.1). Subse-
I llIentl~· . •IS lilt' plasma cmnx-ntration of warfarin falls. the degree of illhihiliull of dullill~
filt10r S~ l l t l lt'sis dccn-ases and IIU' conce ntration of the pr othrombin complex rises (see
Fi~, .'>-6). t'\'( 'lltlli\lI~' returning to its pre-warfarin value. The chango in S~ll l llt'si s rate. R" n'
wi th tinu- is calcula ted from simultaneous JI1('iL~lIn'1I1enl ofwarfarin and prothrombin com-
plex at'thity 0 11 return to the pre-ourfariu valuc. ax follows.
I L \ I ami ' \2 are tln- p rothrombin complex aet hitil'S at tIle !>eginllillg am i end of a tillie
inte lYal.. !!.t, Ihe n the ralt' of change of aeti\"ity is estimated from (A 2 - A 1)/61 ami thl'
a\l~rage adidly within the in!t'f\ 'al is gin'n hy {,\ ] + :\ z )/2 . n,,,, is tlWll caleulalt·d fro m
r{'ar range lll('ul of Ell. 11. '
CHAPTER23 ' 37

12

11M.' pt'n't'llt inhihiliull o f s~ lIt1lt"!'>is i.. tln-u app ro\illlalt... 1hy

Percent inhibition of synthesis s 100 • ((R•.,..lnl - R..,..)/Rl¥"'lnJl 13

wht'n' R....( II) hi tilt" nnnmJ pn""a rfa n n ~ lIt1wsis ra tr-. 11,t' nonnal ran- is ~\1'1I I ~' k, .• -\ (11l,
when- ..' hi ) hi Iht· normal <K:t i \ i ~' of tilt' dol:t i n~ f;ad:or . .-\ p k)!: of the pt·n..-nt in hi hi liun nf
5)lIt1M.'Sis agai m t lo~:aritl HlI uf tilt· warfarin concentranon ~\1'S ti M.' cla.....ic n ...ptm...• \l·r"U..
('tIlK"'ll lrdtioll rt.·laHon..hrp. a.\ ,1111\\11 in Fig. 2.1 -11.
Rt"!iipt m ....os 10 stand anl tlu.,("!ii of warfarin d la.ngt· in t1i......a-\C· states and fnlll,.\inJ.:, t..,,"I-
mi nbtral iull uf ulht'r drugs. R~' a.'i<...· rta.i ll i ll ~ Ill(' n-lanonslnp I lt"No't't'1I pWII M l't IIK...-utruhon
and tlin"l1 ..rTt"l1. tli..tiIK1 iun.. can lit· llI alL.· b!."lwt",·n dlMlJ.:,lOS in phanllalu lindit.., flf war .
farin and c:hallgt'S in n~J1nn\i\1'I\(~" of tilt· dt)!:ting 5)"h'1I1 to thb dnl~. Fo r e-...... lIIlllt ·. tilt'
dilll in bht 1n ...I'M IIl • to warfarin. when ('(tallm illiste-n ... 1\\illl ht-pt abartlilal. is ( . 111...... 1\olt'I~'
by iucn-a.. l dt-a r K..-. tbe n - h IlU dlangt· in Ilu- rnTt"<.1 ~po n ..... II) lilt" dnlJ: t F iJ:. 2.1-1 1).

111t" p mhlt·m of u sin R a pla.\ma creatimm- (""K..-nlr.lI ion In a.......-s... renal flllK1io" \\ IIC'Il
fllnt.'lion dliU lRt'S at'I It·I~· ha..\ lx-en pn~nh ...[. Si lTl i larl~'. tilt· p roth n lRlbin adhi t~· 5 h r afh-r
a CM:N' of wa rfan n is hanlly a II w a.sure of tilt, t·lTt"l1 of lilt" dm ~ in h k.:kiuK III(' \) l l lllt"~i ..
o f the- dotti ll~ f<K1nn . Tn (1Ir1 t.t'r illm trd h ' till' inlt·rpn·t;diun of I ltJll. 'h~atly. ..lalt· ol)"l' r·
vat jon... con..i(!N tilt" follt,..\ ing ~i h l;.lt ioll :

A \t lltl~· i'\ C1m t! 1I(11.. 1to if tt.t· tl m~ Il ll't "hnl iri n~ t ·II7.)"lllt~ X am i r are- imill dhlt·
~ ...
hy plwll oh"rlJilal. of roll lm-rs an' ohla iut...1 fmlll unln·ah...1 r ats ;1IIt!
II t lll K ~t" l;lh's
From ruts p n ·tn·att...1 \\illl phenoharbital to "Uaill a nt! maintain a lllns l;lIIt (lI!1(,,· n lr.l -
Iio n . 111t· al1 i\il)' o f (·;K·1i of til(' ('UZ)l IWS is tlt·h-nniUt...[ in hnt h gmllps nf ra h 5 hr
afh 'r illiliOltill1: pll('llOhar hital ;ltlminh t m{jo ll. 111(' a' , ·m gt· ac.1 i\i ~· uf ( '117.)11 11' X is
i llc n·;l~ .. l to 2MY.t o f c..mtr ol. 111(" an ·raJ:t· ;K1 i \i~' of t·lI7.)l ll(' r is alxrut I ~'i 'l u f
contr ol. bill lilt" \~ll llt· is nol st atistkall~' di lT.·n·nl fm lll 1111' t..lI\lml \lIIIl(·.

100 Hit. 2.1--11. Pn"rr.oI" ..."1 ",,110 1..,>1..1",," ,1.,1 ( ~ . I

IlIIl. ,I.u~. fur l ~ ,~" ""rtmll. 1O,t.. ~ .. ",.fnn· ."n "nnl
,1o't:...........I II... ""1""' ''' '0 II .,,,...1.onl ,10 ..... , of , "rf.,""
1",1fililt..1'" alt..r ,I... lin..." n·L.lk""I,,1'I..·"" ·" .....
II....'......' " ,of rn ltl' n>",IMn t ·. ." ,]'I...... ii\l'~· " ,.. I "'10:'
• ..nl hlll " f II... t .. .. ........ ' ''' .. k..' ,,{ ",."n.. n" In .. 2 1.\I ·..r •
..101 ".. n"a1 .. 'I>,....i: n"'I" ~ "'I" 'ri""'''1 (O J. ' ",.,1,
o 1"1"'..I""hil..l <.1 () me-1•• 3.U f,I \I ~. '.·rum 1. ·\,\ .
( :.• (rKMII~·. K.A • .4.I0....... r. P,\I .. ..,,,I........1,. t : \ 1.:
• l......n I<I,,".... ......1:0"" II{ II... 0'11,..1 " f l",rt..l " r.. h·
U" tI "tit....'/;nLu,' ..i"", ,,( ",·.. n..,;" ill "'.. " el",
11""",, >1 , n...,., 11:372.--377. IY';'I U
o
• o
o
•
.,8 CH....PTH23

The-n- is a It'ndt ' IW\' til (.'o lld udc· tha t ('11:£\ '111( ' X is indut,"tl wh t' n ',ls ('1lz\11W r is 1I0t .
At1ually. (·nz:."IllI· Y m~y han" bl'('11 more iml;I{'t'(lthan ('110111(' X. Thi s l"om!itio ll is shown
in Fi ~. 2.1 -12 , :\ ' t hnu~h induction is \irt ua lly instantuneons 0 11 adlllill isl('rill~ plwlloharhila l.
l ilt' ('!l Z)ll1t 'S !la\(Od ilTt'rt'llt tu rnover churactcn sncs . CCJII·'i<'fllll·n lly. ou samplinf; at 5 h r . t.
i n lilt' fi p:urt·, H ill ' St't'S a l a ~I' r dl anp:t· i ll ("!lZ)111t" X itl1 i\i ty ht"{'ltllM' this (' 1I0111C hilS a
shor1t'r haIr-lift'. EUZ)1lJt' r takes much lunV;l·r to (',"prt·ss its Increused S)l lllwsi.s rat e h('(:a llS('
it normally turns m l, ' T sluw l)". I la d lilt' plu-uoharhit al tn -atnwn t l'C JIllinllt"t1tn ' 2' tht' d C'g rt't'
uf induction woukl han' appe-ared In he.' ('(111<11. w)\('rt',(S at I., a ilion' accurate- csttmate of
m-tual d t"",n,,-' of imlul1 io n \\1111Id !Ian ' Ilt'1'11 obtained. C lea rl)"', lilllt' of sillll pling is ('ri lka l
III all~' interpn -tanon. Furtlu-nnore. had t1ilTt' n ' nl slt'a dy-slilh' concent r ations o f pheno-
ba rhltallxx-n studied. tjn- threefokl Increaw ill t hl' ~-" l tl l('s is of t'llZ)ll1t' X might han, llt'(·u
the muxunum value possi"Il', wil t·n"l-s ('UZ)l lll' Y mi Wl1 han' been 1Ila.'(illmlly Induced to a
value- It) tune-s til(' normal oru-.

TURNOVER IN MULTICOMPARTMINTAl SYSTEMS

Elltlog('llullS eomp ounds, ltke tl m",rs, show dist ribution kim-tlrs within tlu- 1)()(ly (C lmp, 19 ).
·l1lis d isl rihu tion is not appun'ut [rum the plasma l,(lIlt'(' nlm l io n measurement of the ell-
t10gt '11C1I IS cotnpourul under ti lt' usua l steady-state cmultt knts , hut Ilt'('(1II1('5 ~o WIWll il t m Cf: r
t1o~' of tilt' nmlj)('llIld, in an tsoroprcallylalx-k-d form , is admiuisten-d. In lilt' analysis of
ti lt' tr,ll'('r data, two majo r ;l.ssulltptinm an' oflt'n made. First. til(' t1hl)(tSition of the t racer
is ideuncal to tha t of III(' (· nt l( ~l' noll s suhstan re-. Second. hoth inpu t ( fonlmt io n) aur I r-lim-
inat ion 11l"l'1If ill the inili.ll dilu tion voluuu-. Unlike for IUt tSt dm",rs, IheSt.' n 'sl rid ium a n'
ilion' pmhlt'lllatit· fo r hody t'(mst ihlt'nls that an' often Iomu-d ami dl'stro~1'(1 ill tiSSUt·S and
l!Jill d n IIlII t'tluilihm h' mpi<lly hd\\1 '('11 tissin- alltl plaxma .

Mean ReJiden<e nme

\ \ 1... 11 ti l(' hl.1I .l-SSlllll plio IiS al)(In' !ltIld , tln-u it t racer IIIUIt'('III(" (lII a\ 1.'mgt' , n-skles in tilt'
11I. )(ly till' sa lll(. lt'llJ.,rtil of !inlt' iLS ;jIlL'W (·IItI(~(·IJ(}lJS molecule. This Iilll(' is called the "wall
n ',~itll 'Jln' fl Jl U' (,\tn T); il is ldcu ttcal to rlu- turnover ttnw (t ,) of li lt' (' ndngt'lloIlS substance.
Then- an' two p nxx-du n -s (Appt' lI{lh: I -D) 10 t'Slima t(' .\1 n T. O fl(' Im'lhl)( I II ~'S the- area-
ulldl'r -llw.(fir;t )-1lI0llll'll!-\'t'rslls -tilm' cu rve, f ;;t ' C ;' . lit , dt 'uoh'll as A U.\ fC, and AUC .
~ iUll('ly,

t 'i l" Z:l- U:, h HI' M1io " o( " "'0~"" ;;:5
X (.. >li.lli, ...) t...· ~ f....1. .. n( ti m ..' ~,..I
""'0"'" r ( .,, ~ ;,..I III"')10:-' " f...1n • .,(
("". [",,,"'. n """n.,,,,·, I",,, , " f M I · ~ I,
I
1
12
I
I
t,
,--- ••__ ._•. -
.. ._.-••-.
~ 4 Y
1:\"", r i. 2t1Ii",. .. , I.~I n ( "".l',,,,,,X. E 1 1 ,

TI ,,·I,,'i',' ",un,,,. 1." ,·1.'", II... ~ I I .....

i u.lit·" " .. 1 (.1.,,1.. ,<1 h ,,.., ) art' 1 1••••-···
li" ~ 3
•liff,'n,.,l. h,,(-,,",,,,· "r ,hfli·n·..t .. ~ ill ~ 1 / •••••••• ••
,I,,' lun" ",', h ",... "f ,I,,· """ " n- E
0~'1t" , T iu lt' i."'rn·,,, ,..t ill h'nol< of ::;::2
tI... hm lt... ,. Ii",,· " f " '10'''''' .\ . 1/
:f
1i
~
...1,"
E
~
"' 0 6-,-
o 20 40 60 80 100 -
Timel(Tu rnover Time of Enzyme Xl
CHAPTER 23 TURNOVER CONCEPTS 439

AUMC*
MRT ~ A UC* 14

whe re * refer s to the labeled tracer. In the oth er met hod, .UH"l' is obtained from u rin arv
excretion of the unchanged tracer. Provided that fe re mains constant with time , -'lIff
(t urnover time ) is the n

15

.
where Ae * and Ae * are the cumulative amou nts of labeled tracer excreted to time infinitv
and to any specified time, rcspccttvcly.
.
Steady-State Volume of Distribution
Re me mbe ring that ,\f liT (tu rnover time] is the ratio of pool size to tur nover ra te (p. 42.') ,
it follows that

M RT :: ~ :: Va' C;$ 16
R, CL · C;.

Thus, OIlC arrives at the l1J1lceptllally Important re lationship.

MRT = V•.ICL 17

This re lationsh ip is analogolls to the one de rived for a drug base d on constant-rate input
(Eq. ,I), Chap. 6). The value of V...can be estimated nsing the plasma tracer concentration,
realizing that CL = Dosc* /AUC * and l'()mhining £ (1. 14 with Eq . 17, to gin'

Dose " A UMC*

V•• :: A UC* ' AUC* 18

To illustrate the use of a tracer to determine turnover parameters and ' '.\. of all endogenous
substance. consider the followtng btcxpoucnttal equation . whtch summarizes the exper i-
mental observations after a Ju-m cga-Bccqu e rcl i.v. holus dose of a radiolabelled tracer.

C* :: 1.2 e -1. 2t + 0.2 e - O.0 1/ 19

where C * is the plasma coucent rntion in uni ts of mcga bccq ucrcls/l. and f is in minutes.
O ne Hecquerc] equals one d isinteg ration/second. The A Ue is

AUC* = t" C" . dt :: .!...1. + 0.2 :: 21 megoBecquerel.mins/l

Jc 1.2 0.0 1

and that ol"A UMC (Appendix I-D) is

AUMC = f" t - C'

.lo d
. t ::
1.2
('i"2p 0.2
+ (0.01)2 '"
2 00 1 megoBecqu erel-min2/l
,

Ac('()rdingly, the MHl' (E(I. 14) is H.') min. and V.. (Eq. 18) is 4.') L.
... TUIlNOVEIl CONCEPTS CHAPTt: R13

( ;ak'u latilll\ elf turnover run- n -quin-s L:.ll owlt"(I~(· of the rmnx-ntrat ton of tht' (' lId( ~('1I0IlS
suhs tunce-, for example 9 mJiI.. 111(' amount in lilt' IJUl.ly (poo l sin ' ) is Ihcu 9 m)iL X 45
L = 4 (~5 1I1 ~, and frorn IUnJ(J\'('r tiuu-, turnover mil' (/\ •• 1.\1 Rn
is 4.3 IlIWmin . ami Fructfonal
turnover run - is 0 .0 I m ill - I. TI lt' tUOI(J\1.'r of th is substam x- is now completely ClII<lnlinc'tl.

STUDY PROBLEMS

(Answers to Study Problems ore in Appendix H.)

I. Dt'fim' t ilt, r(Jllmti ll~ tenus:
Turnover Fructioual tu ruover mh '
Turnover ran- ~ I I'iUl n-snh-mx- lim l'
Turuovt-r tiun -
2. E xam ill;llioll of lilt' da ta in Fi~. 2..'l-tl im lit-;Ih 's t ha t III(' normal (I);"-·,,,IJ p la.sllla ('0 11<''('11 -
tr ation u f ('1')1hm po i('tin is 10 IIl1ils/l.. Using till' values o f till' pa mll lt'lt·rs oht uJned
filllll\\i uK tilt' i.v. mlllli n isi m tio ll o f r-poe-nn a1fa (V = -I L170 k~; Cl.. :::: 0 .5 L l1lr/j' O
kg ), ca k-ulate- Ihl' ff)IlO\\; Il~ parann-ters for I·ljt hrupoi l·ti n, asslIlIling that epoetm alfa
IIl·haw s ie lt'ntiea lly to 1·r;.th mpu il·lin .
a . Tu rnover rate-
b. T umov r-r tum-
e. Fral'!iollal t u rnover rate-
3. To d larileh ·ri......· Ill(' tumover uf uscorbic ad d . Knllner 1'1 a]. {Kalim-r A., Hart mann , D ..
a lJ( l lI om i ~ D .: Sleady-siale turnover and I Il KI~'IIl Il)1 o f a<;(·orhi<.' add in man , Am , J.
c lill. Xut r. 32:5.1(h'i.19, 1979 ) nrallv adminlsten-d a md iolaht'l l't l tracer do st· 1l ~1' I Ilt" r
\\i lll rl·lali w ly Ill'\\' dust·s (30 to ISO ;ng) o f this vi tamin daily 10 20- 10 -tS-yt'ar-o ld malt'
SUhjl't1S who wen- 011 an ll-\l.u rhi<.· ad d -dl·fidl·lll dil·1. TI ll' follOWi ng infon nat iu u wax
u blaillt'tl in Ollt' suhjl"(.1 rt't.'(·i\i ll,g 30 m,g daily of 'l-<;(·o rhi<: acid until a sh'ad y shih ' wa s
ad lil"''('t!: C.. = 4.1 IIlWL, V.. = 2.1-1 L. Ct. = 6.3 Lli l lY, From thi s information.
l~.ll'lI lah' tht · followi n,g p ara mdl·r.; for 'l-<;(·o rh ie add :
a. )'cllll siZt,.
b. T in' tiun- 1It't't I('t1 fo r input to l'(lual tilt' alllOlml i ll till' IIlKly.
c. T Ill' 1I11'all rt>siclt'IlI'I' time.
d . TI ll' fntl1ioll of III(' orallv admin b tNI'l1dUM' absorbed.
4. T in' "u sual" ph slIla conce-ntration s o f nren alld l:f(·a!illillt· an ' 15 IllWIOO lil t. (2,5 m ~l )
and I mWWO III I. (O.()l.J lll ~I) , n -spect iwly, ill )uung ad ult panents \.\ith n or mal renal
ti uwliun. TI ll' n-nul ck-a rances of till' "'\ 1) compounds an ' 'il) m L /m ili ami 120 mLI
mill , rt·spt't.1 ivdy: the volnuu-s of distribut kru it! sft>iltly state' aft' about tlu- samt'
(42 I.), Bo lli (~ ll l1 pull llt l>; an' ...Iill1 illah 'tl un ly by n-nal excn-nou,
a, ( :HII'ulale t jn- "usual" fmd io nal tumovi-r m il'S of ' " ,th ("()mpc)llllck
h. \\'(' n ' tilt" r ates o f p nll !ll(:tillll o f tilt'S(' compounds II) n -maiu " us ual. - how Itllt,g\\"()uld
it take fur tilt' p h slIllt ureu rmux-ntrunon to mcn-asc by 30 mWlOll IIlL (5 ,0 1ll ~ 1)
and tlu- pLL>;ma cn-atuum- cemcent ratton to tncn-aw hy 2 lIlW101l II1 L (0 . 1,1) m ~1) in
'Ill ;lIlc'p hri(' pa til'lIl?
(', Urt-a is an ('lId p r oduct of p mh'ill IIlt"tal)()IL>;m. Its forllla!ioll c..til 1)(' n'( III("I'(1 by
dt't.'f(·;lSi ll ~ prote-in in till' d id . \ \1. at is lilt' tot al amou nt o f un-a i n ~est('ll and p ro-
1.11Ic'('t1 ill tln- IIlKI" in 2-t IIr under sh 'mh·· stall· l1.lIlclilio ll"?
.'5. If the - tUnlO1OC'r titm: of an euzvme- is -t da\~ and its wn tln-sis m il' is tn st.uulv illl'n·'l'iot'(1
tn a constan t value- thut is tlt;"'(, thnes t1;c' normal ~lte, how lon g \\i ll it t~kl' for ti lt'
t'nzylllt· adi\ity ( 1ml't'lltraliou ) 10 t!c )llhlc'?
6. Cum id C'f two t'1I0 111('S. A mId B, both sllSflI 't.'!('t1 of I Il ' i ll ~ subjt'l1 tu im lul1iu ll hy a
slC'foid IlUrlllom·. t\c1 m illistmti o ll o f tllC' st(' m id to ~"l' lIt'a dy l'tlltstant ptLsma l'l.IIll't'II-
 44'

lmftom. for 2.J h r n-sult s ill a do ubl ing of til.· a{1i\i ~' o f (·II7.)'IIW A. hul c'nryll1t · B
a(:t hi t~· i ll l 'n", L'>t' S insijit'lli fkulltl) , (I(...s than 20t{ ). 8;L~ ...l on thts oI JSt'lvution. till' follow-
ill~ statem ent i!i mad" , "The , It'mi tl has a much ~rt'alt' r (·fT("'l1 0 11 I" . ' S)ll tllt's i~ IIf
t' 1I7.\lIW A than o n lilt' s\11 I h('s i~ u f euzvn u- 8 . Is this (''Olid uSklll warrun h ... l? Hrit-Ih
M

( 1i_<;(~l u . . • •
7. a . Prio r 10 em (1)isutlt· of <1(111(' n-ual failnn-. a 1l;t1it'nl ( lI toj ~ht. lfi.,) t'1Tl: \\'(·i~h t. fi( ) k~1
I.ild a tla.il)' n-nal ('M'rt 'tion of 1.6 ~ (1-1.2 lIu uolt-s) of (·rt·ati niu(· lUtt;1 a Illa\ma ( '1 11I'
(1'ntr",ticm of I m WItlO Ill" (0.9 11I \ 11, 1>llrill~ ac11tt" renal (<lillift'". ti lt' p l aema r-n- ,
ati uua - (UIK'l"n l rdlioll n -.' II)-"3 mwlUO ml, (O.27 1Il \ 1l/c1ay aJKI tilt' lui!)' renal ('\ -
tn'tio n uf (-n~... ttrum - ~ ...... \irt uall)' nil-e-anuria. Cak'ila lc' thc' "no rrnal" IIlI"an
n"!'iitlt"IK'" ti, nt' (.\lHn of creattuin..• in this P;lfit'llt .
h. lI acl iK'Uft" n-nal iu:\uffilil 'fK)' n ...lllt,.,1 ill <lJ 1 illlll l(.,liill ,· dmp ill 1Tt.·ati nint' d t'"mUK'"
10 l Oll of noml.J.l <lIKI ruu.1 t1li:\ funl1iOllal :\t;lh " l't mlirnK'd for all ilKL.'finilt· 1lil.'til . 1
of time, 1M, "' IOIl~ "nuM it take for t ht· pld.'i ma ITt-"llini'M' l'tllK't"nlrolhon fo n "iK'h il
vahn- within ( ()Il of tlw d iIT("« 'IK' · I,l'tw (.,'n t hai n "fltoctilll/: tlw tL.1Ul...• of n-nal
dy~f1UK1ioll lUM I till.' illilioll ,-a..lm·?
~. 11"" tumo c er of alhumi n hil.~ hl "t"n '\t1Kli,., llI..i ll~ Ir.., "r 1t"(·llIliIIUt-S ( Slt' ri i ll ~ K." J. Cl in .
11I"t·..t., 30 ; 11,1" fu rnlJ\Ot"r rate of ...-mm a lbumin in man as IIlt·aum.,II,,' 1J 1 1_ la~t '( l
albumm. I22S- 12.17. 1951 ). In Ollt' of tilt' suhjt'(,1S, wlM' """"'1.,16.75 IIM~ilBt,,('IIII'n']~
of u1 1.1aIM,It.,1 alhu miu in lmu.'IJ( K''ih' ti lt· ('tJIK" nlmfio ll of rdlIKl;K1nih ' wa s nlt",·", ..'(1
to (L.'(,,!i llt" iK"unlin~ 10 I]J(" folloui ni n 'latioll '\hip (I Bt"('(lut·n.f - I di ;i llh 1:(;lfillll P't'r
"'"('(JIltl );

1.5 ,, - 1", + 1.2 ,, · 006'

{tin dartl

K Jl( ,"ill~ Ih"t Iht" p lil-'\lIIil alblllllill l't'I"-"t'nlntfion wa.\ 42 W-l. in fh i s slIhjt'l1 a nd lIIakill ~
till" a."" lllIptillll tt.at hutl. labek-d iUll! ulI]al.l"II'] IllbullIill show the- \allll' kim ·tit' Ill'·
havior (uI N ,,,,"('(1 101M' a !-.'t,ud approximation n~ill" 1I1111'r It'(,hni1Inl...), (111(, llall' till'
folltMing::
a. 11l1" tnmowr tum- uncl fmdiullill turnover r an- of allmuuu.
h. 1111' urnounts of alhumin in illfnnw\(" llar (i ll itia l d ilut io n \ ul nllw) itmlt'\ lr;t\'lt'ol' lbr
lIui,k
c. 111t' 'i)lllllt'sis m ho o f albumin.
U, .\ tlnlV; ill'l~ d in "{,tly h) inl.ih ilillV; the- s)1l11wsis uf <III "lIl luv;(' n()".~ su l ~l m l ('t' (1·.V;., m i t,
alid p ruc.lut1 io n): tilt' t,fTl'l '1 of ti lt' d m g: is IIlt ';l~lIrt '(l im lirt'(,11)" !Iallll ·I>', b)' 1Ilt';I~lln ' ­
1Il('1i1 uf ti lt' pl ll~lIIa couceutruuun o f tilt" t'ut!nV;t'lltJlIS su h..tam e. S . 111t' sd lt'lIIt' o f
1"'"('II1s ( '<III hi' t1t'pil1I'tl lts f" lIow,;:

~~-, 'A' I, ,
Synrhesis ~ Elimination

wl.t·n' A, i~ Ihl" allluUllt ' If S ill Ihl"IMJl I)" ant! k. is lilt" (,limillat KJII mh" t'tJ!l..litlll. l li ll.is
'o(:I.I·lIIt·. ti lt· nail" o f S)lIt hl"'\i~ u f S n "'\lltJllt!s imtanlalll'oll..ly fn dliUlV;" S ill Iltl' ('tIJI('('II'
tnation of tln lJ:.
11 lt" timt'" alKI ('tIITI...pnllllin ~ p la..ma t'()IJ{'('ulrdlioll '\ of dnlg alKt S wht'n a su hjt'l1
is l'hall(' nJ:t" "ilh a )On IIIg i.\·. l J1.tIl ~ (1..1'14.' uf I]nlg:a n · llR"SI"lIh.,1 ill Tahl!' 2.h 1 . 111t'
Ilhilnll<K'tIlim'fil-,; o f tiM." dnJ g a n ' dlilJ"iK'f(ori"A '(,II ~ a 1J1M"-t.'tJJ1lpartnlt"lIl !Il1J(lt '] in wllidl
A; ... n .n~ Ilr - 1 alKI ' " - 10 I _.\'i 1"'1)("(1 1'(1. tlK' n' i'\ ~llk 'la)' in tilt" nl<l\itlllllll I' M"('';111::
u f ti M" p la.\lIIa ('tJllt'''lItm!iulI nf S.
44' M NOVE P CCNCfPT5 CH.APTH 23

T.bI.23-3.
lWi (!wI 0 2 4 6 a 10 12 16 24 30 30 4' 00 n '4
PIolll'lO ccocee 10 QO 82 7 4 61 0 1 5 5 4 5 3 0 2.2 17 0. 9 1 0 5 0 27 0.1 5
wa hon 01
d''''9 lmg/ Ll
PIosm:J concan- 100 n 53 40 31 25 2 1.5 IQ I 24 5 32 4' n as QO QQ

"""""""',
1fOIionoi

w~nce.S
1% 01 r.orm:JII

Cha lll' II~II ~

lilt' snhjt't1: wi th a 2()()-1ll~ bolus dose 011 another occa sion dill no! shorten
tht' time- taken for the concentration o f S to initially f"II Il)' SO%-: il d id , of course, r a use
it <1''f.'IX'J' andmon- prolonged dcpn-sston in tilt' plasma l'tm{'t' u t ra tin ll of S.
it. plot tlU' t ill l(' ( 'OU rS(' of S on line-ar ~mph pal"N,'r.
h . Ba.'>('(!oll tilt' ..c lu-rm- a bove- a m i till' info r mati o n ~\l · n . ('t llls t Ol(:1 a d in "(1 rt"SpOIls('
(inhibition o f S)"1111It"s is ) ve rsus pl'Lsllla d m~ concentration ( 1 11'\1.' , (l li nt . \ \ 'ri l t ' tilt'
ra n- I'IIU<ltiu li for S a nd n 'arrilllJ!:t' it to (·xprt·ss till' 'i)oll l!wsis mh' of S iLS a fun ction
of its pl.Lsma t"ulIl't'l1l rat ioll alll! its d im ina tio n raft" cons tan t: " 111 \~i ll nt~ 't l to ('sti-
lilah ' k, to so lvt, the problem.I
c-, From tilt" ( 'U I"\'(' d rawn in part -1>-, eslim ate> tilt' f:e.Jl , va l\l(' a lltl commen t 011 Iht"
most likely vahu- o f""( in th e n '!aliollship

d . If a conce-nt ration of S, 31 )(t o f ti ll' normal value, is 1I(,"(·t!("(!lu adli('\l ' a ( Il~ in't !
t1l1'mpl'ulit- rt 'SllC}Ij <;t.' , dt 'siWI " sdlt~lu l l' of till" d n lg: « ,,() lIl llC )s'('i ! of a bolu s dU M' a n d
a constan t-rate infusion ) that will. us rapidly as possible. adli{ '\ '('lhis objective For
tilt, purp0st 's o f tl lt'st" calculations. h-t the bolus tlnst" pmmplly a["hit..." , tilt' desln-d
platt"all plasma conceut ranou of tln- dnlg:,
 · 24

DIAL YSIS

OBJlCTlVII
The reeder wi"
be able to:
I. Define diO~i$. hemodialysis. e-nocoporeol dialysis. continuous ombulolofy petoeecl d,-
aly$i5, dialysis clearance. dialyzer, dialyzer effiCiency, chnccl diolyzobility and hemof,ltro-
lion.

2 Calculate the changes in clearance and holWe of a drug and pedcr the linehc event:.
brought about by !'lemod1O!ysiS. coesnooos a mbulatory per'lOneOl dlOlysis. 01 hemofllrrol'on
g iven the clearance by the procedure. the 10101 (bodyl cec-coce. and the holU,fe In the
absence of the treatment
3 Givendialysis clearanceand the phOfmocolinetlC poromelefs 01 0 dlU9 in the absence 01
the doalysis procedure, anticipate II a supplementary dose is desilObie immedtOleIy ohef
doalysis. Also determine who! the.wpplemenkl'Y dose should be
4 Di$linguish among the Iollowmg rechniqo.Je$: hemodialysis, !'lemofiltrOII()n. and hemoperfl,t
sion.
5. Given a drug w,fh known ~ic:ochemicol pooenes and phormocolil'lehC behavior. d,s-
cu~ how well each of the pccedoesksed in ccecnve
A may r~ drug Irom the body
In on ocedose silVOt,OO.

Dial~1i i s ami rd ak () pr ocedures h ;I \ l, IIt'l"(l lllt ' l's lahlh lll'ti trvannents fur p 'lt it'Uh .... tt h ('11( 1-
slap;t' n-nul dl...·,LW. 1111's(' procedures an' dt' siW't"tl to remove todc '\~L' h' products that
accumulute in p atients with th is d i...·a.'i(·. How ever, tilt')' al'iCl n'IIl11\ l ' drugs. 1111ls. sud l
procedun-s lIlay « '(llli« ' adjustment Ilf drug administ mtillll in tilt'S(' patit'llt s, 111is da;.lptt'r
prtwidr-s inforlllation Ilt't'tlt'tl to t1t·t:idt· when am i how to mah· such all atljush nt·nl. COil-
tinuous a mlmlatol)' pt'ri tUlll'al dia lysis is alsll diS{'usS('t1, lx-cau...• it is n·~a n l t 't l ,l' tilt' treat-
uwnt of dU lit't· for lllallYpatk-nts. Ilt'lI\ofiltr.llio ll. a1t h(Jtl ~h nnt stri<1ly a di al~ ...is proo-dun -,
is alsocovered. 111t' I,l,t 1J;.lrt o f tln- chapte r is dt'Yott"l1to til(' U st' of 1ll'1II1)(li;.tlysis. ln-mo-
filimti llll. ant! anot lu-r lIumlialysis lIIo<lalily. helllope rfllsiun . to treat o\l'n lost'tl palit'nls,

HIMODllL YIII
H;'lsit·ully. djuly ~h ilJ\l lh l 'S wparation o f d ilTllsiblt, From It'ss <lilTllsihl<· suhslalll't's h~' tilt'
uS(' o f a S('mip"nm'ahll' memlmnn- \\illl lilIlt· o r 1111 lit'! movement IIf fluid across tilt'
1Ilt'll\l,nult ·. \ \ 'lu-n tlu-.....lIlipt.n III 'ahll' lilt -mh r am- is thai of tln- pI -ritoneal tol \ il y. tlu - d ialysis
is ternu-d ,H: ri tlllll'(II diflly~ j.~ , 111l' o unuu»r t1iitlpis tt"l:hn illlll', 'l('lIlo(lit/ly ~ h . ill\l JIH'S PitS-
sagt· of blo od I h mll ~h a sp h' lII t'o lltailling: all artifidal st'lIlilx' nllt 'abll' meurlmuu-. I\t"(·au ...·
of Ihe la~t· an-a o f nu-mb rauc n-quin-d. slId l a system is. by lIt"l't·ssily. ou lsidt· 111I' IXllly.
At"l'tmli ngly. this 1lU'llu lIl is It'nllt"ll ('xlmc0'1l(m'al di(/Iy,~i,\" 111t" tlialysis s~ ...rem itst·lf is
 CHAPTER 14

(~.lll l"t i a hf '/fulfl I111yu ' r or an rlrtificUll kid/l( 1j. Om- prevalen t kind o f s)"stt"1lI 11'if."t1 tod ay is
til(' hollow -fiber d i,lIp .(·r. It cout uins hundred s o f hollow fib e rs bundled within a compact
","'lill(lt,r. Blood flows th nmgll tln- semt pcrnwable hollow fihf.' rs wllile d ial~"S<lte fluid flows
(lutsid!"tllf' fill('rs ill a co untercurrent dirt>l-1ion .11 Iest' svste ms an' small. e fficient. re lativelv
t'as)" to UM' , am i art' 'it)lllt'tilllt'S n -usable, In the follt,,~;n~ di scussion Oil quantitative pro-
ex-dun-s . diIJly ~i.~ an d dilllY =I:r are terms uM"t1 to (Ies<:rill(' tln- gl' llf'ral Ill('th od ami tilt'
ap pamtllS of Itt'lIlot,lialysis. n"s pt,'<.1 i\1:' I~' .
A l)llil"aIJx'riod o f d i;llysis Ls 2 to -l hr. Evr-u shorte-r times ( I to 2 hr) arc 1I.S("t1 for tilt'
mu..t t,·ffidellt s)'S!t'ms . The actual ti ult' rt"tluirt'(l is a compromise ht'!wl,'f'n tlte tt me 1It.'f'dt"tl
to adt"t l" at!"l)" n-movcllukls alltl metaljolic waste product s an d th e (-'om fort and convc utence
to pa !it,'1l1s ill ~t-'l lt.' r.J . 11le e ffid t'IIl)' o f tilt' di ,lIp.('r is a major determinant of both.
1\ vu ru-tv uf ht,'lllod i;lI\'Sis S\'Stt'IIIS are in use todav. The abihtv of a dialvs is svste m to
n'IIlOH' t.In;~s fmm tjn- 1~ )(ly (it'pt,'ml'i on ma llY fac:10 ';' . 111cs(' in l'iml t" t1nJR~hard~1t.'ri.'itk'5
(molecular w('i~h t . protein hindi n ~, \ 1,111111(' o f di stri!,ut ioll ); mec ha nical properties of tile
dtalyst s S)"stt' lII (surfa{'(' area ami thickness of membrane, pomsit)', ~t'O lII t'tr)" o f the syste m.
t' X , wlw tll('r h lc)(K! am i di alysate IIt",'S art" co untercurrent ur l'o nl'u m'nt) ; and eli:lIysis
(UIlt.!itiOIlS ( (-' . ~. , blood ami t!ial~'S;lt t, 1I0w rates). Bt'<.'a llS<' of til(' variety of !>}Sft' IlI S and
conditions , (lwmtitOlti\'t' {'xlmlx, lat ioll o f data From om' stud)' to another llIay h,' d iffieult .
Xom-theh-ss. a I)(xly uf pnnctplcs applit'S tn all S)'Stt' IIIS and to tbe removal o f " oth t-'lJ( I~­
t'nnus suhs tarwt·s am i ( ! n1~S From tilt' I)(xly h)' them . TI l t'S(' principles and co rukh-ra rlons
u f pnssiblt, 'lIljust nlt'llt in ( I nI~ urlrumistrution in patients u lltll' ~oi n ~ the se procedures
folio\\'.

Dialysis OeoroMe
:\s wit h mmlYot ltt'r applications of pharmacokim-ncs , tilt' most useful concept w hell d ea ling
with dial >~ is of d mgs is clearance. ! Jialy,5b c/t·rlnmC'l.' is a measure o f 111m ' e lTt"'l1 i\'f.'!y 11
dlalvze-r eitll n-move a dm~ from blood. It is the rate o f n-moval relative to th e conccnuunon
in lil(' blood t-' IIINill~ IIIl' d hup.l.'f. TIl(' USf' nf tilt' concentration in b lood, ruther tha n in
p l;lsIllOl. hils an ,\(h1I11t a~e ill n-laung hloc d clearance to blood flow and ill n-lattng ra te of
n-moval to mit.' of pn -sr-n tan on to tilt' d ialy/.t'r . principle-s pn'\;ollsl)" dt'\'l'!ope(1 fo r be-pane
and renul extraction (Chap. I I) .
Tn ;tpp rt'<.·iOlh ' how di;lIysis clearance is measured . {,(lIIsidt 'r the st'ht' matic n-pn-senrauon
of ;l d ial>7,t'r SIIl )\\1 1 in F i~. 24-1. At slt' ady state , i.e., wln-n then- is no net ('h a ll~e ill Ihe
amount of dnt~ in till' tlialy..u-r, tilt.' ra te of its n 'IllI" 'a1fro m hltKKI r an II(' dt1 t' nnillt'i l in
~ '\'I 'ral wa\'S.
Ednu.finn Fn )1TI Blood. 0 111' lIlt'thod is by lakill~ Ihe difft'n ·n(·l" lx·twt'('n til(' rat e s al
whkh tilt' sllhs talln ' t' u!l'rs (9 b.l" . C" ....) aml lt"a\'e s (Q,,, ou' . Ch~ou' ) tilt' dial r /·N , ",Ilt'n-' Qb.,"
<Ind Qh~ou, an' tilt' b't )(x i llow~ and C ".. am i Cb.,ou, a rt· tilt-' ('OII{'(' ntmtio ns in 11ll' artt°rial
" Ill(' d ialp ..{'r .
hlulKI t'lllt-'rill~ and n 'lIous h lt)(Kl lt';l\;ng
Dial~'Si s h lnt'KI d t';lram'(', C L"J)' is tlll'll ~\"( ' n I~'

D ial>'Sis l"!t'ar'Ull,(' . Cl. J" b,l'it-'(I 011 d m~ t''()nl'('ntm tioll in plasTllil t,'t1!t.'ring tilt' t1i.u~·/.t'r, C,",
l·;\.lI lx' t1t'tt' nni llt'il f«lm e l.I) = Cl' /'ll' Cb ,,/C/ft.
111t.' vailit'S uf 9",." allli Q/o""" art' not t,~·t ly t'(lua l. ,\-s l11t.'rt' is u ftt,'11 a 2- to 3· L lo§.'i of
fluid t1 Uri ll~ a t)"pit-'" 3- tl) -l-hr dialysis pt·ri()(!. TIlt' \'a l\lt' of QI',I" is ll()\\' dt 't t'n ni1lt.'i1
at'(:unttd y \\;tll fil)\\' S('IlSl I I"!'. 11lt' \~lla lt.' of Qb"ou, is {'all'lIlah'il hy 1IlIlI Ii pl~i ll~ Qb.•" by ti lt'
filtio of Itt'lll<ttlll'rit " ,Im 's al"nlSS tIlt' d ial>7.t'r.
 ..,
Ra il.' o f Hece ve rv in D i" I",.ale . A second method list'S the Iw l r ate at wh ich ti ll'
sUhs!;Ull't, I,'av('s in l h~. di alysat e'f1uid , Q" ....., . C l>.-f - Qu"" . C u ..... where QIJ.....I and QIl,'"
art' til(" d ialysate IInw'S Il'a\i ll~ and ('nh' ring the dialy...a-r, and C u""" am i em.. arc tilt' re-
SI'IC"l'f h 'I' (~lIlt"('n l ra t io n s.

e lba = IGo....... · CD....... - Go.in • CO,in) 2

Cb,in

(AI-SS of water to l ilt' d ialpatt· is ac.'c..'o llll lt"li fo r here . With the common ll11un'Cirt:'U laling
(singlt'-pll\S) di a l~"5is syste ms, en,.. = O. Equation 2 the-n red uce s to

Amounl Heeovered in Dial)'sal e. A thlnl. and generally tilt' most Oll 't.1 1r.lIt' , met hod
of dc.·!ermi llillg dialysis cle arance is 10 calculate the ra tio of amount recovered in the dialy-
s un- (\'/) ' C,,) to tilt' an-a under the arterial blood ccnce utrutlon- um e curve withi n the
collec tion period, r . 111<11 is.

Cl _ Vo ' Cp
ba 4
f~ Cb. ift • dt

whe R' V" is th e volume of dialYliate collec t ed dllrill~ the Inte rval. r . and ell is th e d rug
l, ml't'ntm!ioll ill tilt" llial>~t e aftN mixing.

·•' -• r-. · . .y .. ...- -. . CO.out

· ... .···.•• · ... . . .OO.out .
0 l:l.il1
· .
Blood
:1· .I. sate D~~

Db""' • DOJn
{ :. c- - -
· 'J...
CO.in
•

Dialyzer
"'i". 24- 1. Sd...."ulk " "f'I"Mt'!II;t!io" o r 11 t,""1< >tlial}~ s~~t ..", ill whicll dm" is f"'l~'"'~' lnu~,r.. rred lll'!'"" 11
..."'ip" m M'ah lt, " ..·",tmu M· (•• • j fnom hlt..l lu tliaI)......I.. . Oru" ill d..l j,....rnJ lu tl... 1)'StO"fl' al noll' V".. ' C" .. and
i' n ·I" n .... II" ,he· ,....ly ;<I mi.· 0"" .., . "'"",.-..n
C" ..... Th.. ,liff..Il'1ll'" In..s.. noh"S i , lhe 11<"1 nol.. "f It_ i",o tiM'
thal~7i"j( fluid. Thi' ra l.· " r " ' lrMA""", i' IIw ""mt· "" ,I ... thFT"T1"fK'1! 11t"two..." I.... r.. t."S It·....; ,,"- On C,,_ ,u MI
o·nl..r; nl: V" .. . C lI ,.. ' I 1~7.t'r in II... , 1i~lOllt·. \\l l hill 11M· clial).·fillj( 5),I<'m_blood <IIltl dial~ t•• fl , '''''~' lit,
'''S~'"hal ly ''''It'um'nl mlt' n 'Um 'l1 l. or c........'Urn·nt. Otl"...run j(un II... 'pll' m Ot'Sipt. • ",..~ in !I". nMm rol1l'
mon .h"'y,, ·r. 1..~ It ...., 61>t·r.;on· "MIllI.·".. 'm'!'!. ...' shown . C",,,; C,,_ .. clro" '''''II,'l 'nlnotit,m in hItltltl ''1' '''ri n"
;II .. I It·.....i,,1: ,li.dyf"'. n.. t"..1iwl~'. C" ; C lI _ - ,In 'l: co,II,'l'lolnotiu,u i" '~""'I .. Mllt'ri "" ....,,1 ';1111: ,\i..J:.71·r•
..... p'.. 1 iw~·. VI> ...; 01>, 1>1... 1 f1, , (u ..... I1~· 21111 1" -11111 m l / m in ) ..nl o·ri " 1I: &lItl lt...';1I1I: II t1i~.,~·r . V" ..;
V",.... .. .bal~~t •• ", ~ ( u."",,I~· JIll) ,,, fitJU m t/ m in ) <'I1 lo' ri"" and Jr....;"" ,.... t1i.alyzt.r.
 CHAPTU 24

Dialp;i s ch-arance- dt"()("Jl(ts 0 11 thl' d ialysis system. till' [ruction unbound in blood. and
Ihe molecular sin ' of till' suhstance..·. A likely value run hl' pn-dicted Irom

Blood dialysis _ Dialysis clearance , / 113 , Iv

5
clearance 01creat inine \ M.W. b

or

Pl.
d laysls
a s, m~ -
Dialysis clearance ~
. . '-_ .
1 3 fu
c leoranee of creonmee M .W .

whe-re f ll/> is tht· fract ion unbound in h locxl (f ll is tilt' fncl'tinn unbound ill pl'l-'Im.t). am i
~t.\\'. is t"e molecular \n'i~h l o f rlu- subs tance (a meusun- of molecular sii''(·).
Bt"('lllls(' protein hindi n.'!; is often alll'n'l i ill dialysis paucuts. 11 mon- useful p;.mmlt'h'r
than hlood o r pl,t'lllla dialysis dt'antl\("t· is

Unbound Dialysis clearance

dialysis clearance '" of creonnlne '
rm
VMW: 6

111l' dialysis ck-arauce of creatin ine , a n.·adily d ialF~lhlt' l'uch'Kt'lluIiS l'lmpound lIot huuml
10 plasma prot eins . is a means of a'lS('ssi ll~ the ('''pahilil)"uf 11 gi\'l'lI di<tlysis S~"S h'lll l o n·lnU\1.·
t1m~ fmm the body. \\'ith current dialp .(·rs. d ialp is dt·ar.ml1.· values fur creunntne an'
usually ht·twt"(·11 SO and 200 ml zmln. 111t' unhound d i.J ysis d t·am.lWt· for t1m~s and most
ot her substances is usually lower than thi s ht-'('a uS(' the-ir molecular \n'i~" 1s an- ~n'atl'r than
Illal of(·n.·alinint· ( ~ I . \\', _ 113 glmult·) alld . ill tln- l'1l.'i4' of (tot al} dial~"Si s dt'a r.ilI("t'. ht-'(¥.tust·
til t')· an' oftt'lI bound 10 plasma pmt cins or blood cells.
11](' pn'lli{1ious uf clialysis clea rance 111t<;c..d 0 11 concentrations ill wholc' blood, plasm a,
or ptL'Ima water (Eqs . 5 and 6 ) It'nd 10 he lInd(,rl'stimal l's of th(' rt'slx '('li\"(' d('an lll{'('s of
drugs ill Systl'IllS with Il i ~h Ibn mcmbruues. T his undcr esnmanou CK1.'U rs Ilt'(';U1sc' till' di-
al)"sis dC·1Ir.-t1l{1· of ('fl·atiniTlt'. a [o w llIUlt-,(11lar \\"t'i~l l t e udc'Kt·uous substance, is Iimih'l l h~'
ami approacln-s hlood How, 111t' weilh'r Iht, t·md t·ul." of 1!Il' dialp .t'r. tilt, ilion' thts t L<;t
statt'lIll'lIl apple-s. In addition, fur elnl!,"" with higlll'r 1I10It'(:IIIM \\"t·i~h l. 11.(' It'mlt 'lIl'," for
d t'ar.IIl(1.· to 1)(' blood-How Iimilt"tl is less.
111('n' is usuallv little. if '1Il\'. correlation of dulvsts dl·arall{1.· with l'itllt'r kmizatiou or
li(Xlphili{'ity Ix"(."~I.l;s(· tht· 1IIt'1II111"<llIl'5 list'll an' pon;us rat hc'r than lipuidal harril'rs.
A largt· nlll~l' o f d ialysis ck-arauce values lla\"(' IK'1' 1I ob st'I'\"t'l1 Wi.'!;. 24-2), Pa rt of th is
\"ariahilily is ('".lust'll hy d ifTl' (('II("t's iu b ifl( li ll~ of d m ~ to plasma protetns. ,LS vhowu ill Fig.
2-1- 2. ~I olt-'('u l ar \\"t'ighl difTl'n'1\{1's, even though rdati\"d y small in tln- r.1Il ~t· uh '\('l'\l 'll fur
IIIc)!>1 dmgs. also l11l1lrihutl' 10 this vanalultty. \ \ l lt'n both of tilt' S(' soun-es an' ael1mn lt't1
for. tlu-n- is stilt conside rable variahility in di<tlysis clearance. Cl\~in ~, in 1:I~c ' part , 10 lilt'
wtdc mn~{' of d ialp .(·rs and dialysis l1lmlitio llS nsed to acqutrc tilt' in formation S hO\~11 ,
R dati ll ~ d ial~-'s is (:ll·ardl\{1.· to that of t-n-arinine for ('aeh t1i al~-/.(· r slumld adju st for more o f
this n'lllaillin~ \1Iriahilit)", In tht· absen ce u f such infonnutlou. ECls. .S ami 6 ('<Il l 1)(· li st'll
bllt sillmid he trt'alt11'L'I nlllgh appmximalions.

Extraction Coefficient
Undc'r stt'ady-statt' l1md itic IllS. mh ' of n 'mt1\111 rt'lati\'{' ttl tilt' mtt· of p n 'S('lltat ion is a
Ilwa.'Iun· tlf till' t1/iOf.,lctj o f a dia lysis SYStl·lI1 . By thi s de finilion. t·ffid t' Il{·y is lilt' dial~-,-t'f
CHAPTER 24 DIALYSIS 447

extraction ratio, or more commonly, the extraction coefficient , Its value can be calculat ed
from the dialysis blood clearance ami blood flow. That is,

Extraction CL bD
Coefficient = Qb,m'
7

where CL),I) is esti mated from Eqs. 1, 2, or 4. D ialysis clearance and cffi cioncy aro measures
of the ability of the dialyzer to remove drug from blood, but they do not indicate how
readily it is removed from the body. A measure of the latter is the fraction of drn g initially
in the body remove d dming a period of dialysis treatment . This value is a measure of thc
clinical dialy::::,ability of the drug.
l'harmacokinetic evaluation of hem odialysis and related proced ures requires information
on the paramet ers eL", CL" p. and VI> (or the ccrrespouding sets of values based on U lI -
bound drn g CLu , Cl.u fJ , and VII ; or on drug in plasma CL , eLf)' and V) and the duration
of the procedur e, In the following derivation and throughout the remainder of thls chapt er ,
lor conve nience, the set of parameter vallies based on measurem ent of unbound dru g is
emphasized.

Drug Elimination
Du ring dialysis, drug is removed by the dialyzer and by the body's own eliminatio n mech -
anisms, therefore,

Clo CLUD CLUD· V MW ,

4.0 • @

20 ••" ~
• f'
•

Ft
L "
.~
-0rn~
'"
10 ••

..,•~
w _0
~o
o~
-ON
04 i;
l;30 I
•
o
-
~.
C
rn 02
,,.
-"
.0
0,",
.e e 0.1
~ -

0.04

0.02
Eg. 24_2. Plasma dialysh d""rant'e aml unbound ,lialysis clearance with all "djn'tn"' '' t for more,'nlar si y~, for
2i ,lilf"T('ut dmKs show considerable vartuhilitv. Variability is grea test for {total} dialysis clearance C1"1)' On
mrn'c!iug f(Jr prote!n hinding to gi"e unbound dialysis clearallce, CU ' I)' varialJi lity is decreased. and thos,' dmgs
Ihat are highly Ixnmd (0) are broug ht into the range of unbound dialysis clearance values of the other dru gs.
Com-orio n of unbolllul di"lysis ,ok"r;lIlt'ewilh Ihe s' !,'are rool of til{' molecular wc ight ( ~-I _\\'.J appea rs to d iminish
,"'IT,abil ity furthe-r, but prediction u,ing both molecular ",e ight alld frad ion " nlxnmd is ,till not to" ac,.'urate,
l're sum ahly. f"rther adjust ""',,t for dialYler and dialysis coudtnons by rd ating dialysis ck-anmce of the drug to
that of creatinine should be helpful. The data in this figun' ",ere ohtai"ed lx-for" the ad\~,"t of s~-st"ms with
grea ter dfici"nc i"s and the use of high JInx membrane s. B"eause the results are expressed relati ve to the mean
of the values oht ain",!. the ohsc rvatious 0" mow recent systems would probahlv remain similar to tho se shown
here . Iloweve r, tl", d ispersio n of the vahll's due to the different s}'Stems may not be as gre et. For comparuttve
purp OS(·s. i1\each t~,l n",n thc' value for a d rnKhas hccn expressed relative to the a\'eragc value for alI2i drugs
Oil a logaritlllnie ' t'ale. {Data from l .c'c, C.C .. and Marbury, T.G., Drug therapy in patk'nts unde rgoing hucmo-
dialysis: Clinical pharmacoki."'t ie C')llSi,!er;I!iolls_Clill_I'harmmn kitwt" .9:42-6 6, }91>4.)
... D" "'"
Rote of elimination from
body during diolyli5 ICLu + CLud • Cu B

If tilt' d (',lnUWt· v;alut,s a re- constant with lim.' tlu-u. o n in ll'g m l io ll. tjn- unbound concen-
tratton at any tiuu- t afb- r starti ng dialys ts is

Cu - CvlOI ' e - lot 9

wln-n- CII(O) is the unbound dnl~ concentration in hlo od at til(" sta rt of dia lysis am ] k u is
lilt' diminalion ra il' consta nt [(eL" + Cl..uv )" 'u! during d ialysis. Thus, {'-im is lilt' Irac-
tion of dnl ~ n"l1lilillill~ at til(' ('11(1 of a dialysis pe-nod r . and so

Fraction Iosl from body _ 1 _ - .ko<

10
dur ing 0 diolylis period - e

T Ill' contri bution of di.dysis In lolal dmg (·limillatioll remains 10 bl' rh-termtn ed. o f t!l(,
total dm ~ t'limi nalt 't l duri ng a dial)"Sis period. t ill ' Fraction n 'IIlI !\l'( 1 by d i.t1ysis.J, ,, is

CLup
II
ICLu + CLud
Fraction of totol elimination
occurri ng by dialysis

TIlt" fraction of dmv; ill ' ht' body at tht, start of d ial~",i s that is t'liminah 't l by tilt' d ialpis
p rtl('t'tlun ' dr-pcuds Oil rln- Iractlon of total r-lnniua tlon that d ialysis n-pn-sents. Ell ' I I. and
tln- fr action of t1n1~ lost by all m utt'S of r-itmlnat ton, Eq. 10. Therefore,

Fraction of drug initially in _ 1 . (1 _ e -lo'1

body elimina red by dialyiii D
12

EffertiYenen of PrOledure
FiJ'lIfl' 2-4...1 demonstra tes tilt' t'fft'1.1iw'llt'ss o f hcmodtalys ts us a funct ion of u nho und clear-
;lIll't' alld unbound volunu- of distrilmtioll (Eq . 12) for a t}lli<''a13 -ho ur d ial,.",is pe-riod. All
unbound d ialysis ch-arauce o f 150 IIII/mill, a common value for drugs ,....ith high -flu." d ia-
Iyl".t,rs is uSt'tl. It is appa n 'llt fro m this fi"'>'t lrt' that h(, III()( l ial~", i s is indTe<-1ive (less than 20%
o f dmg imf iallv in bo dv is rl'Ill(I\l 'tI I",· di"h ",is treatmen t) if tilt' unbound volume of dis-
trihllti;m is la~(' (J?;rt';;tN tha n 120 l~). AI~), if Ct o is mud. ~rt'at('r than tilt" unbound
dialysis dl'ar.tlll"(', d iitl,....is IM't 'tI1l\('s ItOSS d TI'1.1:i\l' in t-liminalinJ.:: tilt' dnlg. 111(1..'("(1. when
C /.I' h -tU() m lJlllill o r grl'att-r. 11.(" amount n"lllll\"t't i hy tlu' treanneut must lit' I(,ss than
~( t'l- (lilt' vahn- o f I n ) (If tilt' amo unt init i:lll)' p re.w nt, rq~a nllt,ss of tilt' \111ut, of \ 'u.
n it' d Tt'(1i\l'llt'ss o f dialph may also ht' evaluated hy (:omparinJ.:: Ill(' half·Ii\"los during
( t V2 , ,," ,,") undl x-rween (1 112) d ial)':'iis trr-atnu-nts. D urillJ.:: dial)':'i is
'

0 .693 · Vu
I 1/2.cJur""9 - 13
(Clu + Cluol

am i. between dialp is treatments

0 .693 · Vu
' 1/2 C Clu
CHAl'TE R24 ...
'nil" ('han /{t' in till' half-lift· durin/{ dialysis is a flllll"t ion of how much dialysis clearance
I'tJlllrihutt-s In tilt' hod y's 11\\11 dt'anllll't' of a d OlI{, Ihat is,

Gu - 1 - '0 15
(G u + Cluol

A d rumuric n-dudinll in ha lf-lift' t1l1 rilll{ dialysis dot's not ~uar.lIlh't' that tilt' procedure
1·ITt't·liq,ly n-tuove-s d OlI?: d Urill1{ a siul{ll' dialysis treatment . Take. for example. pllt'uohar -
hitu ] in a ';'O-k l{ t·m l-slil.ge n-nal d isl·<l"t· parieut whost, pharmacoktneuc parameters art' \ '11
"" j';' I.. Cl .u = UA LAir, k = OJKI5 h r - I and t l 12 = 13i hr . U s i u~ a \<llm' u f 150 m l )
mi n m I A Ir) fo r un hound d ialys is clearance. tln- half-lift, o f phe-noharhital is n '1lm't't1In 5.j
hr t1urinl{ d ial~'!>is . Thus. di alys is accounts for tlfill of d nl g ehminanon (Eq . II ): hut nnly
29'l (Ell. 12 ) of tln- d Ol ~ pn'S!'nt in rlu- body at tht' stin t of d ialys is is rt' lllon'1l t1l1rin~ a
3- hr dialys is I"lt'riutl Evt-n though t ht' half-tift, o f pllt'll oh arhiial is dt't'n ',I.'iI.'1! 2-I-fu ld, Ihl'
fradioll n-ruove-d in tilt' :3-111" dial ysis period is small, ht'i.'1UlSI.' lilt' half-lift· d nri ng d ialys is is
still t'tlllsitlt'rahly lungt' r than Iht' period of treatment .
DRUG ADMINISTRATION IN HIMODIAlYSIS PAYIINYS
0111' ;' ppolitl'h to dU"klgl' atljllSllllt' lll is 10 replace tlu- amount lost in t!Lt· tlia lysatt- during
lilt' tn'a tnlt'll t pt.· ritxl. l1lis amount can 1)(' calculated (m ill Ell. 12, kl\{l\\in~ tilt' amount in
lilt' Ixx ly ill lilt' start of dial~'!>i s. \ ' . C (O). :\ mon- ap lwalillg «pproach is 10 reston- tilt.'
amount ill lilt" Ixxl\' at tilt' eml tlf diith-s is to tilt' \"alut' tha i would haw occum-d l...d tilt'
1l<ltil'll t nol IK't'1l tiialp l'tl: t his pnM.'t~IIIrt' pe-rmits tilt' jlillit'n t' s t'xiSlill~ n~ lIlt'n 10 1)('
matntanu-d ( Fig. 24--1 ). TIlt' amount to hI.' replaced is calculated a.~ follows . 111t' amount
rt' nmilling ill l!tt· lxx ly at tilll t· t hati lltl t1ial)'!>is be en t'll1pIO~l'1l is \' . C(Ol . f, -i -,: tilt· cn rn-.

t·ll!:' 2-h1 . Uisp1.J:.... t i, JIM' fr..·-

to Unbound Clearance h.." .. f elm!/: ill tIM'I",,~ at II..• ,1m
(mUm;n) of .li""~ . tl...1 b .·limil~'h't l l~' 3 In
1.0 ("'''1;'.' or
o ..f , Ii~~.
ul1l.... uxl
tn 'lllu" 'ul ...' it
d . ·;or..,,,'t· hMlll.lialysi•
•·limil1..tio u) "'ltl ulllllll ultl "~'Ill ..· .. f
50
0.75 .li'tlil"'I;',,,. 11lt, ""1....,,..1 ,h~ ..i .
I·J,·;or..,....• i' ",I I.'it) mllmi". ;0
150
('" lUllt''' .;01, f< " tlnlj('! i" hi"ot, Am
450 '~"Jt,· m •. 11", ~'-,"i . vt,.. lIlt' (r...ii.ltl
0.5 of lut;U dimlt l4tiull 'M"\Irril1 !/: ~' eli·
;oI~-.is _ fo:....J. Ii,,,· "ll11 ""'llh tl,,· .....
1350
1" 1(r " " ;' II , ,·I;I1 ,i",lIh..I ",1 ;I, ¢U' II

025 ...._...-.-.-...,-.--........-- ---

1I1l1 "..1 (,10';0"".1' ..., ;I, f"'Mi;'''' "f
11M'"nlltll",,1".I"",.. ..f ,h-tril"ll ;,m
"- --" -- " -' -'
Clt·arl~·. I"IJllt'r it ' m..ll h , ,et... >
C1..,,,) or an ""I",,"xl " ,/" I1..•.. f ,h. ·
o +--_-_-_-~ Inh" t;" 11 lQ1,.. "'r tl,;ol1 ;01,," ' 1 12!1 L
pr<"I'''l' ;0 n't." w ry__ in JI,,' ,Ii·
o 30 60 90 120
.... M' I.I
~""'I" ,I"rill !/: .. 3· I,r .1i..J~"i. tn ''''' ·
Unbound Volumeat ",, ·,,1wi tl. lIlt, hi~ A,,, ~","·m ..fJ,...,
Distribution (l) II""" 2!» "f tiM' "n¢II;I\ ;o1l" M," 1 in
II.., ""' ~" TI,,· "" I"MII"I ,..I" ",,· ..r
,h'lnIM,lio'" hOl-'" J,,,,,,rlimil. 1""1 or
II,,· •."lr;tot..·II"I;or ",Ill"'" (;oIIt"'1 16
I. ). O"~' tl..",· l,".."t;'~ .. in ", I,id ,
l ·" i , !/:rt'ah'r tl,.." 16 I. rllt'n·(" rt'
arl'~' ·
' 5O M VSlS CHAJ7fft 2.1

C;; 40
§.
~

"8 30
'"
.E
~
! Amount - A - A
Replaced- Off 00
:Q
E 20
'"
~
~

'"15 10 Dialysis
'E
~ >-<
0
E
-c 0
0 12 24 36 48
Hours
HJ;. i .f--t . n M',I...... "r J:""' ,unidn r.. ~~l...I I" n-l "n, tl ... . "KKIJII in I IM·I"K~' '" II.. , .,.,,1of .~..;:. '<> ,I -;01 ,.. .
II>.d " ""I.I I,..,,· I" ~'n 1'"'''''''' "" lloat I"'.... h..1 d..· ''''''''''1 'M" I....·" ,"~.,..J. ;. ,10,- ,lilT..,...,..... I ,,,,.
.." '"1. ill tI... I.."ly ..l tho·,-lI.1,,( II...;,," -0.,.J in tho· .J.....,... . 1..\,r.l ..1M1I'n""...... (A ... ) ,,( .I~,J•.n il' rrpt.. I1 ' t
,Ie ' t 12 m\1.1ill .hio " \OIJ Il' >!<' of ;til..,.. -pi"",: p"tio'''' i' d "••' '" t N' ;Il' K'" '" in II..· , lial~"".· h''':.,.ll'''' lill'" I , 1. 11
I.Kt 10:-' th. - In h", ,"u , lI.... ~ .... ,;."'t <tn"nJ: th., di~ tit into'n''''

'pnlld i ll~ amount when di al)~i s is " mployt'1l is \ " . (:(1I\,' -.l. " . , . TIlt' di fT.' rt"III't' hdwt't'll
I IJl'~ '
1\\11 INIlIS p n l\itl. >s a ll .'stiuMh- u r tilt' supph-nu-ut al dust· 1lt'1 '1lt'1l to aehit"\l' Ill('
uhjt'('tiw.

Supplementory dose • V · qOlle~ Irt - e- ' 01') 16

T his kill('lk appmat:h 100\H ,ml dt )s;l~t' udjustment is snllst't!lll'lll l,. illustrated \\;11. ~(' III;l m ki ll
011111 pllt'IIIlIMrhil al.
111t' phanll;wokinC'li<' p uranx-n-rs o f ~t'll l<l m id ll ill lh l' t)Vit,;,I.')!)-,,·a r-old , in-kg pat ie nt
an' (T ahlp 1,\--0 : CI. = 5 .1 l zh r. " = IS I.. t ll:z = 21 1r.fi' > 0.9.'5. Asp ' is gn'att'r limn
OJJ,j and pmhahl)" dost, to LO, thr- killl'lil'S o f tllis dmg an' dr.L~li(:ally altl'n '(l ill a p ancut
\\i llLollt n 'lliIl funct ion. From til(' n-larionvlnp t l!:l(tl l = ' 11'2(, ) , \'1I(tI)I\'II (t ) · IIR,1 CEq. 9,
Ch ap . 16 ), am i ¢WIl thai , ',, (tI) = " ,, {I ), tilt' half-lift' of lhis d m g ill am-phnc p atu-uts h
gn'a h'r thall 40 hr . {\I'('t lless 10 say, admtnetrauon of lhh dmg III an «nephric panc ut
n -quin-s r-xtn- me- caution. For purp ost'S of til(' examp le la-low, assume a half-lift, flf i 2 h r
in an indi\itlu<l1 ;lIlt' phri(' patit'lll till ~t'n la lll id li alonl' , 111is hal f-lift, co rres ponds to a d ear-
all(.'(' of 2.-1 ml J lIlln; till' ran - of administrat ion til maintain til(' S<IIIH,' an'ragt' slt'ad"-slah'
eonc entrution should tlwn'fo n ' 1M' 36 limps II"sS tlrau usual. A eommou n '¢ lIIt'll uf gl'nta -
mit-in for a patient \\; 111 uurmal renal function is ,\I I lUg ( 1.2 IllWk~) , inlnun llst111arly or
illlra \ I'IIIlIlS!v, t'\'NY "l !lr; tlu- initial dust, <Il1d till' mai llft'Il;Ull't' dust·s art' tlu- sa me . 8 11t a
..trnn ~ a~II;II'llt I'x-ists for n'(llId ll~ tht, initial dCN' for an ;lm'phric patn-n t, wln-n the dusing
interval is much shorter than tile half-lifl' (C hap . 16, p. 2(0), :\' '(.'(Jf{ling:ly, a n't'()II1IlWn-
"al illll ftlr an :uwpllrie patn-ut lIIi~h t IM' ;I 40-mg loadi n ~ dost, fol1cM1'(1 hy 12 1lI~ t"\'t"f)'
ut ht'r tlay, .o\s prt "\iutl..I~' t1isclIs",'t! (Chap . 5 , Th t' rdIM'lIlil' H('SIXJllSt.' alltl TU\id l)' ), appro-
priah'llt'SS of larg(' and illfn't!\I('1I1 veraus sma ll am! fl1'tjlll'n t dost's is lIul st,tt lt't! for ami -
1Il~!y('()s idj '''' ('Slll'('ially for patients with compromtv-d n' nal fun ction.
111(' " ' IM'('tI'(! amount ill tile' hudy \\; 11. lilllt' fullu" i llg this n -comnu-ruk-d n -gillll'lI, ill
IIII' ab"" llt'(' Ilf dia lysis, is s11l 1\' 11as C urci- A in Fi}.':. 24---5. TIl(' anephnc patient is dialFA'(1
fur 4 hr (Ill tb y ;; 2, 4 ami 6 hl.'lw('('11 dCN's O il da,~ 1, 3 ;l1ll15 . CUllsitlt'ml iulI (If a sup ple-
CHAPTH 24

ml~lltar:n IIJM' requires all t'~li llla tt' u f tht· fr.l(:tioll !l)',t ill th e dialysate t!ll rill~ 1";1(: 11 trt'atllll'nt
pc·riot!. 111t· d ialysis dt'ar.llll"(' o f ~I 'll t amici n . a d m ~ not hound in plolsm a. in a com mon
di al)7-N is 30 m [)min. TI ••, l"tlmhim"tl d ea r.lIlt't' in thi s p atien t is then-Ion- 32.4 III IJmill.
TI lt' l'lIITt's po:JJ1din){ d imilJafion rate constant . k t ,. is 11.1,) hr - I (t 112 '" .0;.3 hr). Usi ll~ E'l-
10. lilt' Fract ion lost duri ng a -t -hr d ialysis period is 0.4.
Th us. ht 'llIlxlialysis . "' l "f) · 2 or 3 days wOllld n -sult ( I wl'(·k lah 'r) ill H'I)' litt l,' ~t' llt a m id ll
1'I('ill ){ in tilt' ancphn c IMtil"llt (C llrw 8 . FiJ:. 2-1--.'5 ) if till' su ~t'Stt"t l n1!illwll a huw we n-
lIot adjusted. Clearly a SlIppl{'II\('llt' ll')· dOM' at till' ellli uf ('<It·l. tlialysis pe riud is 1U"t'tI('tI.
TI ll' sup pleme-ntary doSt, should la- SllfTi eit'llt to n-tum tln- amoun t ill till' Iltltly to tilt'
vahn- that would haw occu rred ha d tilt' path-nt not been t1ialr'j "tl. thr- l"lmd ilioll simlllatt"ti
in \.1Il'''-I' C o f Fi){. 24--.'5 . TIlt" allloullt coutinne-s 10 <!l'l'lillt' 'li th di<llysis ('w l')' ot llt"f da y
after a Io.l(li n ~ dOM' of -Ill 1llJ:. TIlt' amou nt in tht' hoely at tin' tune- n f tilt' Ii....t d i :J~~h U II
day:2 (-to X I' - 0 fti-lx :ur. Z) is .12 1IlJ:. 11l(' supplt' lIll'lltal')' doSt· is the-n 12 1lIJ:( Ell. 16 ). Tuhk-
24--1 shows "-'pn 'S('n latiH' t1 m ~s fur which slIppl('IIlt' lltal')' dose-s lIliJ:llt lit· 1"( lllSit!t'n"tl.
For a d m~ thut is fe.nlHy di<lIF .t'tl und is n -qutred by lin' Ililtit'lll al all tinu-s . couskh-r,
alio n miJ:I.II'I(' Wn 'l\ to adlll inish'rinJ: it t!llrill ~ tliaJysis treatment . Allutllt'r appmad . is III
IISot' II tllt' ml'l('ut it: (lI11bllllllt l) I"(II W(' 1l1 ration of tilt' d mJ: in the- t1ialysil!t". Alt hOIl ~h t"t"t m-t -
it'iul~' !110 ft" lo¢ ea l, rlu- hun-r appmiu:·h l1la~' lit· n ' l')' (·\pc'min '. 111t' total \u llln\(' uv-d is

40 . '111:. !4-S. Sl" '1d,,,f .." M" ,,,I of ~ 1'to",it~" no II,,·

I ~· ·Allt. lin,,· in ;on .. ,,,,>I,rit· pot''''·''1fin ;0" i 11\
,,, ~.' "'t'"..." .or.JI 1mj( im'''']l~' ;01 .. 1 12 1111( .... . . ~'
, . ~ I",·r.l l)- . <:urw ., (--)--1"'1"'''''1 nut .b~·,, ~ 1.
e"....· B (• •• • ·)--,,,,,it·,,, 1I1"''''rJo:<>inlt , h~q. If". ~
I,
"I ,
, hrl un (~ .. 2. ·t ;01 ..1 ft . en....· c (•• • •)--p..tit1"
" A "'.... ·~~ n lt .Ii..~ ..i. i. ,.,.• .,., .. '''I 'I''''''''''nl''~' ,......

\ "
"
"
"
lc
,ort 2 llJJ:j" " ..fl....·••d , , Iia~ ..h 1",'0<,,1, .' '>1,,'-<""'.
p;t'1""'·"1 11...."·1 "'11h 111" .."1"' '''....'...h.. "l"...., i,
" .....1

o 2 3 4 5 6
Days

, ..... 2~ 1 . ..pt'e_tl_ ~
.......INtI I. P.tI.... U.......I.........1• .,.1..
'- WIlle" . .,...1_..1 De_.....hll.lysl. M..,
••2

144 L when a typical dialysate How rat e of 600 mIJmin is cout uuu-cl fo r ~ hr . For ~(' II t;I­
micin, a therapeutic conce ntration of 2 mW'L in til t' dialysate ,m ulti therefore require tilt'
eddmon of almost 3(X) 1lI~. If tln- dn l~ is an a ntih iolk. mu- mi!-(hl argu e thai d()i ll~ this
would help to prt"\"('nl Infection.
A!tl.nuF:h unly alklllt 29% of pllt'lloharhilaJ initia lly prt 'wnt wax pn....ioudy mk-ulah't ! to
ht· WIIlO\'( '(! in a s i ll ~l t· 3-hr sess jou with a high-f1 l1x dial)'!'i is system. the s l('m l~·.s lat(· pln-no-
harbltal couce-utration may ht· conskh-ra bly rt'tIUl1't! dnrill~ repeated . ..-ssion s. The amount
of phenobarbital ill a patient who has a IwJf-lif(, of .oS» days .U1d a volunn- of distribnnon of
:J,l) L is decn-ased by 12% <e - ct. .t!\'j du rin g the dosiJ1l-: inte-rval (I day), TIw atltlitinnal loss
o f 29% eH'f)' olher ILlY ( n n dial)'S is) \\nuld mo n - than douhl(' tln- aH'r.I~(, pt'n'('111 lost
(l 2%IlLi)' lx-twee n d ialysis tr eatments and about 4U% Oil d ial)'S is (Li)'), III th is patient . lilt'
dosa gl' " ll\lld ha\"(' tl) he doubh-d tc keep the sauu- aH'rdgt' amollnl in til(' hod y at steady
sta te. Clearly, til(, t'fTt'(1 of dia l)'S is should also ," ' r-xannned .11 slt'ady state-. lIlt' the-rapeu-
ticall)' relevant situat ion for plu-uoba rbitel.

PERITONEAL DIALYSIS
1'l'riiOlwal dialysis is accon .phshcd h)' int roducing dial)"ljllg fluid into rlu- pt' rilOllt'a l ('a\it)'
\i a a ca theter. Aftt'r a peri od. tilt' dlL'l'/J time , Ibe fluid is dm.int'(l and di M~drdl'll. Tah lt' 24- 2
lists three kind s of ch ronic pe-ritoneal d ial)'!\is procedun-s 1IS1'l1 d ink-ally, Tlu- mn - that 11 as
IIl'l.l llllt' til(' most common is a mtimwtn a"Jmlalonj 1H.,nto/l('al dial'}\'!\ C AJ>D. T ilt, suh-
S('(lllt'nt dtscus siou Is largely n-stricn-d to this d ialysis modality.

Dialysh; Oearanc.
In CAPD, dialysis clearance. CI." ,. is most frt'(lllt'IlII}' expressed .IS the amount of a dnlg
o r sub sta nce n -cove n-d in till' drained dial)'satt' n-lat ive to th e Aue du ring lilt, dwell ttme.
r . afll'r atlminislm tin n by any rou te. A Il 'lltl~(JllS to ECI ' 4 and with tilt' s\lhM'ripl PC 1II('aning
peritoneal cavity.

CL"" ... Cee · Vee 17

f~ C · d,
when' \'1"{: is the <Iialysllte volume in III(' peritoneal cavity. '111(' pl.I'ima and dial)'sal e txm-
centrsuous of tile ce p halos pori n. cefsulodin, during a commouly t' lllp lnyt,15-hr dwell tn ne,
after int ravenous (Lv.] and intraperitoneal (l.p.) administration s an ' sho wn in Fig. 24-6. AI
tilt' end of the t1welllinlt' . Ihe pentoneal concent runon approaches thut of P"l~lII11 after i.v.
ad ministra tion, and tilt' plasma ccnccntrano u app roac hes thai of di al~'Slltt· afh'T i.p. admtn-

, . ltl.24-02 . Ch__lc ...ri ...... DI_tyll. ~"._.

.,,,'" ......"" t OtAl.

. .-ss
'",","",0
..,....
1'[11 D/lV ,"'"'""'S ""'"
"'''
Iwt PlII:D/lv
,"0'''''' PH D/lV ~, ~,

ConriflUO\lS plOCedule1
Conhf1\.OO\lS ombuklloly peneoeol 6-12 3-5 4- 12 '4
dialysis
ConhnUOU$ cycling pensooecl 8- 20 4-8 1-1 2 '4
d'olysiS
DisconhnUOU$ r. OCedv'M
!'JocIv<no p8f'1Qne01d~ 10-30 5-15 0 ,3-1 ,5 12
Inle<m,lIolon' per ilonea l dlQ " 40-70 20- 30 0 2-0.5 12
CHAFlf l! 24

lst nuion. Clearance. c ll ltaim'(I I~' Eq . Ii . 11... 11 rt,ftt'C.1s tln- lid 11I11\1'11\1' 111 nf 1111' c1m ~ t ili ri ll~
the dwell tune . 11lis clearance term is flot strit11~' a measun- of lilt' ahility of a d rug 10 p;.l.SS
Ir om hlood inlo till' peritnueal (,";lsi t,.. O1.'i its va hn- dl't:rt':L<ot-'S with dwt'll ti lllt'. 11lis sihMtio li
is in rourrast 10 Iht· l'!t·anlll t.'(· n-nn for nOlln 'C.1n ·ulO1tin J;: ht· lIIotli;~ s-.;is for whil·1t sink UIIl'
tiitiulls an' rnain iai lll'ti. A Itllitlin '('tio llallllt'a.slln' l....11 lit' uhtiliUt'tI'fllf p.·ritllllt·;11 tli;~~"Iis if
tiM' d ia!~~ lh' is I'lld lan~t'ti at suffidt'll t fn"fillt-'IK',.. to t'mlln' Ibdt sin k UJIltlititlli\ an' ap-
p rollillldtt...1.
The IInbll'Ulul Ipt'rilmlO'al) dial~"iis dear.tIK't" value fur IIIC~t dm"s !it'S ht ·h" ...· 11 2 ami ";'
mll m in . 111t' rt'a.Sflll fur tltis Inw SWIIt' (,"..l II h., t' llplaillt'(! a.s fulle",,"i. The-n- is Ilt1:li,,;h lt'
pmtt'in in till' t li a!~"t1t' lillie! ( J to 2 W2 L ) 011 lhe t'1lI1 o f tilt ' dwt'll timt'. Cml,\( "f lllt·"tl~·.
whell t"flllilibriulII is adlit"St...1{CI'(' '" Cu ), llw allllMlII1 ill tht' di.l.I~'\.;lh· is CIl . wllt'n' "rr"
ell is Ill., III1IMM.lIld roncentra tio n in pla...ma and CI'(: is Illt" lIulJfMIlle! UIIlC.t'lIl rdtinll in
dia~~lt" If tht' pla.s ma l'tlIlC.'t'lltr.tholl is constant wtt h time. Iht'n lIlt' 1I11111M.JIId ,l l"C is
CIl . t .l1I11Ji. tilt" IIl1blllllltl t1ia!~"iis dt'ar.tIK't' s-..lUt' is ell . ""JCII '
tor ' ·I'(J t . W ilh a 1I\II.J
diah~h' suillmt' of 2(10(1 ml. anti a t o f 3UO min . tilt" llti ck-arano- S-allll' i\ 6 .7 m lJmin.
111i~ It",,· ck-arance IlJI·.tm Ihd l dm~ ehrnination by pt'ritollC.'a! tli,J~"iis is not a ma;lIr ("1 11I -
sicL.·rdtiIMI for palit'IiIS till CArD. \ \ 1wn CA P O Is Ihe uIII~ "Mlh' o f t·lilllilMlitlll dlltl t1n l~
i\ distrilllllt... 1 in ('s1r-oK't'l1l1lll" fluill.. \0 .2:; I A~. t he slllalk~1 voluna- pc)\sihlt' for 1I11111Mlllti
tlnl':;). tilt· half·lift' i\ tlu-n ISW min (t l 'l = 0.OO1 12.')U IniAl{ X 70 "R Y1l.7 ml lmill ) or
1.26 lla~.,. . CIt'arl~·. ullw r nMltt'S uf elimination or tlM'r",X"1llic IIIdIIt'U\t'l'i 10 n'mo\(' lim"
an' R(·'J("r..u I~' of ~'i1It"f illllxl rtalK't" than CA r D .
Dial~.,.is dl·;lrdll('t· SWill'S fur inl.'n n itt t·lIt pt·ritOIH·;t! di.J~.,.is and tuntiltlHIII'i t)1.·IiIlR pl'"
rtone al di~"i i \ can be 10 to 40 m lJmi n, ..-aIm'S much j.,rn~.tl t"f IIMII thost ' for C.\ I>D . hl'(·",,\(·
sillk l"OlMliticms tend to 1)(· maintaiue... 1,,1wII lI\ illR \hort cls\t·ll lillll'S. For Ih i\ n -ason . n ',
II K )\-a1 of a siRllifit."al11 fr.K1iun of dmg ill tbebodv ('"a. 1I CK"l'lr durillR a treanm-ntpenod ;lISt
Ii.S ",th IK·lIIotlialnis. bu l .1ia!Y"i1\ Is then lIut t."I}UliIlIlUIIS. 111t· IIwl htKls uf dll.t!s-,.is " lid
p n ...lit1in n ofd m i n'IIItIS'a! an' illt" same, t'u 't·pt th ai tilt" inlt'nnitll'nt IMl lI n ' uf til. , "IMIILIIif)'
11I11\ 1 hI' irK'tI'l'lllr.tIt... 1.

250 500
i
0 200
A ~
§.
0 400
B

~ 150 Ig 300

~ 100 0
u 200
0

:¥•
0

~ 100
<,
"
.:!
50
0
a .--- • • • •
~ 0
_.~-­
a -a

0 2 3 4 s 0 2 3 4 s
Hours Hours
.,.. . 1-6-6. n pt.'''1oI (tJ.I ...lld .~~ .. , . ~ ...) .....1l.....tr..ht . .. I1( n .f.. , ~ . IIfI n #..I. ... n ","I1I"'''Il· II....
I, ,;rt,....:II:o' tlnl ,1 i" .......111.I. ...flrr i .,·. • lnun" t r.ot. Kl(.4.1 lIn,j i.p. • Innnl'l r.ot 1111I" II r-o-« "lIlt "", I·","""
rrnaI .b......... Ir ,.l t" ..,... -h an "' rl ihhrium .. ;Ihin a :'>-h r I~"""l" 1"""1'11 1m , n C~"IC" "'," rat."1 in pt........
-.fl.. r i-'"- . Imint-t nd.... ,~ " ,1n·1",.. m'lt-h t..-.:........ of It... I"0"..nfo .........f .b .. · 1 lit....." .... Ihr ..." ". Inl
tL... tnl"'hn( int" 11101' 2·1. ,~~(' .. .I" n... (",," It... 1""1. ... lr. "I'lI,,!...r R..itl .. .I""•. o( ,1"ln htll• •• I' . n....fl. In
••• 'I......t. tI... n .....·nlnd.... in II... ,~...." . ,1,,-'['" ........, ...JI:o'.... II .b'lnl" lh~ fn ,," II. · 2· 1, .. .I.."... m'o Ihr 1f>. 1.
...I...",.. II .. ~1, _ I." 11' 1'. 11).d.. f" ,," BfUU,jfll R . T, TS .. '''·" Ij''''. II . ( :."l l..m,n. \ ., .....J K.&III... ·~ " I .
.\ .: Tnn'f"""l'• .....t ". .. "1'' ' ' '
",. 1 piwn..... *ilor1 ll.. ul c....k"'... n ....I •...-f"'~ .bn in f"iIlO"'IIh ' . 1<~.II' '' ", ,,,, ......
It..r...:,~ prttI•....-A .~ .... Clln :s;rpt.m1 . :» I'I:'- 21 ll>. I~'t , )
... DIAlY'" CH-\PTH 14

Route 01 Administration
Altho ugh little dr ug is lost inlo til(' poritom-al cavity duri l1~ CA P!) "nN pan-nlNal admln-
istra tion. 1II0si (tnon- limn 60% ) o f a dost" aduunlsten-d intn tlu- pl' ri IOlll'a l l';,l\i l)' is ab-
su rl)('(! into 11ll' hexl)' durtug II typim l 3- In a-hr <I".'{,II tune. Ht'l'all <;(' (If lIlt' cont tnuous
nature of C APD , tlJis rout e o f admtutstrat ton lias a pot cnttal apphcatton for sys temic- p ur-
pust·s, l'slll,'(;ally for d nl ~ thai can not 1)(· ahsn rbt'l l when taken n rlllly. rhu- to poor inleslinal
permeahility as is tilt' case for mall)' ann btott cs . Dwr-Htiuu- lx-o um-s part il' l l arl~' important
lu-n- ,LS a determinan t o f systt'mic bin;I\1lilah ilit)'. Sol a ll o f rln- d n l)?; imti lhl inl o tilt' cavity
reac hes till' sys temic ci rculation. " lis is shown ill Fi ~. 24-i for te-koplaniu , a ~IYl'Upl'pt idt.
antihiolil'. Bio.mtilahility Increases wi th dwdl tim e am i is ahollt ' SIl ai ,') hr. TIll' data also
ind il<lh' a IlIUl''' J'rt'atN cot·fficil·nt of variation in bioavailabililv at r-urlu-r tinu-s . 11I1I S. 10
i-nsure cons istent «leorprion. a short dwell tim e is not n.,('llllllll~'lltll'li.
I\ 'rilnnilis is til(' major drawback III CAI' D . A majo r Illlt'Stillll ln-n- is wll('l)wr di n -ct
administ rat ion o f an ilnlihioti(' into till' pt' ritOll('al l'll\ity to treat peri toni tis miJ'llt 1'1<' mo rt'
l'lTt'l.1h,,· than systl' mic lIdministr.ltion . Alt hllu ~h inlmpt.'ritollt'al ad ministmtillll would all-
Pt.'llr to hl' superior. d m g may 1)(.' dehwn-d to the sill' of infection mon ° rt·adi ly via till'
ca pillari es thau th rough tlu- peritoneum. III SOUll' situations. a o unbinatiun o f 1.011. Intra-
pt' rilOlll'a l llml olhe r rou tes of administ rat ion lIlay 11(' ad \1t1l la~l'()1IS .

HIMOFILTRATION
Auotln-r h'Clmilllll' Ust'() to treat 1)Jltit'n ls with l' "d-sta~l' n-na l t1ist',L'it' is Iw"'ajiltmtiml.
\\'ith this tec h nique. l·ndogt·nnus com pound.. an.' removed by fil h' rin~ phsllla water from
blond under pn"Ssu rt' (pu mp). Blond ('l,lIs are re turned to III(' IMKly: till' Hln-n-d pla.s ma
wa ter is replaced by an equal volume of phrs i(Jlo~~k /luid adm inisle rt'() inl mn ·llously. Fo r
S)'litl'IIlS in which bo th d ialysis ami fi hmtioll (."lmtri hut t, l'xft'llSi\l'ly. tilt' INlTl/w"" l(/illj iltm -
tum is applied.

t·IR. 24-1. Rt·!.di""d,ip h.-t\w."n .yo· 1

I..",id "'",vlli l..hili l)o·/"M·" " :!: SD "ffi....
!",I il''' h } ..nd t1" .. lI li rn..... I,.. n Ie·it".·
pL"'i" i. ",1", i" i" " n ,,1 i"tr"P' ·,.;tlln....IIy. 0.8
T"" li ll 'l"< uf !M''';hll ..'.,] di~..i~ '''[Utill''
"''< 'n' in.h lll,,1 i1lto tI.., p.''';' m..'''' ('",i ty
r.>r ~ h, in t"'tit'nh UlMIt' rJ:" illJ: {'< lUbn-
111 11" .. ",IIl,l..t' lI) {M·";I' Il"'..I .1i..lp iJ.. Bi... ~ 06
It\'lliLJJi hty "'II-' nUt, d"" "l1 ":0' m m p..ri -
.. Ill "f . ' l'C , <dt.... f"".." i ll!!: ;<j n~' j.p.
s
.~
.....11..,. ,I.",.. .... " .·11 .... (mm l i ll ' ''''Illlllli
u{ .1n'1( """ ,;l.ininl( ...i l " in 111l' !M'ril u' M·..l C5 0.4
<'>I'i l}' wi l h lin.... AI ~ 1,1' (;)IMI min l. II...
I"' ...,"; lohility "''II-'
..t••llt O.; .'i ~' IMIlIo
",(", I"M"- Til<' ('<"I'ffi dl' nl .. ( , '.";"liu n 0.2
t Sl },lnM'" n ) ,,-.. mlll,~' ".... t.·, ..
I 1>'
II"", ..t "'t.. liflM" . 1 ~ 1I1"" thwU tin ..
1I...l't' fu", ,,;... ''''lit'' ..,,"r>!t1" alld t.....
\,"",",hlt· hit"" 1liL.hi.IiI)'. l )l.-dI"lMTi ( m ill o
Ih. ,,);,"1. R.j., K.IIl "ni ~ . j. E., C . ml.., _
to""i<•. J.t ;,. St.-1Il.-n r..1t1. P.l"., S"':fMI .
o 60 120 180 240 300
\ 1.. t"n ..-l. K., atMI T' rIr', T.S .: T . Peritoneal Dialysis
plotlin rt......,.....
Jki,,,'ti<.-s " 'MI hH",,-,uI . Dwell Time (min)
"ihl~' d"rill j( {M'n l unl'lll di..lp is. e l i " ,
I'I.a,n uo<".I. Th.., .. ~ ,Hi7", -n.·H . 1\1\ 9.
W itlo p,·n"i..ioll ,.J
 ...
As \\;111 h('!ncklia)ysis. th e re an' man)' variations in he mofiltrat ion techn iques . The p r m-
ciples of dnl~ removal are simila r. but nol th e sa me . In 1lt:'IIlIK.l.ialp is. molec ular Si7..t· Influ.
C'Ill1.'S dialysis d t'anu w(' by d(·t (' n ll in iJl~ diffusioll across tln- un-mhrane . In ht' IlKlfilt m tioll ,
filtrat ion is ~(,Ill· r.J l)' 1101 affc"(1:c'(l by molecular weight :LS lon g as tilt" Si7.l' remain s h...Jow
tjn- (·:\(,llIsloll limit. tlu- value- uf which depe-nds on till' membrum- 1ISl:"':!. Binding: tn plasma
p rot ein s is also a den- n nmant as tIll' sin ' of mos t p roteins is alto\"(' li lt' exclunon limit !\oi l
that ( 111)' drug in plasma wun-r is filtered. n il" rate o f Iih rution is t1 W Il approximated " >'1111'
n-lauonslup

Role 01filtration - fu · 0, · C - Of ' e v 18

",IWH' V, ts tilt' ran- of filtra te lI"w, nltt'n in tln- .')0 ... tn (50 -IllI Jmin runge. I~'(;m, st· of till'
de pendence of d ialysis on molecular Si7.(' , Il('lllofiltratioll often r{' 1Il0 V{ 'S la~t· (M .\ \', > 5no
Wmole) molecules better d um ht'II\(Klialysis.

DIAlYSIS AND fiLTRATION IN DRUG OVERDOSE

ASS(OSSllll'l lt o f the l'o nlribution o f IW1I1(Klialysis or ln-mofiltranon to til(' f('(11I(.1 io n of tilt'
TIIorbidif)' and mortality of d m v; intoxicatton is fadlitutt'(l by quantitatb-e information ( 1Il
dm~ n· IllO\~II . ~t (" L"u n·nlt"nl o f Ill(' amount of d m~ in the d ialys'l te or filtrate nlom- is
luudcquete. Fo r example, a n 'l'O\1.'I)· of 10 ~ may he u nim portant if mo re th.Ul 100 ~ wen-
in tl1l' bod y at the start o f Ihl' p rocedure. 1nfonnatl on on the Frnct lon of the am o unt in itially
in tln- IItKly that is t'!iminalt'1! hy III(' procedu re is 1lt'1'1 lt'1l.
Severul Factors .t"stJti ah'll wn h tl u- (l\'enll),;('11 patieut may alTt't1 tlu- phennsc oktneucs
o f 11 dn'g, e ./;!;" anoxia. uu-tabolic lKi dosis, carbon d ioxide retention . hypon-nslon. dt'pn'sst'1l
renal flllll'tion, and hypotl l('nnia. Furthermore, txuuplications lIlay a rise ht'('lUl.~ ' o f slow
ttssue distribution o f a dm); (C hap. 19 ) and ht'l"illlst, of the concentrations of dnlV; and
aI1h't.· me tabolites altai ut'1l (C I1<tp, 2 1). Comuwnts Oil a few of 11 1l'~' ('OlIIplk, ltiom are ill
order.

Drvg Redistn"butlon
An important consideration in eva illalinv; tht, potential use of ht'llIod ialy" is or lre mofiltrat km
in all (I\'('nlust, situa tion is dmF: n -dtst rtbu no n . Fo r rr-rtuiu d rugs. the procedure lila)' n -.
11111\ "(' d nl/;!; ilion' rt'adil~' From the plasmathan il can lit· re placed from tissu e sto re-s. then-by

res ul ting in a rebound o f th e plasma tIOIg cone...-ut r atiou whe n till' procedu re is stopped.
Twu primary mechanisms account for this slow return: slow diffusion thruu gh 1I1t' I1IJmUlt"S
and limi ted vascula r porfuston (C hap. 10) of tilt' tissue-s ill which d Olg is stUTt'11.
Lttbhun ( Fi ~, 24-R ) is an exa mple of a d Ol~ that t'xhihils po std ialysis n-bound due to
slow d ilTusion fro m cells. Di al \~is d l"lr:l1ll'l' adds substau ttallv 10 the tolal bodv ch-arance
(\i rtll11lly all ren al clearance) (;f this dm v;. L ithium disappears rapidly fro m plasm a dllrill~
d ialysis, and a Ia~(' frac non in lilt" lxltly is expe eted to lit, n ' Ill{)\"('11into the d inl)'!ial l'. Tln-
slow n -tum from tissue stores. !lu\n'\ '('r, limits tilt' total amount n·II1O\1.'11 mill prod uces a
rebound in Iht' concenr ratlon Uptlll s ioppi n~ dialysis Irt'ut lTit' nt . In this case. USS(OSSJllt'l1t of
Ihe rr:llt ion of tlu' initial .tmou nt o f t!OIV; rt'mo\'l'11 by d ialp is is n·!ativt'ly simplt·, Silll'f.'
\irt ul!.lly all the d m F: t'limimlft'11 hy th e lxxI)' is eX('f(,!t'11 into til(> uri ne . TIle fraction is lilt'
1lI1io uni n'l'tl\'t'n'1l ill tht, dialysah' d hitlt'll hy Iht' Slllll of th e alllou nts in tI,e dial~~t1 t' anti
Ihe uriue durin v; the dialpis pt.'ri(xI,
A lIOd l('f lllf.'th(KI of a.sSt·ssi ll~ till' ('o lilribulio ll o f d ial)"sis to total d iminutio n is to t'X-
trdpolat{· til(' t('nninal part o f III(' (" rn·. when t"<llIilibriulll h as 1)('1'11 r{'l'slahlish('ll. h.lck 10
tilt' Ix'ginn ing of dial)'Sis (St"C Fi~. 24-8). TIl(' d ifft' n 'n(X' l)(,tw{'('n tht' initial ('lllll'f.'n tmtioll
...
Fil/:. 24-'1. l)"rillK6 _.5llr ..( IIt·"..ltb...~ ..i, (.olid Dialysis
h.u l "f ~ r~ti"n l ,.UhOl ...d ... ill, !,tl,ium, I I". 3.0
rra..rn~ n"K~'ll tr;l,tic ", "f lith ium (.> drul'l', ..1
,1 "'..lic.,.]k:; I" ,...•...·, . un ,1;O('II.I;l1l1i"lI: , 1i,.J~ ..i.
,I I»...,ma ('<>IIn"lIlr.. ti"" rn .....itl, " ..Ii'lri l,,, ·
Ii,m of .lmK fn>lll "b.,""" "" Ii ...,
Ii, ,, ... ",,11.' ,,,
,,,,h . Iu d ClI...·I,;,lf "f 1I1l· 1i,1,lum illlli;dl.-in II..·
lu~ " .... "-"",,,...J 1>:- , IW~ ...i• . A nlt'l-of, .~in ...t.·
of (r;Mi io" Ic "" ...... I,,· ,,1>1;<;,....11':\, " ' l r""l." I.. till~
(_. - -I I'.."kn"iI,a1 ('('r"'(.'_.1c I" till" ti",. · .liaJ:,.q <
"'''' '1;<01 ,.. 1, :\ ... ",ilo~ri l hrni<· pI<>l .ho",lel h.-
" .....1 (,,, Ilw ,...lmp" l..liu" in tI....... ,." ...ti" ", in
" '"M''' 11..· 1', ...1<11....,.." (. " ....."I ",IIi"" '..,d i..... hn·
••..rly "n <"t,I, a pl"t, {ti . .. I""", (mm 'L,la .. f Aln-
.Ii,,· ,,,I Sl j"l<n..,~. II; 1I..·, Ii.tl~ ..i. (,.,
litl,i",u p:oi "jnlo: 1 2 :2 13. 196Y,)

10 20 30
Hours

(3.0 lllWLl aud Ihe t'~trapolalt"(1 ,~J IIC ( 1.6 mw'L) relat ive 10 tht' iuitja] ";llllt· is the fral1iun
r-luuinan-d ,,~. dialysis.

(oMe"tratio,,·Oepeodent Kinelks
All additiunal (1l11sid,'ralioll ill the dialysis Ill' d nl ~s in tl.t· ()\"t'n loS(' situation it; coucemr a-
tinn-dt'JlI'lIdt'n t kinetics (Ct.ap. 22). wlwH'lly ('itllt'r tt.(· volume of distributi on o r th t' total
ck-arance. or both . depe-nds 0 11 the cnncentratton of d nl F: in plasma. Erhc hlorvynol shows
such couce-ntrution-dcpendent ktncnc behavior ( Fi ~. 2-4- 9). At normal tlrerupentic doses ,
tilt' I.alf-lift, is 2.'; IIr; in (J\'('n loS(' C'".l.WS it is mcn-ased to men-than 100 hr. probahly ht"('1I1I.<;(:,
of a dec n-ascd nu-tabohc ch-amnce al the lI i ~ll(>r concent rations. Similar to lith ium , et h-
(.'hI0,,)1 Iul alsu sllows plasma reboun d aftef dialysiS, Tlu- redts trlbunon hen- is a conse-
'1l1t'lIl'C lIf thr- hi ~h alli nil>' uf tlu- d rug fur fat. a poo rly perfused tissue.

t 'iK· 24-9. 11........·,:011 <I.,<,li'"· ..f ..t1"..h1.. r-

"Y''' ~ ,'o''''1 '"l r.aIi"" in 1." "..1 .." tI,i... 'mi"'I(iI'
rirh", i(- pl.'" ,," ,......('1 11"'1·nl....l k"' .10,"·," 10·,...... in
all i " rfl~iI"I' '1 I I',.h''''f. D" r'iIlR.......' ""-h, .1i"lp i. c
8
i 150
' 00
DialySiS H

<,
H

~
H H H

""rio,,1(1---11. fl... """, ·nln,h.." (. - ·.1 ,..." .'

n'l I'K'I'III." r " ",,10'111.. ri ... "Rain "~" .,, (haly,q, u0
c
70 \.
,....... .11....'1 "' r" " .. "1. intlit...lh,· or n'l listril..,lin" ( I g ~ 50
"'WI . - 6 ,9 jJ\ lJ. (K''1 IT'll'"' ' f" 'll> T.>;,..,. T.S . ~ .§.
-,
30
Will. 1.,1l " (:. ..... I ~ . T,",l{. T .( ;.. ,.. "I ( ;. n,I" ·, , E
h",Ii... 1-: t:,·.,]"..ti"" of IIt'nlt" li~...i . fIll .1 h.
d,ltll'\)l"~ (1'l... -t<~~ ) ,,,...,, 10....·, ,' tn , J lI... p
I'han n., 3 1 :!J"I>-~. 197-1 Ori ~ 'w1 .Lal" fru'"
~
~
20

10
"-
( :il.....,. 1' ,10' .. ..,"I Wri.l:ht. ~ , : E f IKi,It>(\~l"~ in s
m 0 40 80 '20
l.i" k'!Q...,tl UuitL.: s", '(ifK:i~' "f ,,,...~ n",t!""l, . J.
11...mL ....oj . fiI : I ~ 1 74 . 11)';'1,) Hours
CHAPTER 24 D1AIY~S 457

As stat ed in Chap. 22, concent ration-de-pendent kinetics is pe rhaps more the mit' than
the exception in dmp; ove rdose . Assessment of th e dial)7-ilhility of dmgs under this circum-
stance is more difficult than at the rapeutic co ncentrations.

Toxic Metabolites
I,ittle correlation lIlay exist between the d rug cuncentmtion and the patie nt's clink-a] statu s
for dru gs for which a metabolite Is primarily responsible for toxicity. Climcnl respo nse is
then expected to be mo re closely related to the blood concent ration o f the met abolite. T he
removal o f active metabolite, us we ll as nn chau gcd drug, should he conside red. Oft en ,
ther e is a paucity of informat ion of this nat ure .

Other Considerations
Determination of th e overall hem-fit-to-ris k ratio of hemodialvsis or hcmofi ltrution requires
weighing o f lllallYfactors . The seve rity of the polsonin g. th e value o f other p roced ures such
as for ced diures is (Chap . 11), tlw control of urine p l l . ami the risks of the procedure to
the patient, in addttf on to other cliuic a] \'ariahles must all he couxidcred. Tahle 24-3 lists
rep resentative substances for whtch cxtracorp crcal met hod s lIlay be of pot e ntial value in
treating severely intoxicated patie-nts.

HEMOPERIUSION
:\ final system, which op erates on princi ples different fro m those of pe ritone al dialysis,
hemofiltrattou, and hemodialysis, is lW lIlopcljilsioli . In this system , whole blood is passed
through a charcoal o r resin heel. .\Ioleeules tha t are adsorhed art ' retarded; blood cr-lls and
plasm a proteins re ad ily pass throu 14h. T his system can have a hi14h e lTidemy for l"('m o\ 'in ~
certain drugs. As virtually all tht· d ru14 cun be e xtracted from tht, blood am i blood flows
through tln- lu-mopcrfusio» cartridge can he 200 to 400 m llmin, clearances greater than
200 m limin can he oiliainetl for sub stances that strongly adsorh to the syste m. T his met hod
appears to have po tential ill the treatment o f dmg ovc-nloxc. It is, however, not without its
ow n set of limitations, indmling the removal of platelets . whit e blood ce-lls. various emlog-
enous ste roids , and oth er substances. The plmrmacokmctic principles discussed for nsscss-
ing the effectivene ss o f hemodialvsis also app ly he re , excep t that dru ,l.( re moved by hemo-
perfusion is dctermmed from tilt' amou nt wit hin the cartrid14t, inste ad or th e amou nt
recove red in the d ialysah>.

Table 24-3. Representative Substances for Which Extracorporeal Methods

(Hemodialysis, Hemofiltratian, and H.moperfusion) May Be of Potential Va lue
In Treating Severe Intoxication"
Acetaminophen
Aminoglycosides Diozepom fvlelhyprylon
Amobar bilol Ethanol Paraquat
Butoborbuol Ethchlarvynol Pentobarbital
Bromide ion Ethylene glvcol Procmnornide
Corbomczepine Glu tethimide Salicylic ocid
Chloral hydrate lithium Secobarbital
[Inchloroihonol] Methanol Theophylline

"C........ U .. fO/lor><!. SC. i"k>m'l'lQt>d. PG.H. or><! EIIO"" J ~ E""<>C<><p"'eol re""""" oId ' "9>ond r»$OI'II!>y~od"'~lond "''''''P'''fu,ion Am .
~. f'ho.-macol, T",coI.. 17: 100--191. 1987, Go...,J. T A.. ood lIt.cI....JD , P'i<>ciplel 01 0"'''01 r""coIogy 2r>d ed , ~..,... Pre\>. New YO/_,
1990. PI'. 50-55 Pond, SM. : E.=,poteol'ed-"q..el in !heIreotmeftp 01po;~ pot"'... IV'edJ M .. 154017---622. 1991
...
STUDY PROBLEMS

(Answe rs to Study Problems are in A ppendix Il.J

1. Dd illl' t1ial~"!i i s . ('xlral'o rpon 'al dialysi s, h(· II1()( l ial~"' i s . lu-mofilt r ation. l'l llltin uous am-
Imtltory pl.-nte ml',,1 dialysis. dia lysis cleanmce-. di alp A·f. dial~ '"I.t· r d fidt'l\t" , and din im l
tlial~·I. ahility of it d rug.
2. a. Complete Tabh- 24--4 by l'sl i lllat i ll~ IIllho\l ml and total di alysis e!"' ilr ,lII t 't ' value s . th e
r atio o f Ilalr-lin's 1)('lw('('1\ alld d ll lill~ d i;J )'sis In'iltlllt'lIts, am i the- half-lif..• IX't\\ '("('1l
di,J)"Ji, is treat ments for (,«<:11 of rln- th n -e drugs listed. US(, a crvanuim- dial)'S is clear-
all<1' of 1.511 m lllllin ami a rme-c orupart me-ut 1I10d,'\.

'.It••
CI_,..,".,
2 4-4 ....-HI
H"N-Llfe Ihn /
_ 4 ..tI U
DI.tyel, ,
DI• .,..',
--.. De rl••
H••••U.tysl,., Specific P.tI WIth _1 DI_ _
'-""'<N>

, Q "'.,,'"
Ct£AiJoNC£
"'C"""",
.",,,
(,~;'j
I, '1

• "'" 01" 'V" (h'l

SNoprO><etl
0003 055
(MW • 230 g/molel
TOOtamyo;:,,'
lMW - 46 8 g/molel
"
23 OQ5 03
Ye<cpomil
(M W _ 455 g/molel 350 0 10 '05

h. U sill ~ Ell. 12 and Fi~. 2+-3. il~s('SS Ihl' rlill jn ll (/i(//yulbi!ity,,( rlu- thrt't, t111ll111lumls
hstcd ill Table 22-1 usill~ a -t -hr dialysis treatment. Fur ;lIl)' dnl~ of quesnonable
dia lp.;thility. bril·lly tlisc..'uss 1111' 0111 ' kindit· pmpt·rt y Ihat is most like-I)' respons tblc
fur ils hC'iIl ~ ;1 poor m mlidatl' for n-ruoval b~' d i<llysis.
3. In a study of tilt' n 'lllo\1d o f pheuyt otn by he lllod ialysis (Adaplt'1l from ~ I artill . E.,
(;:unl J( · rt()~l i f). J.c;.. Adler. D.S.. TtY/,N , T.z..: " Homan, I..A.. alld Gmus1.. II .: Rc'mO\OlI
of ph(,II)10111 hy ht'lIIodi alysis in un-mie pat teut s. j.-\\ I:\. 238:1;.')0- 1;5..1. 19jj1 the
follm\i l\~ ,lIta WNt' ""tailll,1in om- of ti ll' subje c t s . Sodi um plu-nytnin (350 mg of add
fon n u f dnl~) was admlmsten-d illtra yt' llomly OYt'r 30 min 2 hr be fore he mod ialysis
tn,'atnl('lI!. Tile ,I\ t'ra~t' blood and t1ial~"s;'It' [low s t hrtlll~h till' di ...l~7A·r we re 305 and
2fi7 m LJ min . n 'sllt,''l1in,ly. TIll' ptL~llla pl lt'n~1 ()in coucent rauon dmppt'll From 3.9 to
3.5 lllWL du rill~ tht' (j. llr dialY!lis treatment . Til t' fr.al1ion unbound wa.~ 0.2 1, am i tilt'
amount of pl.t' n~1(Jill Ulllt'l1:t'l l ill tilt' e-hr t!ialyS<lft, \\1L~ 14 Ill~. Ti lt' di al~'Sis clea rance
of creatinine- \\"iI.' &'l m lJm in. Tilt' l,ml"t'litratioIlS ill bloodand p la sma wert' \irtllall)'
it!I'n tit"<l1.
a. C Ul111all' tht' dililysis clearance of phenytoin .
h. \\ 'hat is till" (,mdt'lll')' (extract tou m d l icit' nt ) o f till ' dial)7.t'f list'll ?
e . The bluod concentrations into and Ollt of tln- d ialwA.' r co uld Im\'{' been used 10
den-nnim - dtalvst s ch-annux-. If tht'" had bt,'l "n IISl,(t. wh at \\'tlllld 1111' r atio (outli n)
ha\'{' IX'(' II 10 ii\'{,
the clearance (Jb~'r""t'(l ill -a-? A ssu nu- 110 net loss of fluid Imm
Iln- ht)(Jy inlo Iln- d ialysal e" Do )UIl Ihin).; dt'anlllt't' (.'Olllt! have been dctermmed
,u:t:u ratt'!\" [rom tilt' h ltJl)(l l'J1I(, 'lllmliolls illin ,lIltl Ullt of til(' dialwA.'r?
d . Cak1llatt: tht, ffill-ti oll u f dnl~ initially ill tilt' IlOO:ly thai is t"!i millait'tl by dialysis.
e. Is ti lt' obwrw-d dial~.,.is d t'amll(." of pht'lI)1oin ( ~ I . W" = 2.52 Wmolt' ) clost, to tilt'
m lllf' p n 'C li (11'C! by El l' 5 in till' h"t?
4. Ti lt' (Lit:l ill Tah1e 24---5 on \lln('OIIl~'lin Wt'f(' ,1(' lllin '(l in piltil'lIts n't,."hill g CAPD
In "IIIII('II1 . \'all('("n~1.in \\11-\ ~\"{'II inll'<l\"('IlIlIl\ly ,lilt! illtm pt ' rilulle a lly ill t!oSt-os of 10
 c••

IIlWkI! nil se pa ra \(- O('(';L~i nIlS . 111t, fi ,""t d·\.\'('11 ttuw afte r \'U1("l)IJ1~"l'in administration \\1lS
4 Ill'. Two add ilional -l. hr e scbaugcs and an owm ig;ht 12-lJr dwdl tune wen- IIS('(I.

T.ItI.24-5,-

In"ovenov~ 9 15<
In"Q per'!OI'IeOlln~TIIIoT'on 2.5"
'tlaool-.,..,~ • . C M
On ~ 1
~ . GII e.... , M ~
340] 1-037 , 1983
"
s,a"" IIS ondlcltiC yon:<l""j'< .. ......-u<i.<"'9-.....~~doo/yI..

."".~ I"" bnOaI ,. d"'7c. U Cole_ ~_ Doooo! J.V:::'

' ~,n d-olyoolebo<-- 0 O"d n .. d.....dodtry ""-C """'",..., __ - . d
·~ ," d """""' ~ 4 ondn" d ....dod I>, ,t,(JC _ " .... ,,,,,,,,_

a. 'nil' authors t-laim Illat t he \'alll(' of vancomyci n pt'ri tollt·:tl (Iial~.,.is <:!l'amlll,(', (, ,1-
('ulalt'(! aftN i.p. instillation, differs From that after l.v. adminis tration. Do ~llll a~n'('?
Dj' fl'nd sum all~...ver.
h . Can ~ll' ; explain lilt' d ifTl"r( ' IWt'S oh st,!,y('(! in the estimates of clearance from lilt"
two r outes flf atllllinisim iio ll?
5. Tah lt' 24-6 con tain s the vahu- of scverul p hannacokim-nc par-ul1t'ter'S and tilt' n '(.'IIII\-
nu-ndr-d tlosa~t ' rt'~nwn for adults with no rmal renal Inu cnon for t1igito.'Iin am i tilt'-
npllyllillt" In additioll. lllt'i r upproxnnate values for dialysis clearance art' gi n ' lI.

T.~I. 24-6. hlMtetl Pha..._.lcl........_ .......,

• "tI Dlal.,._. CI_ _....... DIII..:II:I" ."tI Theephylll_-
De_.__.. 1.__•

Ho~~ i!e Ihr] 160 8

Volume 01 d , ~" ,bur ,on . p1a r.ma III 3B 35
froclooo excreled unchoogud 03 0. 13
Route 01 odm 1J\'~"O f>On 0 01 001
Uwol mo,ntenonce dosoge 1E'9'me<I o I mg doily 240 mg ewry 6 h,
DlOfysi ~ clearance. p1a~mo (VhrF <0 . 1 2.5
Froctoe unbound 003 0 .44
...,--..,.~-~
' f it_I",.., Eq 5 Clo:>/orIo. <IoooO"n<J ' _..... ".. "" ............ .-:J .. """"""<l '" t. 110 ...../ _

In an swering tilt' tjllt'sti uns 1N.'low , lilt' foll{J\\ing ap ply: metabolites art' lnact b v aml
nn ut(J\i(' ; noun-nul clearance. volume of di stribution , and btoavarlabihtv in normal am i
auuric patient s an' tilt' sauw; tln- plm nnat.'(lkhwti e p'lnllnt'tt>r values .: n ' inti t'lx'ml t'll t
of eonce-ntmtiou; and dislrihulion to l ilt, tissues is Instan ta neous. Also . tlwo plJyllilll' is
lhllligh t hy the dillieian to IN.' t's st' nt ialln tln- the r apeutic mallagt.' IIlt'ul o f thi s anepbnc
(lin n-ual fnnt1:iou ) pati ent wh o is Ilndt' f"Roing n'('It'ilh'tl lat'Il1tKlialy'Sis t reauncnt t ... 't'r)"
ot lu-r dav.
a . u ;l"t'ti on plmnnacoknu-ncprinciples. ind it.-all' wln-ther or 1I0t a sup p h-nu-nt ary dose
lIli ~h l IN.' appropriate :II tilt' r-nd of a -t-br dialysis period with the dialyze r II M"t1.
Show how vou t.'I llIl(' to \uu r concluslou.
h. \ \1Ial supplemental do';' would you SUggl-'st for postdial ys is admtntstratton?
c . Fu lly dt'lillt'a!t' tilt' dosa~t, nW1l1t'1l t ha t )'011 "'Oul d recommend for illitiati ll~ and
maiutaining tl lt"(lp hy llillt' therapy in tilt' anephrtc pati ent 1I11t1t' rxoin~ Ilt'llIudialysis?
6 . From a phurmacokinetic point o f vie...v is digil o)(in ( M"t' Table 24--6) a candidate for
IW!l1odi"lysis (24-h r tlumtio n ) dl'l mifk-dliull of a M...erelvoverdosed pat ie nt with normal
n-nal fUIlt.'tiun?
... CHAPTER2.4

i . Ctsa pn de a new dmg fo r In oating disorders of ga.\tmi ll lt"~ li llal llloti li f)· w a.\ studu-d ill
end-s tage renal dist>a.o;e pati ents u ndt·rgoing Iw!Oodialp is (problem adapted [n un dat a
in Gla<l7jwa. U.• Ban's, R.. Klotz. U.. Dakslunamurty, K.\'.• IUd . T. II .. Seik-r. K.U.•
and Srcberth. I I.· G .: Pharmacokinet ics and pbermacodynanucs of ctsapndc in patien ts
IImletguing bemodialys ts. C lln. Pliarmacol. 111er.• .50:6i 5--68 1, 1991). The kinet ics of
ctseprtde in th ese patients (while nol 0 11 Iw modialp isl after o m! admlnist ratkm of 20
109 is sum marized as follows:
' 112 - 9.6 hr 'o '/f' - J,.'jCl l f .. ux
During a s..h r dialp is period. till' A UC lI _ t wa s 2-12 J.Ig-t.r/L. and tht· amount n-cow-n-d
in tilt" dialysa te was 0 .36 mg.
Calculate th e followin g:
a. I>ialysi'i ch-ara no-.
h. To tal clearance (CI. + CII,,) dll ri n ~ d ialysis.
c. H('('{)\ '(' f)' in dialysate iLS a fmet io n of Ihal d iminat("(1 h y all pat hways t1 l1rin ~ d ialysis
treatment (fu )'
d . Fraction o f dm~ initially in body th at is lost in til(' dia]ysiltt' dll rill~ di alysis tre atnu-ut.
8 . Since the lntroductlon o f membranes " ; 111 high mO!("l11Iar wt'i~h t <:11100' values. lJi ~h
dialysis clearance s of n,latiw !y !a'1!:(' moh-cules have lx-en possible. Valll.u mydn ( ~ I . \\'.
"" 144.~ g/ molel is an example o f a dnlg: tlmt had 1)('('11 shown to hi' t's<;('ll t illll~' 110 11 -
dialp .ahlc \\; t1l previous con ventional memhram..-s. ~)hler et aI. examined ti lt' di alyz-
ah ilit)-· o f va ncomycin ,,;111 higl.-lhu , h i ~h mn]l"l'II,lr wPigllt <'1 ltOlT membranes . Tubh-
2+-7 lists ti lt' plasma concentrations of vancomycin with tilll(' ill Olll' patiell t foll(J"i n~
i.v . Infuskm o f I ~ over I h r. HI(xJd samples wen- taken al till' tiull'S (after l'll(l o f
infusioll) ind icllh '(l.
,.It..
I
2 V.lMeMyeI. c.__......_ .. V.rI_. n_ 0._ 1 W_k
7 . PI
1...... I ••• 1....._ .. 1 • 0._ 1 "r.1MI WIt. w••
WIt.
M.-"I.tpH _ 0.,.. ~. S••IMI 7-

0 .17 43 0
10 313
40 22 .0
60 187
24 12.5
66' 100
665 865
67.5 802
70 6 410
71 801
73 850
76 874
110' 7.33
114 522
120 672
158b 564
162 374
167 4 75

a. Prepare a Sl'lIl i !t~arit h m ic plot of the d at il.

b. \ \ 1mt is till' half-life o f vancomycin duri ng d ialysis?
c. F iv(' tn six hou rs afte r the end nf each d i,d}'Sis pi 'riOt !. ti n' p la.\ 11111('tlll('('lIlmtiml had
rt"l"O\'t'rt'llllloSt nf tht> decline ()h~ry\'(1 d ll ri ll ~ t1ial~'Sis. Giw en e xplanation for this
observa tion.
CHAPTII114 ...
d . VaIK1'1ll) t.i n i~ usually I'i\'t' n ( 111). O!KT a week 10 Iw mutlial)" b p<11ic'lIh. ~l aill lt'n;lIl(1'
o f a plasma (''UTK't'n tra holl al'lJ\l' 5 mwL ts (k-sin od. l >t: 'l ~ l!ial)'''ii ~ Ihn" 'linlt><i a \\1... -k
wil la tilt' dial )·,J.·r u'W '1! appt-a r to SlIAAt'St 11K' rn.. '(1 fur at.ltlitinnal du ",'s uf van(n·
1II\'li n?
c . l iTis p<ltit'n l wa.~ dia1>7J.od min~ a blood fl(J\\' of al'lmt 125 lilt /min . Wuu ld ) l MI t' \ llt"l1
ti lt· noll'l ",;!1 of \OUK1)1ll\t.;n to he ilK'TI""d.'W '(1 if Iht· h1l:ul flfJ'o\' 10 lilt" diaJ..-'J.·r " 1.·n ·
mcn-ased tn 22t) m l/mt n. a value used for ot her pah('nh In Ih(' shld)'? f':( J(''I'!o )our
an swe r ("I t ht' apran'llt di stribulion of til(' d ru j;t.
9. (A·fpmnl. a hnMl I.spt"t1nlln oral cephalosporin alllihiotk. i~ com pov-d of d~ aJKI t r.U1~
~! ..nrn1ric i'Wlllwn ill all appronmate ratio of 9: I . Butt . i"":lIllt"n an' prima ril~..t·un-II.. I
lIIK.Jld.n~'(1 ill llri llt· in Il,llit'nls \\il h normal renal flJlK1ioll. Tahlt· 24 ~' Ii..rs ",·k'(1 t'(l
pholrmatoL.irniic pa rollll(·lt·n of tlK' <1S i'Wllllf..r aftt·r a I IlOl). lIIjot sinj,tk' ural tltl"'(' of lilt·
IlIh t u n ' in ..ul '1 ..1$ \\ilh \aI)-ill~ tL.~n"('S of renal fUlKiwm. iIK·hltli n~;l j,tn " I1" ((:" " 11"
\') IIIKle lJ,toill J;: : lnterrmttent helJulial)"Sis. TIlt' hrn1ic Ix-h.a..ittr o f tl K' trans io;clJltt'r w.....
..i rt llal ~· itlt'nlk':lll to 11...1 of the- cis. Hen.. otli~~i .. wa.. p...rform...1 ",itl. (wl""l aprot~oln
10 h~') a lai~h .flU\ tlial)"zl'f fo r .3 h r apprmi lll;'lIel~' I ~ hr after il(llIIini~t nllio:m of tlot· <101~_
Tlu- hal f-lift· t l\l rill~ tlial) ...i .. \\'".l.\ 2.05 hr. The iL.... ·rd~· amnUlI1 of tiM' mittu n ' n ..,r\I·n"(l
in li lt· 3- hr dial) .....h· "'-...~ 3n m~.tt\l ri n~ wh if:h lime tilt" .\.l:C W ll" 5 .75 mg-br/L,

T.w. 2....... .........

......... cetpredI After
• • .AlI ._..n -..I OIt••
1 O~ 0-1 h . -
n.t._...... CIs
WIIIlo Y..-yl. .
D. . . . . . . _ _I '-ctIe.-
GO<»
• • •
(,eat,",,_ ceo-c-ce >90 61-00 3H>O < 31 ~oO~llo
lml/ ....n!
p~/cb.etvo"o',
c..... lmg/ll 13 J< 101 220 30 4 307
[1 011 IJ 11 12 4 ) (Q5I 16 21
1M 18 27 40
T_

11/1 1h.l
"
lOll
17
(0 31
11
10 81
J4
37
11 01
51
11 31
50
1061 (0 61 [I 11 11 11 1I II
~1mg-h, /U 40 n 117 100 373
III (Ill 11 41 1061 [511
"SIo,oo.w c .' _
_
"'--
'- ""
J 0..
.... ~
~ ~
JI 302-3'1 IWI
_"--...., ~ .... _---.....
Wbo< 1 8 ............. 0 1 0'd~ 1'"
""-ol_ . r:J ~ ..- " _",""" _ _ _

a. E\pl.lin wil)' C..... alld , _ . n-nd to iucn-uw O il ~oi ll~ from ( ;n lllp ilo ( ; mup V.
h. Calt1110lh ' till' ht 'IIII'llial)''ii ~ d"a rall« ' of cis n :·fpm"j l.
c. \\ 1ml fnKi ioll o f dm ~ k is io;clllwr) in tilt' l'l'l k lit tilt' lJO. 'Wllll ill~ of t1ialv'iis is n 'JIIIr\"t'(1
t1l1rill ~ a 3- h r procedu re? ' .
d . I'n '(liti tln- di;tl)'sis d t·a raJl{"!.· (ha.<;('(1o n plaslIla (UIl('('llt nilioll) "\pt '(1,,1 Inun klluw l-
1.. 1~1· Hf Ill!' tlm/o(5 IIIOlt"l.·lIlar " 1.·ighl (407 Wnwllt·), its proteiu h imlillj;t (f ll = 0 .7 )

a nd tilt· tli;tl\"Sis d,·ar-allt'(· nf m 'a linim' ( I.')·'i 1II1/lIIill).

('. IItJ'o\' \\1.·II I~)t'S tilt' IWlrKltli;II)''iis c!eardnn' o f ('(·fpmnl (pa rt ~h~) ..gn'(· \..i lh )lIur
pn"( Iit.1iull <p;.l rt ~d~)? If ttlt"y a n ' rK)l: in a~,(· IIlt'nl. s u~....1 a n 'llo;cm fur Ih.· .Ii..-
cn·I)"Ul(.)··
10. TI lt' p l""nJM{"kilJ('tit-sn f r.mititlillf.". a \\l.·I!·kntJ'o\11 JI1, n "l"!.1)f:llr all l a~t ", i \t 11",..1 in tn~ol l­
illj,t pt -ptic Ilk"!.'". wa~ slut li!'(1 ill (" nd -!>Ia~c n 'nal tli",·a.\t· p"lit'n ls 1II11 L· rw tin~ h. ·llIofil-
t ratio:m (p m" k' J11 ao: Laph '(l fmm data ill GLttmua.. U.• "': ri~lma. D .R .• K lut /~ u.. Iu d .
T .II .• St:huuL.·rt , II .• Gk Jt:kflt·r. \\".~I.. ;l1l.1 ~I all ll. II .: Ph ann.t<" killt1 k"i of r.amtitliJk·
462 CHMIEl! 1<1

ill Il;ltit-'n ls u ndt· '1t()i ll~ lua-mofih ratlon. EUf. J. c lill . Pharruacol., .1.5:·12'7-1.10 . 19.';.1) .
Tl a- d m g wa s ,ltlmillistl' n'tt inlra\"('lIouslf (SO 1Il~) illllllt'( liale ly alter tilt" start uf n 3 .5-
IIr IX'nod of IWlllofiltnttinli lISill ~ a blood fill,," of 34"l m IJ llIin and all a\'l'ra~{' filtrate
fluw of fi6 lil t /mill . It illitit!i1w (M\\' = 3.51 WIlHlld is Hnly wI"i1kly hOllnd 10 plasma
Pnlh ' iu (f ll = OB 5 ). 11 11' 1,(1Il1't' lI t rdtiuli o f r.l llit itii ne i n Iht' to ta l filtrate \1,lm m' ("01·
k-ct ed Will' O,·fj IIlWl ~ 11M;' A UC frmn t i lllt' zero h I 3,,') liT was 2.11 mg-hr/ L, TIl('
clearance (in till' aIlSl.·Jl{'t' o f Ill'lllofiltr.llion l in tlit'S(' patiellts <l\'l'rill?:t'() 29,1; m )/ lIlin.
and li lt" half·life was 2.fi hr.
a. Ca k- ulate tilt" ln-mofiltration d l"aran{1' o f ranlt idim-.
h. Gin'1l that tlu- blood-to-pl asma concentration ralio is dO\l ' to 1.0, r-stiruate ti lt'
t,md t."llL" · (t':dml1iun ('o...tTicit·nt) uf l ilt, 1lt' lllofill ra liun W .. !t'1I1 in t '\lml1i ll~ ramtr-
dillt' fn ll'll blood. •
c. Detr-rmlne tilt' ('ulli rilllltio n ofl w lIlofiltralion 10 lo lal d imin iltioll t1\lrin ~ tn-utnu-ut .
d. 11M' n 'l'ITllIIWIltLllio ll fo r r,lIIitid int' in pal it' nls \\; 111 M ' \ 'N t' n-nul fu u('tin ll i mpair-
mcnt am i o n tn n-nniuent ht"lIlod iul)'liis is 10 n "(IIK,' dOSil~t, (fur n -ual funcnon Im-
pa in m'nt ) to Iso 1l1~ t'wl")" 2-1 l.r and to adj ust dosi ll~ so tha t th t' liTllin~ (If a sched-
uk-d dose ('oindd t'S wit h lilt' put! ofht"lllotlia ln ;is, Do \l) u lhink this n -commeudanon
would work for lu-mofilt ranonus \\·""I? Rrit,ih' (lis(·lI~s.

lOOKS AND 5IlECTED UTiCUS
Sd t'c:h -d n·f(·n 'IK'''' 10 muncJ)..<raph", and
jOl.l m al artic:k", lunt.u ni ll~ lll;jfc·riaI rela ted
to tnllK'S uf lhishonk f"UlI'''''' 11...• n-fen-nces
iU\" li~h"tl I,,· It'll K' an-a. \lall\' of tht· n ·f·
('O"'K't"S ''IK;K1 IIt>lblt'tl in m ;lltip)t' areas .
partit'llar!~' tI..... ~1·I ... ral IMN"'" tI,,,1 '\"1'\1.' -th.·
fi(·kl. Tn ami d n -pt1itKm . n · fc, rt"IK't"S art"
li'h...1 in only Ollt" edlt~IJ I)' ("",'n thC M I,~,h
Ihe'Y may co ntain m alt-nOli pertinent 10 S('\"-
c'rdl ud K'n .
GeMr.1
IWTM1. 1. 7_. \1.1-' ''"" 1, ~ .• • IMl C;a lllht·rto~lio.
lG . ho.t, .): l'Iwm Ul" l iIM-tk' n.....i, ror I>m~
TIl' atm"1l1. S ,"'" Yurk KitH'" PIl",,"_ 19'W.
t: \ 'lll !i, \\' E., SdM·llt.~ ) .) ., .I1MI j ll \L ,. W -J.
(c'tk ): ''' ppIM, 1 11.ann.." l il It1K"S, 3nl Eel
s.." Fr.u oc:i\c.u . ,-\rr 1},"(1TIM·r.lI,,·uIK"S. 19!::tl.
FC'ITlIiOJII, n.1 ~ . MuM...r. ~I.A . ;Inc.! Cluff, G.A.
Ie..k ): J'hanndt..'ulit..J IJiOh-d IlMI!<lj{\'. \'01, I.
l' nll l'ill 11Ian n;...u lh...lk'li an.1 ~"1 al loli\lI1 .
X,"\\· Yorl , 1'!l·1l111ll. 199'2,
(',ar-t.rll M·. " .Il ., CUIl Mlnl, W .."" . arMI \l ululmfT.
~l . (1'11\.): 111im n....'l.lilM1it" allcl 1'!lanllitlu ,
J plamil-s . \ ·ul. 3, 1', ,1l1<k"l. I't'ptnic!s, ami
I'n lll·lns. CirKi1111i11i. Oil . lI a rw~' \\'lillW)i,
19!U.
( :iloal.li. .\1.: Ui"'pha n nal'l'lIlil'li ami Clinil'loll
11Ian ......ul ilM1k-li. ..til Ed. 1'!,i1atk·lphia. I·A.
I"'a & F,·!lilt<·r. IW I.
( ;iba l<li. .\1.. anc! Pemer , D.: 11lan llam kilM1k s.
2u,1foAl. :","\\' Yo rk. \Iarwll>tl 1'· r. 1Y.' d.
11 1111. C ).: 11umlalulit"'lic" fllr ,\ m-"II" "Iia.
1I111h"",," rtIJ·l lt·illl" nmnn. ( h fon l, 1!J!:j1 .
Kilt!. II .: ()o,'l''''lc"\\' of 11M' rham uc'llkilK1ks of
anh' -plo.-plk· tlnl l....."1 Dn l ~ Cnn lrlll F.pi.
Io.,"'y. t AIiIt..1 I ~' C. I ~ Fain~ "d anti (',,11 .
Fnmun. Ht..'01 Ilil nn. F I ~ C Re. 19!U. Pi>·
36 1-37 ...
I .."\~, . R.II .. alKI SIIaIKI. DG.: Clinit.'OIl ill1 plit
Ii'Mlli uf .lmlt-pRlII';nh'IMlin!t. Pn..'l....lin!C' uf
a ~lIl r-,.jll m . c lill. 11laf111-.l:o l int1.• 9-.51-
Il». 19'W,
SELECTED READI NG
.\In., ,II\'. p .:. In l.); <:linit'Oll 11laf1 nalu LilM1il:s:
Pflt-L,"f H,·fr n·'...... :\ nM·,,,:.1I1 St..;."" uf II t...-
ptlal 11u nTUIt; ' h . 199.1, .
H.M-LmtL .\1 .• aI.. 1 Tilt-l..r. (;. 1 1..), 11lam u -
ls:oL'M"fM:S' TIM"~ aIMI \ lc11 I",Io'l{\ . (h·
ford. 1''' ncan'' '' 1 1m •. l!f'tll.
St:ht• .,.....kI. H,D ., 11la111U1tllLinO'ik-" ill U I:U W
(tnl" clt-ll\1"~ . In Hitoplan n. 0.'11. Dnl " l>t·-
Ii....-rv. t AI,,,..I I..., P. tAlnu n. Ht..'a Kaluu . F1..
C I( : . 199--1. JIl): I.W- Ilii.
Slan, ld. DH.• aIMI WaILill' . WD.: DOl~ l)j,-
p....ilit"l in AIM....tlM-sLl Conll'" & Str.dI"" .
:"1"\\ ' \·on.. 19\2:.
vn..-, T.R.. al..1 1I.·\." k ' . L \ .: ( j ,llic-.J MIaI'-
1I...... .Li IK'iit.~ IIf Sulf'"lal1litlc-s .nd II..-ir \ Ic"-
1a!.>IiIM.' An l': nt.) t"''1'l1..Iia. H.......1. S K~· r.
19\7.
W~,,·r. J.: 11laf1Il;l(o LiIM 1it.... f"r 11M' 11u n 'la-
.....ltit.'OIl St;'''IJtht . l .a'..~..., h·r I·.... T... ~ IlM.mic·.
199-1 ,
\\·....1.·'. HC.. anti .\IAi!>;....,. II I .: I',·n...tal""""
...1...."111..,,1..r .In,I:''' Clin . I'h...nn ill'l.LiIM'i .•
23:2.').1-;266. 199'2.
\\·,·lIilllt- I'.. ...,.. 1 T .. ·• II .: 11,...rm... ...Lin.1K'"
R,"J~ulatu~,- 1 mlll'lriaJ ·...t"IMlc·mic· I'c'o l" ":--
IiH "li. Ul flll:" ,,, ,,1 11M ' 11..tnu..... ·nlit.'OIl St;-
..11l'l"li So·r.• Xo. 3.11. :",..... \·url . \1 " R'l·1
)).:111·r. l!J-W
Wc·llin!t. I',G.• ami T.. -. F.I. S.: 11Ian H,lt' ILi' K·t·
ic.. of Canli....'a'l' llar. ( A'lIlral :"""'''.1' S\'i·
n-m, ami Antimic:ruhia l Dn 'l..... l~ l1 l(l.·lt l .
Hun ll St..·ic·lv uf <:ll{"lI1 hl rv. l!J'-'!i
Willia;u\. IU . :Urolh·r, D.C.: am] \ Innl,·nli. J.
h ..ls.]: ClillkaJ I'I,anll am k'l{\'. \'01. Ill. Ita-
liuna! TIlt.' rolpl·lIlic"l: ... <:linit.·.J 1'I",n nat""
Ic~' ( ; lIitlt· for ,1M' Il c·;a]II, I'mf.·" itliJal , :","\\'
Yon. . .\1.' R"t,I I>t.).;l.·r. 1!I!J1I.
. . n....·1. II.C., antl l·''1It ... id,. :'\(;.: 11u n ndlt'l·uti-
cal l>c.....\t,· !'"onns arK I Dm" (>t·li.,.,.:. S~ 'i .
kill'. 5th Ed 11Ii1.lItlo.·lr!,i... 1. ';1 & t·.."i~·r .
1!1J11.
1>C·'";uIIt·. C. 1..••" ..1)11' \." . W,J.: ()t ~· "'1:'''M'11
v
. .. .It-si~'l l . I·h...n n ol. TIM·r.• J;",I ·U - IM . 19\1.
c....lm;ul. I ~S IKI G, IIIUII . ,\ ,: TI",· 11un'la-
t.uk¢e'Oll 8 h "f TIM·r.q'll·lllic-s. \" .1. I. 'oIh
tAl- :'\...... \'"n.. .\h ( ;r......-II ill. 199'2.
...
H e ilmenn. K .: l1Wnlpt'u l k SySlt"1I1S. Ralt,·CulI-
tn~Wt;1 D nl l( o.·lh'· I)~ CfM" :t -pt anti l).",. t"!-
up llw nl . 21MI Ht,\,. Eel S t"4' 'fo rk . Th it'm.'"
Slr.lltun. 19o'l.1 .
J.,
Ulit·mm . iUltl l>(·kf'flll. C.: 1'han11a(1,kino1k
ul)t im i!loat it~ o f au lk-....K '"r tht"r.il~ ' e lin.
rtlMl lI;K'UkiIll't ., 2 1::213-23 1. 1991.
n , Om!: 1;.. 5\"51.. 11 PIlM1' >a'
0.1. nit" " IJ :I .i9-Ut1, 19'51.
Lin, J. II .• c...dMito, () ,M • aJl(I DujiOC.rn. D .E.:
Plu b-in hill. li ll~ a. a IMima.,"drtt"nninan l o(
t1w- "mio.:a! pb;tml<llC"l~i"rtK- p rop" l1it-$ of
IInllSlt"nlil l,J ilnl i-inR..lnnwlK)' .Jm~. Chn.
rt lilJ1llA"l.oLno.1 .• 12:.w-2--e32. 11:194.
P.-ifid . C .M.• n Uli, A.: \1 .11~b
of d...t ermm-
inl{pL.-'lll;lllOl.l Ii"'"' bindinR of drujt': phar -
m;ar;okinrtil: ('(JI""llWlI(". Clin. ~u.­
l'Iokint't., 2J;~94M. Iw..
Pun.!' S.M .. and 'rea-r. T S .: Fi"'t -~" t'ti lui·
IlO4lMJll : 14.ic: lUU(,-pCS ,mOll di nk-,d ('fM l"lt "-
'1\JII.,K:n . Clin. 11"'rtu;KuLino:t.• 9:1- 25. I~ .
Stt"inl..~ I.. ;and .......\ It·. D.E.: Rt~· ('OIIlJXN-
tiU" ;md pllMlJliM.'l>kiIlMK's. Ht"P. H..."" Co"f.
\l lod. RN.• 6;Yfl-102, 1!h5.
TIIIt-">t"flI. J.. P.. and l.i lll" -n iaud. E. (t"t b.): Pro -
!loin BiIKlinJ;t llntl O nlJ;t T nanspol1. S~mf'O"ia
\I t''tOC-ol Ho.'(-I"I. 20. S t"'o'· Yo ri.. F K. Sc:hat -
b u e-r \ 'f'~ I ~.
IndIYId.oIZG.kM1
C~ rw ...1
("1I~'" o f
Un ml-. K.: Pl lllm lal, .l.::i' M-tir: (,.1on ;l\
\,.m"il i ~' in n "lp"JI.\f· 10 IIl.m \!t·m id al anti -
inftu lllllalu ry d m~ . Aj,tl'ul' Action' Su1"pl..
l i :W--6.1. IOO4
1>..1iI. S.G ,K1 llak P.A.: l'h ilOniK"Olind i<: ami
rha n '(-'utl)lta ,ni(· (;M.1 un ("il' I-\illJ;t V'.ui ahili ~·
ill A'\ p"" I:W' 10 III'un >l'111ic lim p . l'syd lO"
r ha m lal"Ol. Sn , 3:266-275. 1994.
I>a~,· r. I'.. \I.·rio·r. G .• l't·m ·,,, Mld . J.J.. ~l an ny,
A.• a nti 1~ 'IIJaI1lI , T . 11I1l'riI Klivi<!ua,1 pil ar-
m iK'l. kiTK'lk llll(1 ph..n n:l('lJ(l)lla m K· variahil-
nv of d ifTl·1't'1I1 hl1 a hlod .l·rs . J. C a n liu'..a w.
I'l la n nal:ol.• f1(SuPJlI. 6):520-524. 1994.
Huwla ,Kl. \I " a,"1 Aa m n 5, L, (t'lk): SI,"' Strut-
t'W'''' in Dm~ 1>t"''l·!.-'P" II·nl alltl C linK-ai
E \"a!ualttKI. TI lt· 1'('1MJ lation "Prnu :h . Ltu-
t-I11 IJ()(ITK- Q.m m i\..'linn o( tilt" E urupf'an
O :lIl1 mu niti, ,,,. 199"2.
Row....' ltl. \I .. Sllt"illt" r. [~ B " illlli St t'i"lt-r, J . -I~
("-i'l.): \'aria"i li ~' in J)mK 11 w r",I'Y' S f'\\"
Yorl. Haw n Pn "\.'l. 19\.'i .
W,·th ug. P.G ., ilo(1 T~· . r .LS.; r ad un conlrih-
utinJ;t In l16tiJ.IMIlt)· in tlnlJ;t phannal'llkint-tit"'.
I. A~)fl'liul\ . J. e lm . 110\1'" l'I lMlll.• 9: 163-
I<Y. 19IW ,
Wh ili n", 8 .• K,·!nl>Ul•."-.W .• ;and Gn"'o't'l. J.: Pop-
ula tion I'la..rm ilm killl't tn: TIIt't ~· am i C lin i·
(.J " rplic.".di ,," . Clill. 1'1':lr" 'iK,.l.::illt·l..
lI:3'l7-4Ul . 1 9-~.
\\·il:ww,. K.: St.,-n ·Lth'( l (lifTt' n ·m, "I Iu d fllK (Ii'l'
I"l'Iilion in tnau. C lin. Ph an".tt..-.l.i IM1..
f,t:l 1,;9-2f ~2 . 19-\j.I,
(~nM M;,
Kalc ,.,~t, \\' " ( ~ II:'(It", . \ \ '. 11 .• itllli '''-Il:a rwa.l. Ill'.:
Etlmk Di fT.·o ·ut., "'l ill Rt·....1 icH.' 10 I>fIllC'
and Xt-nt Jl Iic JC k~ . :'\t"'o'. \·nr k. ."-lan R. u«,
' 1M.
Prit:v E\"'II~. D .A.: G"IM1 ir: F....1nn in nnl~
TIw r... ~' . C.aIllI,rit:I).,'t". Call1l,",II:I· UlliwRit)"
Pfl"!,'l. IWl
Tud'f'r. G.T.: Clinic-a! implic:<oItwHI'l nf ~'IIl.-tic:'
IW~TIW trphillu in dm~ nM1 a.1 l1 J1I\ IIl. J, Phann.
Pha mul:tJl., "fi,41';'--1;2:4. Iw.t ,
WI"I1O.·r. W .; ."-('l-n L.lnr (;( '1"'''' ""ItI U n l( He-
s1"orf.\t' . S ,.....· \ :nrl. (J\(onl Uni\l'ni~' Pn-ss,
1y,<,7.
'''-J::~ . nd W~iJtht
Hh'in . RA . K.nlllt·L.. J-I I..
"'1101 ~l.u", .II J . : III'
A'M·llt"l' of IJl"...i~· on ( I m~ tll"l"l'\i linn , Chn.
1'11010 11.. 6:':'16-';'14. I~
CIM'~TIKJl. G.: C linic:"a.I phannanokiTIt1ir. o f (In l~
in ( JI ,,"'i ~' . ."-u Ul"l.d'-. elm . I'IlO1oll ,.li11t1..
2.5:100- 1H . 1W3,
G n..-" I.la tt . 1>'1 " lI itOlIOlI1., J.S.• a1w1 s ililtlo.·r,
R.I-: Chnir. pl lanll"lu L.itM1ir."lio( iln.\it~1ir."li
ilIKI II~t"K >l i('S ill tl Ot' .-I.I,",I~·. TI " ·I"ItIM·t1Iic:·
{,",'itit-r",tic",' . 1';&11 I . elill , 11 ,a n n"l" kind .•
2 1:1ll.'>-177. 199 1.
G n"l."llhla tl . D.J., lI.m n'lll . J-S .. ..nd Sf'al it-r.
R.I .: C ]ini(·al pllolrl1l oM:tll.ind it:~ " f amic Jly tic:'S
.. 11(1 l1\ll' K>l M:'l> in til, · t·kit·r1y. 111t-rallt -ut k
(u",i'~'ratioll ' 1'",11 II eli" , 1'IlOI n niK,, ,ki' It-t.•
21:262--273, IWI.
Knll,,·r. It. alltl D.twr. I'.: F.· I>l1 t lnJ ~ 11 ,, -1...111>'
Ii'llll >In, 1 it. 11I':"' ihl•. f'li ni' ~11 illlpli("ltlinn'l
C lill. l1 ,a n n;l(ukil... I.. 2 1:, ().....N I. IIIIJI .
S o rlJJall. T.R : Pl. arma(" kindi(· a.' llot 'l.1S o f all-
litl'1Jn'~\ill1 l trr-atnn-nt in tI ll" t'l' '' 'rl~'' I' rUlot·
~ (·II " .. p,-yd" 'pllilrlJJ'K" '- Hiol. I'syd Jialf)'.
l i :329-.144. 19'J4
Rihd,,·1.\ \ '.: r",·nllll"li nd k., : 1'1,..n n....'llkillt·lk-s
(If D m ",\ in II,,· EI.it ·rly. Telfor dPn-se, IWt9 .
W alLK..•• S . ~l .• alll i \ ·t·r1" "I'l.·k. It K.: l'Ia.'lllla pn..
It'in hi", IiIlK o f Jim"" ill thl· d (it·rly. e lin.
I't I;&nllilt"kiI1t1 .• 12:4 1-';'2. 1Wt7.
W(lI.. UIt",\f·, K.: Dm~ alltl tiM· liw r. Pa rt III :
"~('ill~ "f tlK· li\ 't'I ilIM I ti lt· n...I:,I..>l I\1II ,,(
dnl~ . Bil'llol.a n ll, I>nllt l>i'lllot l'\.• 13 ,31 1-.320 .
I~.
Di..........
lk-nIK1 t. W .M .. A"MIt,fT. G R.• M" rri :w,n . (;.•
Golpt'r, T ~"- .• I'u lliam . J.• Wnlf'IC ltl. ~1.. il1Itl
Sin~·r. I.: DnlJ;t pl't"lCfil>injitin n ·na! fa.ilul't';

I>....in~ ~lIKw ·lin.."lO fur .. 11I1t, Am. J I\Klnt, '
Di , .. 3 :1:;'>- 191. 19\..1-
Rid "t"\,. S ...-: " IJ m jt ..I.... inj!; ..1"rinjtl.'l'>r, tin"' MI' ar ·
It·ricll\'t' ,.... I~ IWlrlu filtr.lli..u . Clil1. Pharm..
;": 19\-2fWl. I~
Bn·IllM·r. 8 .\ 1.• a' MI ".'(:1(1r . F ,C . Jr. lt'tk ): T1w
": Kl l lt~' . , 'uk I .I!I<I II 3nl r.o:! Ph iLM Il·lph ia.
1',' . \\ '.8 . SdmMlrn . 1w-.6.
( :ul>I>in,. 1',0.. and ~· rtrh , t.: ,E.: D nli!; ah~orp­
h.... i'l ){.t.~trni nh....lin.d <li....-a....• ;lIMI ''' rw-·I~' .
Cl in k al phann;o.(.'l'll i. M·hc: .11,,1th,,· r.' pt-tltic im -
l,fkatK" ,~. eli n Phanll.iln ,liIM1.• 2"4.11-4-17.
HfYl.
11i.. 1,It·rnann. W.. 11o..·III,,· T. T.• ":,,·alin K. \ 1..
P1unlt'tl . \ \ '.. \\·o n llilll1l . B.• am i .' mln 't·lT,
.\1. (.....k ): A('lI h' 1...·, lkt·mi;L'l-- Pllan nao.'l'l!d.
IIt'!ie. : l'h ann.l(u killd k s ;Ul ..1 .\l;uMl:t·nll.'llt
u f 11..1;11'.... "(1 "lid Ikfr<ld "~' l>iM·a.....-. Xt·w
Ynrk. Sprill~,· r .\·t·r1;,J.:. IW :2.
.\Id ...'an. :\.J.. a mi .\ l n~;u •. I>.J.: Clnucal phar.
III<1lUkiJwli('S ill jl;di"lib "ilh Iiw r di w a.\ t'.
C:lin. I'h"nnac:oki!ll.·t.. 21:4:2-69. I ~JI ,
R..... 1:1~·- "nm m l,· n . I) .• BnM"'r , J.•ami ",e·II(Of. E.:
1>"'1: d.....al:..• ill jJah"·llt.. ..lu rillK ('l'>ntimKM 's
n ' na] n 'Plat t '" K'llt t ht·r-J.~" P1.a nnac:'l'lkim"tic
.1.11,1 tlK·r.II...-t.tk ('l' >II~i, ll· rat i< "I' . Clin. Phar-
1ll.K'l',killt1:.. Z-l :.'36:2~179. I~J.1 ,
W iIlWm•. ar. , Beater. D C . ;IIKI .\Ionw·nti. J.
1,,"I; k): DOle; ., .. In,inh lrat i< m ill Di.........w
Stal t'"> , ~_. York• .\lan" I IJ. 'kl l·r. 19'1-~.
\\'on. ma n. P.• and G r.lh am. .\I.A, (t'tk): l'har-
nJiIIl'l'lki....-ti(-s ;lrMl ('.arM"r C)"'IIMJtkr-~'.
ICano.." r SOl "''':''' Se-r.. \ '01. 17.) Cold Sprin~
lI a" M>r. X'I. CoM Sprin( Il am o r l..J.h()r.. . t~·
Pn -w, 1993.
I nt l" rari in~ Dru(\
1I"'l'h'Il. P.D.: Dnl( Inh' rillli i<)II' , Clink-:J Si(.
nine-al"'" of U nl (-Dn. ~ 1uten.....i i...lls. Phila·
d.· lpl,ia . Ir a Oc F"·hi ~,·r. I ~JlI ,
lI am h ·ll. I'.D .• .uKI lI unJ. J-1L IlmK Inh' rae--
hon ~ ;a... 1 L'p,L.h ·\ . I'hil;a..ldpllia. I.,,'a & Fl"-
IIiw·r. 19'-.).1.
Shinn. A.F .• ami Slm ,.IIII l),. IU' ,: A rnt'ri(~an
I'haflll'K"' nl i(,,1 .\s i "ti" ll, I'mf.·ssi.....al
l >n'l-: S~"lt ·m~ . I II E\'al llat i"'l ~ of I>m ji!; Inlt' r-
ad illllS. 3m E. I, SI. I...m is• .\10 . c .\'. '\1,...1>\,.
19-....'>. ' 16:14.1--166. 19') 2.
\\'t·llilll:. I'.G .: Inl..·r.....1'on.. "ff''tiin( d nl K at.-
s...rpti on. e lin. I'han llililu kimi.• 9 :4()..f...4.14 .
'""
W' MII!. .\1.: 11Iam lac..,\..i ' M1:ic d n !!!: inlt'rilll-tions in
itJl..~t hl1 i(· p rillli i<.'l.·. elill. r1...nnililukillt"l ..
2 1,2-'\.>-1 07 . 199 1.
.\Io n itu ri n (
Rurtnn. .\I.E .. \·a..~ ko . .\I. R.. itIMI Bratl"f. D ,C.:
C..., mparL'iOll o f tlm( dU~inl: nK1IMXk. Chll.
J'IldOllilll"(,h l...t.. I t),) -J':'. 19-\..')
..:...Ia· ":imll"'. \ I.A.• '1"'11I( . l~ 'I.• G II~id nJo. J-.
Jr .• alKI ":rad jan . \\'oO' .: lf alK!lMIIJl;ol .' pp!it'd
46'
Tbt·ral......tM:s . 2rK1ed. Spokane, \\'A. .-'tppli ed
11K'R pt."I;.ttn.I99'1 .
Lin. F..T .• alKl Sao:lt'f". \\'.: Dm( I.~·""I .\Ion itor.
illJi!:: A~tK-ai T..rnni<I' In• .\f e"Iaholism and
Pharm...rokinMtn. ' ·oZ. ;!. X~· 'lor\;. will"\,
Oc Son s. I~. .
.\ 1I1.~ .\1 X (l'tl.l: Pt.armacoIci~and 11...r -
ap" utK' .\Ion ito rin( of ~dlwric I)m !='.
Sp rinldit'1lI. I L.. CI...rit-s C. 11)(,rnu. 199:1.
S ahata. M.C .: In tr.l\\'00115 infll5ior1 ......lI.liti<.,n s.
Im plioc:at it.." for p1Lar111aco1dnMic moni tor ·
illK. elill. rIIamlilll'tlkillt1 .•24:22 1-229. 199.1 .
P.....-k, C . c.>nIK' T. D .P.• and .\f llrph~·. \1.<: .:
8totL~i.1t- C linic-a! 1'homll il('l'Jl; illt1 ~: Simpl...
hodmi' IIII."lO fllr jlll. li\iclllali1i n~ , lOll( tllt' r-J.f')'.
Spobn e. WA. Appl i("I;111K·r.lpl."utk s . I Wi9.
Ru~taJ . II ,E.: lm mu nos upp ressi..... tlm ( •. 1111'
1II't....t for t11" ralwll t k' <!nl~ llKlll itorinl(. IIl 11ll'
munophannacol. Alltoinlllllm e Dis. Trans -
planl. E..lit.....ll >y II ,E. Hllhrstilll .l ~ i':ndn-M·n .
IU)(I F. Ot1'''ll·jn . :'\t'w Yo rk. Pleneun, 19'i).l.
1'1'. ",1-2<,
SlInsl.ilK'. I ({'(I.): " ..' ...· nl ()t,\"(·IOp"WlltS in
TIll'rapt.·" tic DOll( \I onitorin/t ;o.IKI Clink-.d
TOU<'l'* lJ{\'. S ......· Yor\;. Dt.·kk e- r , 1W4 .
\\ intt'r. \I. E.: Ba.sk- Clink-.d J'I~u\..illl.1ks.
3nl Ed Sp< >bJ.... W.-'t. Appli ed11...ra' ...· utk s.
''''''.
Seltde<l Topks
Di\trihution KifW'tin
Gihaldi. .\I.•;UKI P.. rri,."r.IJ.: J'I&J.fm dl:oli nt"ltn.
21K1 Ed .• :'\ ~."fork, .\Ian -M Dt.·kl e-r. 19')2,
Shaf,,· r. S,L .llnd Stamki. D.: Im p lU\i llKt1M" d in·
ic-al utdit)-' of anntlw1icdru~ phannilll..lkillt"l.
ics, AlK'Stlw-siol<'I{\' ;"6:327-330. 199'1 .
Pba nnaC'O~ R ~ron'C'
11l·lInis. P.J.• alMl Stan.ki. D.R .: t-1'an nillu ki·
l....t i<- alld J'Ilannaco um a mic Filli un 11lat
Gowm dw ClInic-a! Uwof \ lu....·I.. Ild a.\aIl IJ.
III S...rnina n ill A'M·stlwsia . \'0J. 4. r.dilt..J I.,·
" .I ~ Kat l . :-.'..'\\' "fork. GmlM & Sl ratt on .
O
\1).'1.') ,
lI olfon l. N,II .G.• lIlKl Sh.·im·f. L H.: Ki.K·tk s o f
pharmilll... >IoWc rt.'!ipt.m...• . !"hanJliI('l'll , 111t·r.•
Metabolite KillC."ticso
Eat l.... \1.) .: "'o m llition of actiw mt1a1:)(>I ih-s o f
an tic....I~'IIL""11 d mlt" : A rt'\~. of tJ...ir pl.u.
marokinMK- a!)(! tk tapMl tic sij(llifica:r)(..•.
<..1in. Phannanlki no..1 .• 21:2':'-1 1. 1'J9.i.
[ '"han.. A.• and f lljimu ra. .-'t .: .\It"t.u x>lltn uf
antlh~'('l·rt...n m.... d nJ~ . An upeL t....1 rt"\'lI.'\"of
dlt'i r clinical pharmaco l i lM"tK" and Ilttorapo.'\l.
he im pJicv.hollS. <..1i n. PlaarrniK:tlkirlt"t .•
21:3.1 1-:»3. 1m .
Gar-attini. S.: Acti,,· d mJt .lM"tal:ll>litn : All " .....r ·
\-WW of t!wir rt'1l'\1lJIC'(' in clinical p1ldOn;a.
...
u .Lint-tK-:lo, clll!_ 1'I...n llolll. o kilMi .• 19:2 16-
22";, I ll'~_
11,.. "t.." , J iL li: i ll..t ic:~ o f (L~P'"ulio:" , of wno-
" tnt M:'! and t1M'; r ,,It''t.J.oI i l~_ I>ru ~ \ It't.m.
nm~ l nte-.... .1,. fi,.. ;-J;,.1 . 199-1
I'an ~. l.:.S.: " W\-M....- of IIlC"bhlllK" " 1Ilt11("'l.. J-
l'Iwn ll..,.LIM"t.. Bi...I'......m.. IJ:fi,."l-Hi:2.
19'1.').
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I...hn·u lm'. G ., .IIMI Ko·LoUIl:'·" P.M.: Ti mt,-<Jt..
p' -IMk 'IM;)' ill lht· p l,a n IlAlold no'!i("\ a m i Ili'!-
' ... ...ili.. n nf tim ,., . I" T upk "lo ill I'I...rm....x-u-
ti<'i.1 Sd.' IK"'1 . F.(lih ..l lw U .D . Hn ';m.·, and
I', Sp.·i...·' ..\ l1I' k n LulI: 1-:1......, .·" I ~'j . PI'.
I fl7- 17'!:,
I A'IIl Il "" , H.: I m p1i(~dti"II ' of d l nmo p llanll;KO-
ki1U ·ti("'\ rn, d m~ tl.·!i\'I"rv: An tia'ldlluali("!i ,
Il.-hl..d ...·.... and cnn h..\'a~' , Ltr 'M:t i \l ' dm~ .
.\ t..... J) m~ l J.·];w ry It,...'.. 6 :.'j,.1 -IU I, I YO;.J..I ,
" ;In KI)'i,\ III1l. J.M . VlIn U II!o:t'll. G., ,IIM I Hu'W·.....
J I' ,T .: 1>. ....·-(10' .·'"1..-111 r' ,an n. 'oldn. ·lic':I..
P1" m ll.Kul n il" " ZI :;;_ lflO. I~l.
Tu""" c-r {'.ol1o«"p h
R. "\(; ~lo. " .• and Sl",·. G.: Tllnll....., . / n I>n l)t
;tlad T r.M't·' Kilwt in. W061d u m. M.... oW....
.10·11. Il:lffi.
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fflr III \'~u Ki 1 1('S: 11lt'll ,~, ;llld ..\ ,-.plll.'a-
tium , St....· Yurl. ('". I..-mit· Pn ",,,, 1",,2.
l>iah-..h
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I>j,..h ,i\, ":"lilll ll ll'l~'" Clmn-h ilJ 'l .r.i ll!C'IClllt',
19"16.
r..' .: K i n.1 ic.~ ufllt"m.. ' i~,i\ ...\ rt . 0 llt.•
( ~ ,tl-h .
10:272-2\ 1. 19"lfi
1It'IKIt·NlII. L W .. Qt ll"llIll '~I . E..' .• liaIcLulIll\ ,
e,,,.. alltl l.~'Y,,"t . ~ 1.J- (t'tI~.J: 1I.·lIltl(;h ",·
lin n . S .·w 'I'n ,k S pli ll ~::t',- \'('r1dlto 1w,6.
I'nllt!. S . ~l. : Ell l'lltu l1lO,n 'ltl 1t't,llIliflllt"l ill lilt'
In'almt"1I1 of poi....un-d 1),;ll it·ntl . Mt-cl. J.
" 11\1.• JS-J :6 17--fi22. lW I.
Sit·"t ·rth. 11 ( ; .• ~l ;l nn , II .• ;11111 Stu mll1 \1lll.
II ,t .: <A",lillll' MI\ 11.·t1 K,fI ltmtitm. 2' KI II1Il" -
lla li<lta.J COUr.·A·IIt't· " " C'JIl th""MI\ " " nltl-
filtr.lt iun . 8 ;1(I..-n .' nun.... St, lI. In-.I I, IW).
S .....· 'linn . 100 1.
 Appendix I

ADDITIONAL CONCEPTS
AND DERIVATIONS
 - Ap pen d i x I-A

ASSESS ME NT OF AUe

Scvr-mlmet hod s exist for meas uring the an-a un der the plasma concentration-time curve
(ACe), O nt' met hod, to I..., t1iS('uss(·d he re . is 111l' simple nu meric cstnnanon o f urea hy till"
t m ,H':,oir/fI/ rnlr. Til l' ;lth~lIl ta,gI' of this Ilwtl.otl is that it only requires a simple extension
of a table (If {·\ IH.·ri nw ntal da ta . Other met hods iU\llh l ' r-ither ~'atl' r uuuu-nc (·t llll p lt' xil)'
or filt i ll~ of all equatinu to till' o!)S('rv.ltiollS anti t1WIl (,"dk' llalill~ the an -a It)' ill h'W"d.lin~
lilt' fitted ('(!llatit Ul .
C l'lll"rll l Case: Couvider tilt' blood ccuceruruuon-tfme data, first two (.''llIUIllIIS of Table
A-I . ob!ailll'(l follH\\i n,g oml admlni strat inu (If 50 Ill ~ of a drug. \\11<11 is th e total A Ue ?
FiWm' A-I is a plot of concentration a~ai llst timl' aftl'r d m~ administ ration . If it pt·r·
pt'llIlkllb r Iillt· is drawn fmlll III(' concentration at I hr (7 IllWLJ dO\\1l 10 tht' time-axis.
t" t'lI tilt' area 1)(llIlId t11 1)(' lwI '('1I zcm tu n e ami I hr is a Ira pt'7J lid .... tt h au an-a ~\"t'n ,,~,
the- product of an·ra.!:t· concentrannu aud time interval, 111t' an'm~t' eonceutratiou is 011·
(aillt'll by atltli n~ ti lt' concvnt ratlous at tilt' I )(~nnin~ and end u f tilt' tlnw lnn-rval and
d i\idin~ hy 2. Sinn', in lilt' Hrst inle ....111, lht' rt'Spt'(1:in:' concentrauous art' 0 an d 7 mglL
alltl tilt' tiun- inlt ·rvul is I hr. it follows that :

AUC, • -0 +7
2- 0'9/ L x 1 hr

Area of trapezoid Average concen trolion Fir51 time

w ithin the over the fir51interval interval
fir$lltme interval

or,

AUC, - 3.5 rng-ht/ L

III this r-xampl e, Il.t· ('(lIl('('nll1ltin n at zem hnl(' is 0 . Had th t· dm~ 1)('('11 ~\l.. n ;lS a ll intra -

r.II•• &-ol. c.lculott•• ef'''''AUCU.I.. tlter........ltN .....

TM 8l000 CO'<£N1 I,o,1I::)N TIYiI! NTff\'ol,l "I'tRAGE CO'<!NTV.hON
il'vl I"".VU ltv! loog!lJ

0 0
1
, 7
10
J5
85
J5
85
,J 5
zs
75
J 75
7.5
375
5 "5 1,88 lB8
6 06 O.Q3 O Q3
7 0' 0' 0'
8 0 01 01
TOIOI As~ - 26 60

...
.7. ""NO'O-"

10

~ 8
.§.
c
~ 6
"
~
u
c
0
'-'
Q 4
2
c
8
in 2
Area
2
0
0 2 4 6 8
Hours
."iK' .-\-1. 11,,1"f tn"n'u lr.di..,,·lm... ,Lt. "rTaI,,," .\ - 1. n ..., ~ .."..11i1l'· h tt..· .... ".tI:l.,u' K. 'ulnll i,," in , IK ' fir"
inl""''''

\"('1\0115 (t.v.] bolus. tln- coucentrauou at ",t'm ti ll lt' lll i ~h l l. "\t· II('t· n lilt' (':\Impolalt'l! value.
C (O).
,,", an-a IIml('r (-ad , time- interval cau lit· obtaillt,d ill all iUl il !U" OIl S unmru-r to th"t
oullillt"tl aIMJ\'t·. Till' total ..\ VC (M'T all tunes is tln-n simply Wn'll hy

Totol AUC .. Sumof the individual orec s

USlw.Ily. tottll AVe IlwallS III(' an-a un<!N t"I' ('UI"\"(' fWIIl "",'m tim!' to infinity. I II pmd k t "
infin ite time is l a h ·1I us til(" li llll:' ht")'tlll(! which ti lt" a n -a is i ll si~ll ifi(..UlI.
1111' (, IIl'lllatiu lis used to "hl,ull tile A UC. displa)"t'll ill Fi ~. A- I, art ' shown ill Tuhk-
..\ - 1. In this t'xamplt· tht· total A UG is 26.6 mg-hr/L.

SPEC IAL CA SE
.-\n Int ran "no u!i Bo lu s. \\ 11('n a <Im ~ is gi\ 1 ' 11 us an i.v. ho llis and fl..' . 1.1.·lillt ' ill pb.\ lIla
('(lIll1"n l m!ioll is rnoll()('!{polU'lItial, IOlal ..\ UC is l~dk' I Iah-'( 1 l!lost m pitlly by di\idill ~ lilt'
ext rapolated ".(·n:>-filllt' conceut ratiou (C (O)) lIy 111l' d imill;lliull rail' (1.lIlstiUl I (k), Fur ( ' X-
am ple. H C (II) is IllO mg/l, and k is 0. 1 hr " I , thcu 111l' total rUl C is 10011 !II~.h r/L.
Proof 111l " total r\ UC is "'\"t'll 1Iy

Totol AUC · r C · ell

BUI C - C(O) · (, -4" and smcc C(O) is a constant . if follows thai

 ~SSNtN T OF AI..C

Iotcl AUC · qO) 1" e -.l:' · dt 2

1 1 =~ 3

\\1"'n Dl"<'line h L.j[)~ari lh lllic. "n it" IIUlIIl'rk method used tn t~tl l'llat l" ,\ l'e II,· 11ll'
tra pezoidal 0111' il-\ MlllWS a lilwilr n ');ltiumh ip lx-twee-u ubwrvanons. Fn'lIIll.' lllly, l"S1ll.-'ti ;llly
dll ri n~ tilt' l ll"d im' (If t101~ conce-ntmtiou. 11 ll' fall is (' \ jXllU'ntial. Then ;I men- al.'t.1lrah'
Ilw ll.oll fur t..tk' i l atin~ a n '.. d urill~ thr- d,'t." )jm· mil Ix.' IN't1. Il.t· lo/!, tnJlw=tlldul n,I" , us
fnllnw,;,
ClillSid Pr, fur r-xamph-, two t"l lllSt'l'ulin' ClhSt' ''~ll in llS C(I,) ami C (I . + l ) a t ttnu-s I , ami
I , .. I' f('sl )(-'t1 i n' I~" 11l t's(' uhs.t'''·ali ollS a rt' n -Lucd to t'adl ul lw r hy

qt,.. II • qtJ · e -.l:" ,\ '. 4

when- 1.: 1 is tilt, rail' l"llllstallt that pt'nllit s the concenr ra tton III fall (" Illlltt' ntially [rom G(I,)
to e (/, .. I) in tilt' ttnn- inle ""·...I /, .. l - f" tlnu is, !'J,. "111t' \'allll' of k, is ~,,-n hy taki llJ.t th l'
It ~a rit hm nil IMlt h sidt's (If Eq. ... a nd n'il rr.Ul ~Il J.t. so Ihal

l' ICItJ/ CI',• .II 5

~ ',

:\IIW IIU' AVG dll ri n ~ t ht' time interval !'J., :\ VG" is lilt' t1ifTt'n"Ttl't' Ix.·twt"ell tilt" lotal a n 'a.\
From I , III x ami From I , .. , til x , n'sllo:'l1 i\ " ly. l t tla-n-fon- fnllllw,; from ("\...-ut s after a n i.v.
IMII" s Ihal

AUCi =
CltJ - Cit,. ,) 6
k;

ami, hy appmpri"tt'ly sllhsti t u t i ll~ for 1.:, in Ell . 6, Ollt' nhtain s

Al!C _ [CltJ - q ". ,11 . M, 7

,- 1, [CltJ/qt,. ,iI

This t~l ll'llat inn is thi-n n "I)(';lh'tl Ior allllhse""'atiulls that l i ," I x. ~ um l tilt' pc·ak coucent ratio n.
III pral1it1', a bll:'o ( li st'n 'palll~' ;lriSt... 111'1\\1'('11 tlu - 1I11'thtMI ahm l ' ami that u sill~ l h,'
(Iilwa r) Impe o;tAlilbl ruh l lIlly wln'n (1mSl'l'lllin ' nhs.t'''''"ati cII IS <lifTef hy mon- than tW(lfcllt!.

STUDY PROBLEMS
I. nit' fnlln\\i ,, ~ data (Tu hk- :\-2 1 wc·rt· obnuru-d fullu\si n~ tilt ' ill ~l'sli()l1 of sn lH ~ of a
d nl ~ _

T,me(h,) 0 OJ 15 2 3 4 0 8 12
PIo!>/T'lCl c onc::en lro ,iQn
Img/U 0 0 38 00 0 73 0 85 0 95 0 94 087 0 00 037
472 ASSf59'llNT Of AUC

Eslimalt' tht· lolal .-\UG . It should 1)(> nolt'1:llhilt thl' Ia-..' ~u n pll' was take n lx-fo n- the
t,lIIl't' lil ratio n had fa llt' ll to a n i llsi~lli fle"'l1l value. ( I l inl: T o l'stim" te the A UC l ll'\ u lld
tilt' Ioest obwonucu. ima~fI(' that this last meas urement was tilt' ze ro-tune l'OIl<.'t·; ltm-
lioll fnlll )\\i Jl~ an t.v, b olus and that tilt" d ispos ition ki ne-tics of the d m Rdol's net c ha uRc
1__-yond Ihe Iast ebse-rvation.]
2. Eslilllatt' tilt" totul Aue fu r th e (Llta se t in Tabl t" A-a oh taint't l aftt,!, an i.v . dUM',

Taltl. &-3.
TM lhr) 0 4 6 , 10 12 16 20 24
PIo~
cooceo ncnce
(mg/U Ill" 63 4.0 2.5 1.6 10 0 63 0.25 0.10 004
·' -"""" b., ~ CW'I O ~ "",, ,, _o _

3 . 1111' ..d of tLlta di s pla~l'(l in Fi ~. A-I ls unu sual in th at the timt' be tween collectfon of
blood Sillll p it's is consta nt. in thi s ("ll....•• 1 hr . Pm\"(.' in thi s special case th at

Tota l AUC _ Time [(First + Iosl conc entrotions) + ( Sum of a ll othe r) ]

Interval 2 concenfrohons
US(, tlw (LIra i ll T ;lhl t.> A-I to confirm thaI this simple me thod \\l Jrh salisfal1oril)',
4 . 111t' rmu-ent rutton of a dmg d('Clill('s exponentially a('<-'t lrtlin~ 10 tln- equatkm C (mw
I.) := 64 (, - 0 1i1r ( t in hours ), Complete Table A-j to ~ huw tilt' errors. if a ll ) ', in eac h
uf tll(' A UC calculatlnn s (Jvt'r the Interval ¢ \'t' n.

'."•• &-4.

164 - q~l

0- 2
Q-4
0- ,
0-12

Answers 10 St nd)' Pr oblems an- ill Appt'mlix II , p, .5;2.'5 .

 •r A p p en d i x I-B

EST I MAT IO N OF ELI MI NATIO N HAL F·l I FE

FROM URINE DATA

<'.onsid(·,. the urine data in Table B-1, obtained lilll(J'\\in~ a 50..mg t.v. bolus du~' uf a
dnl~. These an.' till' same data :lS pn'S('nft'(l in Tabl,' 3- 1. n il' oh servauou s are times of
urine collect ion. \1IIul1I('5 collec ted. and concentrations o f unchanged d rug in each s ample
11lt'S(>(lata arc In.'aft-II t t l tlt'rin' fu rt her info rmatio ll. of slx·t:ial Interest an.' rate-tum- pl1JfiI(.
and cu mulative amount excn-ted. n i l' amou nt C'X{'f(·!t'{! ill e ach tune interval is the pnxlud
of \1I11II1IC of mint' c'(,llc"l1t'i! allt! l'(mt...· n lralioll. to. ~ . • the amount ill Sample I is J20 III L
tum-s 13.1 J.I Wml. or If) III g~ the refon-, tl u- a\"t' ra~l' rat e of (' Xl'n'tio ll ""cr th e firlOt 2· 1. ,.
1'l('r1txl is S mgtllr. n it' cum ula tive amount escn-ted up 10 '1II)' time is the sum uf all d nJ~
excreted tip 10 Ih'lt tune. Hy 24 hr. 11ll" l'ullllllativt' amoun t excreted is 39. 1 m~, ami siul 't'
37.2 1Il ~ was l'xen'h-t1 in tilt' first 12 hr ami u nly anot her 1.9 Ill~ IM'r the next J2 hr. 39. 1
m~ approxnnates the ultimat e amount of d m~ excreted.
Excn-non rate data are IK't'l.L<;ioua lly di splayt'tl a.<; a bar I. isto~~r.un . hilt this form of prt' S!.'II·
tation ts not ,L<; useful as ()Ill' ill which the rate datu art' plott ed av;;un st the m idpoint o f till'
<."uUt"(1:ioll Interval on S('m i ll~aritlilnic Jlapt'r ( Fig. B-1 ). Th e time for th e e xcre tion r ate to
fall in half (t '.V;., fmm 5 mwt1r to 2 .5 IIIWhr) is the e lim ina tion half-life of the dmg (2.S lrr].
nit' reaso n for lISill~ midpoint ttnw W i t >; ~\"(' Il ill Chap. 3 , namely, Ihe mensured u rtuary
excretion rate rcfh-cts the an'mgt' plasma conce-nt ration du rtng the l't)l!ection interval .
Formal pmof o f til(' oh'>('I'Ya lion of elimination half-life is nol dffficnlt 10 dt'rin-. Usinv;
El l. 21 o f C hap. 3 ,

Excret ion ro te - Cl l/ ' C

If DoS(" (' -AI is su hsti tllh'tl fllr C .

,.111. "'1 . Uri. . D... OIl"'Ine4 • • n_.I..... I. .. . . .I • • De_" Dn.w

O8So! "''''TlON m"'IMENlOI Dill'"

_a .,,,'"
a .....
CQNClNllATlON
a
l.N:HilNC,lD 0IIllG
oe-e
1>NCJU'.lf EXCRETED
,,,,
ElC.l:fTlON
""""
>NOM
... """"'.
~ ,o
eomc
coacro-, N
1Iog.' '''lJ
N TI'.If M!VY.....

'" ..-, eomo

'"
&

'"
""'"
~,
h'
0 0 0 39 1
1 <>-2 120 133 160 8 16 0 231
2 2.... 180 50 90 45 25 ,0 14 I
3 4-¢ 80 63 56 28 30 ,6 85
4 <>-8 340 10 34 Il 34 0 51
5 8- 12 178 18 32 0.8 372 19
6 12-2 4 950 2 19 0 ,16 39,1

4"
.,.
Excretion rete - 9:E
V '
Dose . e _ .1:1 2

a lltl l a ki ll ~ lo~:a ri l l ll lls

lnlexc retion rote} = In r~ .Dose}- !: . , 3

'1111" slope- of tln- curve- is - I.:. the- m it- (''Ollsta n t for ehminution o f t1m ~ by lui n mlt-s . E\1.'n
if n -ual 1'X('rd iol1 wi-re tlllly a small Fraction of tot al dm ~ r-lnninatiou. tIl(' ('x('n 'tiun n il"
wouk] still dl'( ,lin(' \\;,h ti UlC' in plirall..1 wit h coucentratton. Concentration is tlw dri,; n~
(on" for re-nal t'x('rd io ll: a... concent rat ion declim-s, so do!.·s mit' o f cccrenon.
In prad kt', 11Il ('t·rtai ll l~· of ('o mpll"II' bluddcr t'mpl)ill~ and need to (''011('(1 urine O\'t"r
short tntr-rvuls, rdati\"(· to tilt' ('lim illati n ll half-lif,· fir tht' dnJ~. pUS(' limitatiollS Oil tht'
'1IIaht)' of ewn-nou m it ' dalli. \\l wl1 complete mint' n"<.'(""t'.'Y of t l m ~ is ensured. {'st imalt·s
of I'!iminaliun ha lf· lifl' an d e limination rat e constant ca n a1su ht, mad.· by analp j ng cu-
mulunve vxcn-t ion data , Tlu- cumulaticr- excretion plot s (Fig. B-2) gt' nl'tall~' te nd 10 lit"
SllIuo lllt' Tth an Iht, l'l.)rn'spuIl(Jing excre-tion ra te plot s,
Ti l.' cumulat lw alllollnt l'x('rt>h"tJllp ttl any lilllt" t , ,\dt), is uhtaillt"tl h~' slIlIIming till'
amu unt I'Sl·Tt'h..1 llllt'b'lllgrtl in I'a('" lilllt" lnte rvulup to that time. Fur example, hy lot h r.

10 t 'ljt. 8-1 . S.·llIil"l{otnlhnul: picot t lO r • nd.· ,,( Ml.,...·

Ii.." ~ r"l Ih., millp..i nt tim ....( uri, l~oI""'! i..n _ n it"
5 p"'rirMI "u'r " ,"it'll tI,,· ;/u·r-.I",· "\('n'lilll' I'l ". "... ,II..
! l.ti rnl i~ ' '' I''·ri ll' p''..." I Il"tll (n>tn TII!.1.· 8--1.

~
g 0.5
~
0.1
o B 16 24
Hours

t'i l!:' 8-2. n ... II"M'U'" ,,( ,Inll: .",·n'l,..1 ond ...n"",,1
in II" , ..rirM· ....~' '''' '''''l ... "'~TI'Il'tutk...J '" I nl II li ml·
40 lin~ .-..I'M f,"
" Al '• • i 1ljil . ", h '. 1.01,,\ lI.t1 f d l.ll
lirniti nl: " nM mnl b .'u -I, .. II " ""•• 1....1(.lif.·.

o 5 10 15 20 25
Hours
 4"
3·1.11 1lI~ h,l\'l' '11:'( '11 ewn-ted. Initi.lIly. mIX'-' amounts an' r-xcn -ted . hut as till' amount (If
d m~ in tlR' hod)' falls. so does tlK' oxen -non rate, II)" 24 hr. it l i miti n~ amou nt (39. 1 1Il~)
has 1)("('u l').('n-I('(1 IFiJt. 8--2 ). Sma ll amounts contimn- to l )t· t"u' rdl'tl hl,,)UIKI 2-1l.r. !loi lll't·
tht'on1: il....Ily tilt> amount of tlruJt ill the hndy appr ooches hu t IW\ l.'r falls to zern, IICM1'\l' r .
t1...~. ;... klilimW .Ul lo u n l s dn lIot substantially alte r the 24 hr v,.III( ' , :\l,(' JRli n~>" 39.1 Ul ~
CiUI II('taken til h..• an (-slim,d ,,' of tilt' hJl:a1 amount of t1n l~ til ht· (""crt,It...1U1K·IIaflJ.:l'tl (iV..).
Halr thts amount (app m u malt't,.· 20 m~l is e xcreted by 2.6 hr <FiJt. B- 2). Inh'n -slill gl)",
again. this is tilt' 'milt' for the hal f·life of this d nl~. es timated Irom plasma concent ratjon
am i uri nal)' -e:"fl1ion rate data. .\S the rollou.; n~ an alvsts ..IMl'\lo'S. tltiJi is mort' than a IlM" W
Cl.riI Ki(L.·rM...- .
TI M' r.h" o f Men·tio n a t any ti me- is ¢wn h~'

TIM' a mou nt .'1C1l'tt"tl up to rime- t is oh taiJK"(1 hy i n t t'W"dti ll~ the rate equarem .

IR K('
= _ _ ' r - b so that
" '

CL ( .
Ae{~ - ~ .bDose . lI
1t- · . d, 6

."
Ao{~ - ~
Cl ·Do.. -
V
['-"r
-I 7

Ao{~ -
el, ' Dose (I
V ·I -. " - B

h ut Jiin(..· ,, - - "" 0 , and \' , k = C L , tht, amount t' uTdt"tl hy i nfinitt· HnK' (A t'. ) must l>t'
¢\l'n hy

Ae _ el R • Dose
• CL
9

Ao{ ~ - .... 11 - . -', 10

.,. ESTWATlQN Of Eij\.o\NATlON HAlHn f~ Ui lNE DATA

11

and l akin~ logarith ms

InlAe", - Ae(~ 1 = In Ae" - k · ,

11111.~ , a M·milngilrithmi<: p lot of At'" - Ad O agaillSl lillll" sho uld ~w a sl rai ~ht hrn- \\i th
it slop,,' of - k.
As till' difTN{·!l<....•• Ae" - Ae(O. is till" amount n 'maining to hI.' l'un'letl (ARE), tlu-
resulnng plot is sometimes cal k-d an A n E plot . In pral1il't·, tht' value o f A RE at each ti llll'
is obraim-d b,· subtrm:ting the cum ulat ive amou nt ewre tedup to that lim e [nun tl lC" total
amount oxen-ted . T llesc-' \11111('1' art" presented i ll ti ll' last column o f Tabl t' B- 1 alltlt ht'
com-spending S('m ilogariti llnic plot o f AilE \"t' rsm tum- is shown in Fig. K-.'l 111(' elimi-
nation half-lift" taken as the ti uu- for the Mi F. 10 fall II\' one-half is 2.8 hr. 1It'1Il't'. k '"
O.25 hr - ' . '
Sccerul points should lit, noted. Fi rst , at zero lime tile value for AHE is Ar ,.. SM.'o ml.
the \"alu(' or AR E is plo tte-d <Ij:!;aimt tilt' act ual ttnu- o r mint' colh-cnon, t' . ~. , tlw tiun- al
wlnch 5.1 mg; remains 10 lit, excre ted is S hr(T abl e H- O, In Illis I.L,t f('Sp("t"t , tilt" A RE p lot
!la.'I a t1islill(.1 atl\~Ultagt' O\"N tilt' excretion mil' plot. ill whicl r l ilt, exc re-tion r an- is plotted
agains t tilt' midpoint or till' urine t'olll'C!ioll interval. Hecall tha t tilt" Wi(> o r Ih,' mid poi nt
thne \\~L'I net.1:'ssai'y be c au se ti le excretion rate is an a\'t' m~e \1l.!lII' (J\'N till" period or col-
leotron.
A lthou ~1l the ~\ RE plot It"mL'I to smooth out tilt" data, it is uot use-d a., rn"ljlwlltly .LS tilt'
excret ion mh' p lot ror rour r(".I.'OIlS: (l ) It n -qutn-s all ac cu ran- es timate or A e,., sinet' an
IIm k'n.-stilllatioll or AI'" tends to ~ross l)' Illldt'f('slilll.lh' ti lt' true AR E values .I.S Ar (O ap-
proae hes Aell<' Tlib nu-ans that th en- has to lit, complete urine {u lll'{.1 io ll rur al II'iL,,1 rOllr
half-live-s, w!tiel. ill clnucal p r.u:"tin ' is ofteu dtfficult to ensure. The rate lIw l h(ltl dot's nol
rt'<luin ' uri ne to I ~ {'l,lIt"l.1 t"t1 until un mort- t1ntg is oxen-te d. (2 ) Ae(O values are us ua lly
ohtuim'll hy slIllIllIing Iht, ulllo unt t'xt'n:h"tl in each ("olll'(i io ll pcnod. Hence, a..'Isay errors
a n:' ;u:"t.1ull lllal ('d , wh ill' raihtn:, to obtain a complete urine collection pr oduce-s it s)'s te mali{'
error ill all subseq ue nt esuma tes o r Ar( O. The excretion rate analysis does not contain ti lt'S('

_ 50 Fil/:. 8-3. '0... '1u .... "'1 " 'l!l ;<in illll: 1<> I..· .'\("" 1...1
g (,~Rf:J, f" I" ""i"l: 'I" Lv. 1• .Ius I .. .... ,,{ ,1mit- ,h :lin.os
r\I.II "''' li'lJ l~''''; l h Ii"..,. I" .....· li'lJf-hr... II..•.~R f: f...."
I~' ,,1 .. ··llillf.
~ 20
w
~
1:: 10
g
o
.s
.e
5
E
~

1 -1--~-_-_-~

o 4 8 12 16
Hours
 ESTMAT!ON OFElVv\lNATlONHAlf-lif EFRO'A URiNE DATA 4 71

sources of error. (3) Smoothing out data can obscure i mport ant infonnation. Urinary p I!
and urine flow fluctuate throughout the day. If the renal clea rance of a drug is sensitive to
these factors (Chap. 11). it is readily apparent in an excretion rate plot hut tends to he lost
in the ARE plot. (4 ) \\11(>n the dru g is administered extravescularly, e.g., oral ly. delays in
excretion caused by absorption produce distortions of the A RE plot, frequently maldll~
analysis difficult. In contrast, the excre tion rate plot can be readily analyzed.

STUDY PROBLEMS

1. Swtntosky e t al. (Sulfaethylthiadtazole II. Distribution and disappearance from the

tissues follo\\ing Intravenous inj ection. J. Am. Pbarm. Assoc.. .J6:403-U 1, 1957) stud-
ied the disposition kinetics of the sulfonamide, sulfaet hyltb tadtazole. Table B-2 con-
tains a list of the amounts of drug excre ted uuchnnged with time followtng an i.v. bolus
dose of 2.0 g sulfaeth ylthtudmzole to a subjec t (weight 8 1 kg).

Table B-2.
Time interval (hr) 0-3 6-9 9-12 12- 15 15- 24 24-48
Amountexcreted unchanged (mgl 534 436 IBI 139 110 202 195

a. Estimat e graphically the elimination half-life of sulfaethylthtadrezole from a se mi-

logarithmic plot of excretion rate against the midpoi nt time of urine collection .
b. Owen that the cumulative amo unt excreted unchanged up to 48 hr represents a
good estimate of Ae" , calculat e the fraction of the dose excreted unchanged.
c. Estimate the elimination half-life of sulfaethvlrhiadtazole from cumulative excretion
data, and oompare the answer with that obt~lled from the excretion rate data.
2. a. Suppose that the uri ne sample collected over the 3- to 6-hr Interval in problem I
was Inadve rte ntly discarded . Using both the excre tion rate and ARE met hods . de -
te rmine the elimination half-life of the drug. Briefiy discuss the problems e nco un -
teredo
b. From the answe rs to proble m I, estimate how much unchanged drug in the body
re mains to he excreted at 48 hr.

Answers to Study Proble ms are in Appe ndix II , p. Si6.

 ESTIMATION OF ABSORPTION KINETICS
FROM PLASMA CONCENTRATION DATA

T \ \ 11 methods are p n -sented to calculate absorpuon ktncncs from plusma roucem nuion-

time data foUn\\ing an extravascular d USt" The first ll1l'tl.ud applies when absorpt ion is a
first-o rd er P" X'('S5. TIl(" S('t'"OJl( I, a III11l1l'riC andmon- gl'lll'ral method . Illakt·s 110 assu mption
about th e natu re of the abso rption pmee ss. It relics Oil muss balance cons iderations ami is
commonly referred to as the \\'01!.IIU -X elSOIi md llOd. Hotll methods require that 01\(:'-
co mpart me nt linear disposi tiou kinetics apply. Ollll'f It'S:; res trict ive hu t ~l" lIe rally mo re
complex num eric methods exist to tical " i ll. mon- complicated situati ons . Finally, if an
equation exists that ad('(lua tdy d(·fhws holh ahsorpnon ami dispositioll, it ran he Iitted
dirt'Ctly to th e observanons to estimate the parmnek r values charucn-ri..j n~ the absorp tion
kinetics.

FIRST-ORDER ABSORPTION
Consklor til(' plasma data in Table C- l , ohtuiued fol1( )\\i ll ~ a J()()-mg ora l do S(' uf a dOl ~.
F i~lre C__I is a st' mil(J~a ri t h mk plot of the samt' dat a. Till' half-life, cst unan-d from Ihe
linear portion of Ihl' decluu- phas e. is S h r. Gi\ill~ the d nl~ int ravenously l,(lIlfinnt"(l thai
this is till' r-hmlnation half-life of Ihe d m~. 11('11('l-' , disposil ion rate-limits dn l~ t'iim illatioll.
A ~mphk procedure to test whether o r not ah sorption is a first-or de r prul'l-'SS and . if so,
to det enntnc the absorption half-life , is known as th e "U'tlwd of r('sid ll(/[." . TIlt' pr ocedure
is as follows: (I ) Back extrapolate the log linear port ion of the ded iul' phase. Le t C denote
tilt' plasma coucent rution along this extra polated line. (2 ) Sub tr act the ohse rn'tl plasma
concentration (G) from thl' l,(lrn'spomling extra polated \1I.11Il' at ead . tinw point . These
calculations are Shm\11 in Tahle C- 1. (3) Plot till' res iduals (C - C ) a~aills t timl' on til('
sallie senulogun thmtc gra ph pap<'r.

,.1,1. C-l. PI•••• c...c..............n•• DohI ••n.wI... 0-1 ..4.1..1......_

of. 100••• Do_ of. D-.

EXIlo'J'().AltO OOlH tlfNCfN

PlASMA C(;t.,ICENIiAnON CONCfNliATlCNS
t . l...ylJ t - C.Img!U
I 0 .38 1.90 1,52
2 0.73 165 092
3 0 .91 1,40 0,49
A 0.97 I 23 0,26
5 0.97 1.07 0 ,10
6 0.92 0 .95 0 .03
8 0.71 0.71
10 0 .53 0 .53
12 0 ,40 0.40
lA 0.30 0 .30

47.
 fSTmT1ONOfA8SOllPllC)l'.ll(lNET(;Sf~ONCEN1R.-.!lONOo'TA 479

If. il\ in Ih is ('xam plt' , tjn- n 'sitlua l p lot is a st"'di~h l lim ', 1!Jt'1I al)s(J'llti oll is 1I first-order
p n lt'C"". 111t" alrsu r]ltillll half-lift" lak('11 as tilt' lillw fnT till' n 'sid ua l \111m' 10 dimi n ish Iry
o lw . llillf, is 1.3 h r. 111t' t·o m.·l>puml i ll~ aIN I'l)lioli rate- l'um:tant, krl, is O,fi9.V I.3 or n.5.1
hr - I.
l1wo n 'l k ally, ahso rptiun half· lift' (';111 also ht , e-sriman-d fmm uri nal)' exert-non data .
\\'ln-u renal d l'amm.'C' is ('lost'lIlially con stan t, cxcrettou ran- puralk-ls plasma conccntmnou .
111(' ml't!lod of n "!iitluals shou ld . tln-refon-, lit, ('"( 11Iall)' a pp lk·'lhlt, 10 t'u n 'lio ll raft> dOlla In
pTlIl1k'C '. llllw l'n 'r, estimates IIf ah..o rptum lI,tlf-lif(' from IlTiIl' II)" dat a art' IIsually poor. '111t"
ahsorp lio ll ha lf-lift, of mall)' d nl ~s is 30 min (I I" less . lucomplen- bladck-r ('lIlpt)ill,l.": ilIlll
ill'lh ilily tn t~ lll(,t:t sam ple-s fft '"(IIIt'nlly ('lltlll,l.":h to dlar.t<.1t'ri:t.t' sUt'h ah so rp licm p rtl('C 'Sst'S an-
twu majo r sellln'C's of v rm r. ( AlIIst'(Plt'lltl)', an al)'si.. of pla...ma dat a is lilt' p rt.'fl'm"llllwl!lIKI
for t'stillla ti n~ ahsel'l,tillli kim-hcs .
Let \I.. examiue tilt' ll ll dt' rl~i n~ ha...is of 111(' 1l1l't hocl of f('sid uak Al illl): tun e tht' p];l..ma
eonce-nt rut ion fllllo\\"in~ t'\l m\1l'iC:'u!.tr adminisl ratioll is ¢ n 'lI liy

C• ' Dose_ · kl'0)Ie - t·, _

(F'vlko e
_ l",_ ~
J

when- all n-r ms an' as pn ...i om ly dt 'hllt '(l in lilt' IKltly o f t jn- II'KJk. 111t' p n Klf of E'l. I is
im d n'(l and Ilt') , md ti ll" )(.'C'lx· of Ihis IKK>k. \\ 111'11 ( ;L~ i.. m ost fTt"lI"t·nll)' l ilt' t~d.~') ah loCl'l).
tin n is a mo rt' rapid p TtIt'C 'ss than t,liminatinll (ka > k ), tht' value of lea . t is always ~f('lltt' r
than k . t , and In-nee (. - l • ./ :lpp n l<td ws ze-ro rmm- m p id ly than dlK'S f'-·-'. AI SlIlllt' po inl
p:tst tlu- lx'ak p!Ol"lll;l <,ull('('lItratio ll. I ' - Lo" is ('~ 'iI: ' lI li<llly zero. ahsorptto n is O\'t.'r ami tlu-
l'xtr.l !xllall'tl lillt, is ¢ \'t' T1 hy

t _ ( F . Oose '
1110 - II
e- '0) l-' 2

S Il "Ir.1(1i,, ~ C [rom t: t1lf'n 'fllf(' ~il ' ld s

t1K. ('.... I . B~ II..· nlrtl....I " f n ~I, ...k ,..' ....h "'~I. · lao Time
(..n I..· ",.. ",.or I..~" tI.., ;,ll....'rpt ic.n half·hf.· If",,,, 2.0 t
sl<'I'" " f <~ ,I.. n..llhK' ) ,uKl lI..· L..jt ti " ..• (n"t...I I~
..m .....-J, f..n,.....i"" " r..:J .. Ir" i" l" .... til ..' of " .Im lt .,:.
S
c
g 0.8 •
~
\• c
"g 0.4
~
u

<.>
'yC- C •

,
0
~ •
c
~
E
~

i!.
0.2

01
0 2 4
\ 6 8 10 12 14
Hours
410 ES(l,\,'ATION OF ABSOf!:PTlON KINETICS f~ P!ASNIA CONCENfiAl1ClN DATA A9P£NOlX K

t _ c ., (F' Dos.e . kO) - ~O' I 3

\.1ko kl e

and taki n~ natllrlllll ~,ui till ns

In (t - q = ln ( ' . Do se · ka) - ko"

Vlka - kl
Hence , if absorption is a first-orde r proces s, a s(·ll1 i lnJ.~ari t h lllie plot of t ht· n-stdual vahu-
agaimt tinlt' )id( l~ a straig ht IiiI(' \~i t l. a slopt, of - kfl. \ \11('11 t his rt'sidual line is 1101 I t ~
linear. ahso rp tion is not a si mplt· first-onlf'r pm('('ss. nml otllt'r lIw thod_~ an- 1J('t'tlt'tl to
caknlan- how ahsorptio n varies with tunc.
Lt~ Time : Exemtnauou uf Eqs. 2 ami 3 S ll~t·sls a simple ~r.lpll i(· uI(' th otl fur t'st illlalin~
la~ time. that is. the time ht'twl't' n adm inistration and shirt of abso rption. By dt'finitioll.
absorption !N.'WllS when the extrapolated am i n-slduul curves illh·fS('t't. 111is IIlllsl IN.' so
si ll('(' only at that lilll(', ' = n. when (.- ""., = (. - AI = I . an- tilt' vahn-s of the t.... u equations
the same. am i equal to (F . Dose- ka)J1 \'(kfl - k)J. It is St'(' 11 [rurn Fi~. C- I tltal in lilt'
p n-seut exam ple thelag tlnu- ts llpp mxi malt'l)· 30 mi ll,
Events at the Peak: 111t' peak conccntranou. C....... and tlu- tinu- of its 11('(1 ITTt ' lI n ·. t.......
a n ' ofh-u important fal ioTS i llfl ll ('u dTl ~ d n , ~ 111('T;IP)" Tl ~t'lhf'r . tht·)" can Stllll('ti llll' S alStI
p r ovtdc a simple measure of IIre speed of d nl~ abso rpt ion for a ~n'll dost' of drug. 11l J\~'t'wr
hoth C...... and t...... ;m ' also infltU-Il('('t! by IIi(' d ispo sition kinetics llf tilt' t1Tt1~. ami llut'slions
sometimes a riS(" (,( lIIl't"nl i ll~ Ihe Impact o f (·han ~('s in absorption am i disposltton Oil thr-se-
val ues. 111t" answ ers to such II" l'stions an' most rt·'ldily pn J\i dt'tl b)' sohi ll~ Eq. I for Iht·
rondm on at tilt' peak. II is St"t'1I that if 'N....
is 10-111\'11 . C...... ( '1111 Ill" calculated . 111(' value of
'N... is dcn-nnua-d as follows . At that tune, rate o f abso rption is matched by rate of elimi-
nation , and hem'(' rai l' (If dlallKe of plasma co ncentrat tcu is ... .(·Ttl, t.c.. tlCltlt = 0. So, to
den-mum- I_ . . .....e IIIl1st fi rst dt'tt' nnille acs«,
which by difTt'rt'uliatioli of Ell. I. is

cJC F . Oos,e . ko k - A·, k - Ao ,

5
+ o' e
-
dt
-
Vlka kl l - ' e

At I N", • • ..... hen rlcldl = O. it folio....-s Imm [<1.5 that

I (ka) 6
'....... ,. Iko _ k) In T
Equ ation 6 dearly shows Iha t only tl.e rate eonstants for a!Js0'l)lioll aml l'lililinatinn Intlu-
TIllis. for a ~\'t' n value o f k. t..... ea n II(' ('<tit-lilah'll for various values of kfl, :\'oh ·.
t ' II('(' ' .......
1I1J\\'('\'t' r. t ha i if t ...... and k an" known, ka ca n 1)(· determtm-d o nly Ii)' sll hsli l llti ll~ values
for ka into tilt' right -hand side of El l. 6 un lil tl.t· calculated t...... equals ti lt' ObSt'f\l'(l value.
Finally. when then - is a lag t ime, C...... 1l('(.11TS al 'N "" + I~ .
WAGNIA·NllSON METHOD
At a n)' time, lilt' amoun t ahso rb("(! is ~\'(' n hy rlu- familiar lIl,l SS balan('(' equation

Aob = A + Ael
Amou nt Amou nt Amou nt 7
ebscebed in body eliminated

;\;nw A = \ ' . C and A"J = C f. · f.,C . tit. whit-I. O il sllhslillltinn inln Eq. "i. ~ws
 Aab = V · C + Cl . .bC .dl 8

11t·1It't ·. if C /. am i \ ' a n- known from i.v. (lila . <" han~('s ill NIb wit h time t~UI tl n-n IN,'
<''ill"ula!t''tl. Tln- vuhn- rise-s un nl a hsorplioll slo ps. 11lt"1I. " fib "" F ' Dcl'i(·. allc l\\ill~ lsio..
aViliiah ililY to II(' dC'lt·nnillC'(J. ~ uti,,'C· t ha i 110 assumption is made ~ardill~ the nature of
tln- ubsorptton pro(:'C 'ss: it could he simple or complex . 11Idc'("c'1. the <''iI!t-ll lah'<l absorption -
tinu- profik- can II(' allal~·J".t"c' 1 further to characterize tht' absorpnou p ro('t·s s.
Oftell. no i.v. dos;I.I?;(· fo rm is a\" i1ahlt". ami then Eq. I must ht' modffied to allow a.s-
~·sslllc ·lI l of,lh"orplioll kim ·ti<."S. This is accomplished by ncttng th at C/. "" k . V, so that
dhisioll llf ECI. 1 by \' ~il'ld_"

Aab {'
--V = C+ k . .b C , ch 9

T hu s, kllCJ\\illj,t tln- c·limillalioll ran- constant . k , till" mlio An/,{V <'';111 he detenut m-d Innn
tilt" p];1-Slllll {"CIII{"C'ntratiOlHiIlW datu . wit h A UC 10 t'adl time l'stima h-d hy tilt' appropriate
numeric IIlI'tlll l(l (Ap!N,," c1 h I- A).
tJ ltimalC'ly. the vulue (';.IIl'ulah'tl mill ~ Ell. 9 reaches a n IIPlx'r limit. s i ~ l if~i ng that ah..
sorption 1,,1-" stopped. Tlu.. Iilll ili ll~ \"IIl{" is tln-refon- f ' [)osdV. ""hidl also ('(llliIls
k . f~ Cdt , as F · Dose "" k ' \'[;;C(II. Al"{"C )l'(li n~ly. till' fraction of lnoavailabh- d(J~' that is
a!l\clrll(·d with lillie' can II(' esttnmted . it i~ gfven by

Fraction 01 C + k '.b Cdr

bioovoilcble
drugab~
=
,k . r
Cdr
10

To tllustrun- tilt' 11lI't llCI(I. cons kh-r tilt' concentmtion-rime da ta Iish'(! in Fi/;t. <":-2 a nd

0.1
o 6 12 18 24
Hou rs
412 ESTWATlC>N Of ABSORPTION KINETICS fiO\'. flIASMA CQt\K:ENTUTlC>N DATA APP£NOIX I-C

displa)'t'(l S(' m i l(~lri tilln ical l)' in F i!'. C-2 fnlln\\ing tilt' oral atlmin istr.tlioll uf a Il JO. m~
doS(' of d rug . First , k is estima ted from the dt't.. l i n in ~ concentranon- nm e data; il is 0. 101
hr - I (1,,'2 '" 5 h r]. r\l'xt , the AUC to ('ad I tilllt' pui nl is ('ak'ulalt'(l; tln- value s. calculatrd
llS i ll~ 11.1' trapezoidal m it'. art' also listed in T able C-2. 111t' prudu{1. k · 1:1 C (It is 111t'1I
t"l.k'Ulatl-d and atldl'tllo the pLLsma concentration 10 )id d ALlll f\ ', Fo r exa mple, the ' ,IJUt·
of k · A UC OIl lilt, firsl samplillV; tune of 0I1t" hum is 0 .14 h r - l X 0 .04.5 mg-hr/l , o r n.ooli
m!-iL whic h when adrk-d to D. IIS mgfL ~n's O.11S6 o r 0 .19 IIlWI. for ,\ f/b!l ', 111t'values of
AnIJl\' \\illl time art' ltsted ill T ahl e C-2 a nd d isplayt'(l ill Fi ~. C-.1. Tln-y show thai ab-
so rp tion pnK"t'('t Ls almost lillt'a rl)' wi th timt> for much of tilt, absorption p rut'(·ss. hut
ah m ptly stops at about Ii h r. slIAAl'sling thill uhso rption ilia)' II(' dust· Iu ...a-m-order. F ur-

_n_
r.w. C-2,
OllSEIV"TON
btl_tl_ .. c......... A_.t" BI-..n.w.
11f:AIIo'fNl Of 0,0..1...
~ D...tM4I

'WM'OOVG C . I·>\UC ''''''''''' o

llIQ/oVol.lABlf

......, CCN:lNl 'ATON »oc r . «c

'""" OOVG

0 """'" 0
'....IU
0 """"0 ''''"'"
0
""'""0
0
05 01 8 0045 0006 019 0 .095
I 035 0 ,178 0015 038 019
2 0 66 0 ,693 0096 075 0 .38
3 091 l A68 0110 1.11 0 .56
4 1.11 1 483 035 1 47 078
5 117 3678 052 170 090
6 118 4 953 0693 197 0 00
8 0 "" 7 223 1011 200 100
10 075 8 96 3 1 15A 200 100
12 0 .57 10 283 l A39 201 100
15 0 38 11 708 1638 20' 100
24 0.11 1391 1 1946 105 100

o 6 12 18 24
Hours
Fi ll:. ('.-3.
Af'PfN[)IXI-C ESTlNATlON OF ARSOWfICN I(lNEfCS f~ PlASMA CON:ENTRATlQN OATA 413

tlu-rmon-. statements t-au 1M.' made- about tl.t' Fract lnu of tilt' hioa.....allable dmg tha i is ah..
surfl('·t1 al various tillles (also show n in T able C-2) hut, obotcusly not the amount absorbe d .
Fin ally, a word of caution is neede d hen-. Criti cal to th e Illt'thod is an accurate esti male
u f k . Pmhlt'lIls uriw when ti ll' dedille of plasma concentration is absorption rate-h mued.
111t'1l. 110 n-habh- eslimate of k l~U1 ht' mad e . This problem u ftt-Il artses when t'\'al llalill~
u lIltm llt"tl· n ·I" ,l'\t' products. A pussiblt, solution is to use an estimate uf l: ill tln- subj ect .
ohtaillt"tl full(l\\in~ admillistmtiull of a mpid-rt'lt'aw dusa~t' Form 0 11 a \I 'p;lr-dle occasion.
The ,lSSlIIllptiollS. ofh-n n -asouabk-, an' thai Iht, ded inl' ill plasm a concent ruhon is new
limited hy elimination am i that tilt' tlispusitinll ki ne tics (both V am i Cl.) in tht' suhjt"ti to
not \my siWlifk ;lIItly fmm run- occasum 10 another.

STUDT PROBllMS

J. T Ilt' fUl1 fl\\ill~ phsllla t'tml't'ntmtions (T able C--3) wen- ohst'rvt"tl ill a patient who loo k
a 1lJ(J 1llJ!: tuhlet of a t1mJ!:.

Tnr.e llul 0 25 05 2 3 A 6 8 10 11
PIosmo concenl'OIIOl\
(mg/Ll 1.6 27 37 35 27 2.0 1.02 O A9 0 26 0 . 12

a. Pn-pan- a st'lIIil(~a ri tlllllit' plot of Ihe data and dt,tenninl' Ih" r are coustau ts for
ab\(l'll!ioll .1II11chuununon.
h. Esthnun- when abso rptiolJ IM.'!-":an .
c. Giwn tha i ahso rp lio n is cemph-te (100% ), cal culate : (I ) clearance. (2) m lU IlW uf
distn but iou .
2. T Ilt' ilhS<)'l)tioli kim'til.,; of a d m ~. kno wn 10 he acid labile, was stndk-d in two gro ups :
!-":nmp A. patients wit h normal Wlslric function. Wimp B. patients with achlorhydria (a
t1l11t1itiun ill which lilt It' IJT no add ts secreted into tht, sto mach ). Eat:lI Wflllp rt'('t'iwd
till' sann- doSt:, of d nl ~, A n al~.,;i s of the p lasma coucentra tion-tt me curves )id dt"tl th e
fllllm,i llj{t'stilllillt'S: J!:I'tJUp A. F "" 0.30. ka "" 1.15IJr - I , gro up S , F "" 0 .90; ka ""
0.39 hr - I . 11lt' jn \1.·sti~atllrs prtlpnSt:"(1tha i t!lt' longt' r half-lift, for absorptfou in plllit'llt s
\\i lh ;whlo rhytlria was caused hy a slowe r gastnc t'lIlpt)ing ill this group. SUAAt'!i1 a ll
altt'mali\"(' proposal that is l1lIlSistC'1I1 wit h all tilt' oleervattons.
3 . A SOO'IIlJ!: con trolled-n-k-asr- oral form ulat ion wa s te sted ag'dinsl a solut ion (500 mg ) of
:J d m ~ in IS Iw.lIlhy volunteers. A previous study demonstrated tha i th e drug is rapidly
aml l'()lIIpletl'1y abS<lrfM."t1 wln-n ¢\'t'll in solution. Subjt'(is took a Single dose of t';I(:I,
formulation O il a fasted stomach 011 Sl.'pilmte oc cas jon s.
l'!;lSlIl:J d m g concentration-time da ta fol kJ\l,in~ oral ill,l?;l'sliun of the l1llllmllt'(l·n'-
It,a,st, product un- lislt"tl in T able C-4 for on e subjt'li . Folltl\\ing ad min istmtiull o f till'
ura l soluttou, tilt' AL'e aud half..lift· of tilt' drug in th e SUbjt'<.i were 1;6.6 IlIg..h r!I. an d
S hr. rt'sllt "t1:iwl~"
...
, . .... c-4. PI _ _ e.-.--.I_ ..... AU C ..... ' .lIewl. . . 5 0 0 • • • C.....II ....
....._~.ct
I'\.A."M.A CONC EN1U llCN
"'"
'""""
'''' '""'u
'"0 000
'..../u
000 ""'"
05 0.76 OIQ
1 1 42 073
2 2 48 268
3 324 5.54
4 375 003
b 4 27 1705
B 4 31 25.63
10 4 00 3403
12 372 4 1 ail
IB
24
2 46 00"
zz u
" 5
30 0 43 833Q
4B 011 8663

u. lJ "i ll.L: tilt' \\·a~~lIt·r-N ('l" lI11 nu-thoc l, t,(llllpide Tablt' ( ::-l hy l.tll' llali ll~ .\tlbl\ ' \\ilh
lillI(', fH lIll"ill~ adm inbimtiull lIf till' ('unlmllt'(! n ·II'iL'\(' t111o;a~(' form . In }UIIT cal-
('Illatioll 11M" l ilt' half· lift· o h t ah lt't1 in th is suhj t't:f fotl(J"ill~ administration of Ill('
•.nluthm.
h . \\'ha l ass umptions haw' yUII lIIat!(' ill <Ippl~in~ th t· \\'av;m'r-St'lsu lJ 1I11't 1UMI?
I" \\1.<11 h ti ll" h ioiml.ila hility u f the- <1m!?: in tln- suhjt'{1 Imm th e n ml ru llt't l· rt'l t·lL'W.·
p rnd ul"l rdatiw' In Ihal From till" »rul <;n !ulill"?
d . By an apprupriatt· v;m p hil"a l a nalysis o f the ab sorption da ta. ,ls('t' rt ain wlw tl lt'T ah -
SCI'll!iOll of t1nl~ from t ilt' (u lltmllt'd-n,lt'il'i(' prl M:lud it! l"iw is Hrst -order, a nd if MI ,
till' hal f-lift' o f l ilt' ;IIN J'l lli o ll p nl(·t·ss .
4. In p mhlt' tl\ .5. C hap . fl , p l;l~llIa (~ II l<"t' l1 lmt io l\ ttuu- d a ta a n' p n l\i d t'(l tl u ri tll-( alltl fol,
I( l\\"i ll ~ a :2..& -h r is . (~ Jltst il ll t · mlt' infusiol\ a m i a rt"'l1a l d t·li,"t'')' ( I( ",i(~ ' o f drope-ridol.
a. ( ;i\'(' n 01 half-lift, o f 1.9 hr r-sthnate-d Imru l ilt' t1t"'l' li n ill~ rmu-eu trut ion afu-r stllppi n~
till' t.v. infusio n. apply tilt' \\·agllt' r-:\' t,ISm l tllt'lh(M:1 to till' plasmu conccnt mtton-
l illl(' d a ta 10 ('akulate Iht· ubsorpnon kmetk-s "f d nlpt' rid n l f()II( lwi n ~ admlmstranon
o f l ilt' n-ct al tlt'\i('('.
h. 111(' d t,\; ('(, is Inn-nrk-d to d d i\"('r th t' dnl ~ a t il cons tant rat e fo r 15 hr. D o ti lt'
absorption ki u(,t i<:s ill t"it"(l un-et t his t'lI. P('t1il t ioll?

Answ e rs 10 sillt l~· Problems an.' in Appl· ml i.\ II , p . 5. 6.

 ~. • AP pen d i x I-D

MEAN RESIDENCE TIME

A duq · uf d nl ~ ('Ulllpri...·SlIIim y lIIillinm u f lIIol(".'\lII's. Fo r example. even a du'\.t' as small

a." I II\~ for a dnl~ wit h a 1Il0It'(1.Iar wefg ht of 30() *,mo!t' contains dost> to 2 X Ill i ..
IIIU!t't11It·s !( HI - :l ~ I() ) X fi.lr13 x )()2.1 (A\ngad m' s numlw.·r» . On admlnistru non. tlll'!\('
d m ~ lI1 u ll,'(: uII's spend di fft'rt'nl thnes ....; 11Iin tilt· hudy. S ome an:' chnunated rapidly. others
slay fur a 10111-: Iilllt'. A few lIIay remain fo r a Iift-Iilllt'. 111l' n-sult is a distnbutfou of n -sidl'llt'(·
!iIIit's that can ht· d laT;lt1t'ri7.I 't 1 hv a tnt-an " 11m'.
Tlu- "1("(/11 n '.\ idnw(' tj"w (.\1 ni) Is tilt' awr.l~t· time tilt' number of lIlolet'ult,s intn.ItK,\,<t
( X) residc' in lIlt' hody. tha t is .

MRT · ~
/- 1
'IN
wln-n- t) is tln- n ' si dt'IJ('(' ttnn - of !Iwi''' 1lI0 11'{111(· (tillll' 1)(·~'t't·1l ib input and its dimillatiCiIl
[rom tilt' IMMly). l ut!i\id llal nmlt'(11It'S cannot 1)(· counted. of course . but ~IIIPS o f them
m il. Ll.'I l i ll~ " . 1M' tlu- munbe-r of moh-cnh-s \\111. au a\",ml~(' tinu - ill tht' lMMly of f ., the
total n:'sidt'lIt" til1lt' at'1 1111l1!att't ) h~' t his gn mp of 1Il0!t'(11)es is ' 1 " I I ' a nd tilt' \ 'aill t ,

I'] , nli + 1'2' '21 2

n] + "a
is tln- uu-an n-sirk-no thue of two Sill'll ~n:lIlPS of nlOlt"t11It'S. Edt'mling this concept 10
account for ullmok-cuh-s aduunisn-n-d. 111(' mean re sidence lime 1)('1.'O Il I('S

•
~
MRT = ~
Ii '

' -~~:-­
nj
,-, 3
N
~ n,
j .. ]

wln-n- '1, is the number of mok-cuk-s ill t he i 1h group ; I, is t heir a\"t'r.1gl' tinn- ill lilt' IMMly;
111 is the 1I1111111t'r of gru up s; and tl«- dl'll11lllilmtof is till' lota l numla-r o f lIlo1t"t11lt'S in l ro-
d ll t,'11.
111(' ,\ I nT is den-nnun-d mort' f('ilt lily cfte r an i.v. bolus dust, than artt'f any ot her mode
of tim)!; at lrninistr.llion. Hen- 0111 1111;' molecules of the dose start their n-sidt' llt't, i ll the IM I(I~'
at lilt' sann- tilll!'; thu s, for each group , ' . is the tnne 1I1.1\\1'('n dm g ad ministrutiou and
t,limillalio ll. \\ 1lt'1l tilt' number of molecules eltnunan-d in t,tl(.'h group (d ll) a p proaches a
rdatin'ly small value tilt' mean res hh-nce tune C"Ml he expressed in inlegml notation.

...
...
The limits correspon d to tilt' munber of 1ll0 !1'(1111"S (·lilllina h '(! at zero ami infinilt· tunes.
S OIl(' o f til(> molecules has 11('('11 e1im illillt't! al thnc n ' nJ: a t infinitt' tinu- all han' lx-en
elimi nated . n il' uutuber of lllolt'(.11It'S dimi na l('d hy all P<llbwiI)'S can lit, expressed in terms
of tilt" ,III1(J1l1lls elunmuted. At'l. 11m! is, ~ ·l = 'I . (molecula r w('i~ht )/( A\n~ad m's 1lI11nhc' r) ,
So thai

1 AM,. t . dAel
5
MRT "" AeI.

TIll' denom inator o f Eel' .') is till' dow (If d rug ad muustr-red. In lt',gl'dti oll of E'I . 5 , by parts.
It'al L, to

MRT co
r IDose - Ae1ld,
Dose 6

",11('1'(' . \1'1 is tilt' amou nt dilll ill ilh'(! up to a ¢\1.'n f illlt" t ,

1111' .\ lIl T after all Lv. bolus doS(' c••U1 1)(· (·slima!t..:) fm m ('itllt'r urinarv excretion o r
plasma <Im,g ccncenrr anou data a.s (0110\\1.... •
Excr e tio n Dala: \ \ 1w II the Fraction excreted IIIl(:h;lll~{'(I . fi', n 'mains constant wi th time,
tilt' amou nt o f dmv; excreted IIndmllg{'(1 ill tilt' uri ne. , \ 1', equals fi' . A t'l und A I's 1'f: l lIal~
IE" ' Dose. O n
suhslillltinR these values into Eq. 6. it is appan'll t t ha i ,\tRT cnn 11'1" de-te-r-
mined Irc m urinary excretion {Lila IIsiuJt tilt' n ']atiollship

MR T -
r IAe. - AO{~ldt
"'---c--- 7
Ae.
FiJture D-l shows Ill(" cumulative amount t'\(·fl'h'( luJl('hallV;{'(1. Ad t J, at various tune-s and
the- amou nt ultimal"')" e X('f{'It"ll lllll·ha nV;I"lI, Ae... 111l' area hdwl."l'u tl lt"~· l'lII'W S (shad{'(!)
is the- numerator ill V:I' 7. FOf a gh"('1\ amount excn-ted uncha nged. it is appan'nt that tln-
an-a and. therefon-, tlu- .\ f RT an' illl'f{'ast'f:l when dr ug n -nuu ns IOIlV;I'f ill till' hody.
P la srn a Co m.'{·n trati o n I>ala : \\111'1I d l·ar.U1l't' is constant \\;Ih tune, till' mil' o f elun -
inatinu is p ropo rt ioual to tlu- p lasma couceutraticu. th at is. d,u·lldt :: Cl, ' C. SllhslilutillV;
C L · C ' eft for lL\t,/ amI C /• . {; c« for t"" s in to Eq. 5 V;h"l's

111{' product t . C ls ealll'f:! till' fi nt."umu',,' of rln- conccntra tiou, 1 1I"l'ltll ~ concent ratton is
mulnphed by tune rersed to thl' lx)wl'r of I. Tla-n-Iore, thl' numerator is {'lllll"li ti ll' a n 'a
under the (finot)- mo lllc nt \"t'fSUS limp cline (t\ V ,H e). when-as tilt' t!ellOlu iliatuf is Ilw an-a
Illllll:'f the plasma couce-utration -tt nn- curve (A UG) . 111l' lillie ( 1 11lfSl.' of IM)th ti lt' plas ma
conce ntrau on a nd its first-moment a re Sh m \ 11 in Fi~. D- 2,
1111' .\tRT (1)IJ(1.'p t is ('filially applica ble to measu n-un-nt of tilt' turnover o f au ('lltlt,!:!:t'-
nOlIS subs tance, lIsin~ a tracer, and determtnanon o f th e mean lilllt' a tlm v; f('sid('s in till'
body. ..\ s an example . let us examine lilt, nn-asun-me-nt of .\tRT af!t'r all i.v. III)IIIS tloS(' uf
"'"NO'' ' ' u,

a drug from both the urinal')' and plasma data l'unlailll"(l in Tabl e- 1>- 1. The ,,~..Ju(" of Ace
("WI 1)(" ("Sti,ml.h-d as SIKJ\\11 in Appt·mlu I- A. TIM." , .uut' of AV.\ I C is calculated from Iht'
tint-moment Icolumn 3 ) in a man ner similar 10 thai of A F C . but the extrapolated 11m ,.
aftt"r Ia...t point (C... al ' ,..) is difTl'rt'n t. In dais the area n'maininR can be slK:M'n 10
C"d..' it'

I.·

n c . O-I. n... .b.ff I."""....... .

"",",\1 .... 80
(.,......1 u ••-h.u'I:'..J ( bd Ii"..) IU Il I a",nunl ultJ·
mid.·!>· M.<T1"tnl (d... .J Ii",", i. ,I.....",,,,,n' .....
m..!"inK to I , t', ..
d . T I..... r.·..
untl r r Iii..
,u n.. "", ... I1 in; nlit· t.. ·I...·... cr.·h '(I· l i"'.. ('11""('
b l•• lnl) , ","laIn... to tnt..l 8"M,,, ,,1rouTl'"t...1(}:"I. ..
in tr d ), i. .. , nr;uu,," flf"""",,, n -oM.......... ti ....· o f .. ~
~
..,I..l al w:r' in t1... t..ty. J);d a fll "" Tid*" Il - l. 0
C
ee
~
U
c 40
=>
~
~

;; ;
U
•
~

;; 20
~
0
E
-c

0
0 6 12 18 24
Hours

Flit. 1>-2. .'tf'" lUI t v. h..lllt ,...... . thr ,>tull,,", 10 20

('<1I1t1'nl r.diun (lu ·k ("n ) ."·dll"~ 100;11,111"... 11...
G", -",,,,,,..,,I (t".Ior....1..., 'ro). p n " lu(1 nf lim., ..lid
(~""~'f\l ndic",. n_ Iu .. pt...l 1ll,,1 .10..:11".... will>
Ih'..·. n ..· .."... 1...,......1 II... t...1 ~lIl 11i"R lim.. i.
much 1tfr"I,·r 11. It... fint ''''' '' '''"111 Umr ( 'U...... II....,
" ... It... n.Il'f'flI...tion·lim.. ( 'U....... I). .. fn " " Tal»"
1>-1

o!-_-~~==~ o
o 6 18 24
... AWENDIX I-D

wILt'n' }.= is tl\(' rat e constan t of till" terminal dl't--.ty of the plasma dnl~ conce ntra nou. \\11I'n
th,' r-u tin- ('l:ll\{'(' n lmti oll -t i nw proflk- ca n ht' <!t'sl:ri!){'(1 by a slim o f exponenti als. tilt' area
unde r the first- moment ('IIT'\1-' ca n Ill' d eh.'rmill l'(l dm -ctly from ti ll' cuefficients am i expo-
IIt 'llli'l l ('u (·ffi d ,'uh ddlnillp; tilt' equation. Fo r example, if C = C 1(-' - .l.,1 + C~' - ),01 111('11

10

In tilt" example co nsidr-n -d. tln- (~dI<:1I1at {'(1 I\ Ve. A UMC, and area under the a mount
n 'lll aill ill~ to be excn-tcd ve rs us time l 1UYC art' 44.2 1Il~. h r/L. 17.7 m~- h ~/L and 340 mg-
h r. fl'SPt't.1 ivd )'. 1111' an -as n' lIlai lli ll~ under rhe fin;t two <'111'Yl'S afh ' f the ta'" tim e point
an - lU i 1IlJ:-hr/ L and 4.9 1IlF;-III.afL n-spc ctively . F ij.,'tm-s 1)-1 am i D- 2 l'Uu lain t!lc data
from T able D -1. 111l' cuk·u latt'tI .\tHT values from Eqs. "j (urinary dala ) an d M( plll~ Tlla
d atil) art' t1wIl 4 .2'5 hr am l 4 .n hr, rt'Spt'<.1ivd y. 11It· simulan-dvalue is 4.3 hr.The difTt·rt'nl't 's
an ...• [nun approximations introduced by th e use- of tile trapezoidal mi l' to calculat e art-a.
TI lt' .\lRT. cak-elan-d b,.. t'itlw r ECI. i o r H, is a mt'a~lJ n' of 1Ill' il\"e mgl' ttnw a SuhstUlll"t'
~pc ' nds in thl' IXItI,.. after an is. I MII IIS dct'it·. \\l lt' n a d rug is ~\"t'll by a coustaut-ra te Lv.
in fusion o r I ~' an ext ravasc.. lar rou te. the dnl~ spends additional time- in Ihe syringe o r al
th e silt' o f ad m inistmtiou tc.g.. ~,l~ l mi n h-st i llal tract . 1Il1lS( .'It>. or SUI1l1ItlllU'OUStiSSIll's l. l1lt'
ohst'l"\,t't i tilllt' , t'stimatt't l from Ell' "j or H. is the n tlw su m o f the mean tunes at these sites
ami ill the body. Tablt· D-I shows the m ean input ttme s (.\ U D and obst'I"\"('tlul(',Ul total
resitlt·lll't· tnm-s for tlm-e common modes o f drug input .
FuIlO\'lnv; t'xtm\',l"Cul;ar adnumst ranon o f a dnl~ so lution . th e observed tot al .\ tRT is tilt"
SH ill of ti lt' .\tRT in tilt' Ixx!,.. and til l' mron fl}mlFJlt lml ti".I' . TIlt' mea n abso rpno u tiuw
can ht· dt·lt 'rmillt't! fru m tilt' dilh-n-nce hd Wt.,'1I tilt' .\tRT values (cal culated from Eq. 7
o r lo: q . Ii ). aflt'r extrava scular ami i.v. ho lus dclS('S giwn on sepa rate (x't.~...ston s. AftN gi \; I1 ~
a so lid c!osaV;t' form. tlu- UW ,Ul input time indudt,s time fill' di.s inlt-v;r.lIioll . deltAArt·Wltioll .
d issolution . and absorp uou Irom solution. Gastri c emrf:.ing , inlt'Stinal motilif:.·. anti other
physiolu).,rje ancl physkoc..'IIC'Illil'al Fact ors inlluc.·lIl't:' th e mean ahso rptioll time as well.

oeseeo
w.1>N ~5CltNCf
MCO<,'
S'ngle
"""'AN N'VlllW
""
,n IrC1'>1!f"lOU S
bol..s dose 5 -2.... 0 1/'
ConSlOnl-lOIe
onlrove<lOJS
onfusion ~~ ' '''2< II I + 1,,/2
Single
e.trovoscu!or
dose 13~~ ll lo II I + l ila

"Tho "'"'*"" '"

"00_ _ .. --.:I., ... """""'"' ""'" 0 O' .. ~ . """"""
donoooo 0 boIL<o _ _ .... ~
".. ~ ,... d.oatoot> <i .... ...........

STUDY PROBlEMS

I. UsillV; lilt' dt·finilinn uf .\tRT in loAI. H and all equahou for th e ti me-course o f plasma
t1nl~ coucentrunon aftt' r lUI i.v. Iltllus do....•. prt)\'(" mathematically thu t till' oh!;.t·l"\l,'(!
,\ IRT ~\'{' ll in Table D -2 for this route of administration is co rn-et for a oll e.(,nnpill't·
IIwnt III1KI,'I.
 WAN ~ 5OE NC£ TIME
•••
, ..... D-2. PI•••• e.-.IthwtI_-T1••,.H UrI_ry • • cretl_-tl•• INN
'.II.wI"••" I.". 200-. . . .I•• Dtl. . .t. D....
"""""
""",,,.,X;
r-S1NO\llENt
"""'M """"
"""""""
~
' 0&
.,""
0
CONCfNTU.TON

'~'"
10"
.....'"
CO'!C( NflA.!JON

0
EKIfI'EO

'"0 ...
ElClEI'EO
'
SO"
2 03 12.6 30 50
4 40 160 48 32
0 25 15_0 00 20
8 10 12_8 07 13
10 10 10 0 72 8
12 003 70 75 5
14 03Q 55
10 0 25 40 78 2
20 010 20
24 0 04 0.Q6 80 0
......Iogao-_ pb., _Q _
'I!.......-b,- .~ f;;o Q
...... ~ """"" .""_a~ .....

2. I'mn ' that the mean tinw tha i a dnl ~ is in a srri n~t" dllrin~ a consta nt-rate l.v. lnfusa m
is ('lillal to t,../ I2, wllt'n' t,..r is Ihl' duration of tht, infusioll .
3 . 111t' o bSt·,,-('t! IIII'im total residence tim es in an Indjvtdual sllhjt"l1 . l'alcu lalt"tl fmm
plasmu conce-nt ration-time data (E'I' ti ) followtng all i.v. bolus dOM'. an is, in fusion.
<lml illl oral doSt" Oil St'lliU<IIt' 1 1l'l'iL~ions . were S, 10. and 12 hr. n'sIK"l1in ,ly.
a. A SSlllllill ~ a consta nt- r ate inpnt , det r-rmtne the duration o f the infusion .
h. A SSU llI i ll ~ a Iirst -onh-r oral input . dcn-rmtm- the absllIlltinll half-lift',
-t. Using: Ell' 1 in ApIK'IltIi... 1- (; ami Ell ' S o f this appendix, pm \"(' math,'matil'illly that
till' vnhn- o f ..\ U.\ fCIA L'C aftN e...travascular udministratjon depends on Iw ithl'r the
do St· no r h illil\ "itilahi lilv .
.S. In problem S, C ha p . 6 (p, SO). plasma coucentratlou-nnu- data an ' procnk-d dllrin~
alltl ff)l1 o\\;n ~ a 2-t-ln i.v. consta nt- ran- in fusion and a rectal dt'1i\ ·t' l)' <l1.'\ ;l" (If dmper-
idol.
a. From til(' l.v. dat a, 1';111'11"'1(' rlu- r atio of AUMCIA UC and heno. ,\fRT of dmperidol.
(:'\ott': 111('t ·...trupolun-d..\ U.\ IC ht"'1111d thclast concent ranon measun-ment is ~\"t'n
by Ell. 9).
h. How dn!.·s ,1111 r es tima te o f .\ fR T l1lmpart' wi th tht, calculan-d value o f 1.4-t 1112,
\\'IWH' t 1l2 ( 1.9 1I r) is till' half-lift' afh'r st oppi n~ tilt' infusion . am i what conclusion
do 'l l11 d ruw fnun t ilt' l'tlillpariso u?
I" Cillelllat!' tllC' r atio ..\ U.\ICIA L'C usso cian-d with till' n -ctul <ldi\"t,ry <l1.,\;l'(', and hence
till' menu input t iun-.
d. Assl.·ssl."tl i'l t Um . rln- mean rt'1l.·a",' lim e of the rectal dt'l i\1.·'Y device is 9 hr. If this
t illlt' ulso upplk-d in d Ul. what is till' mean abso rp tion t im e of droporidol From
sohition ill the H'l1.11Ill . onl ,(' rt'1l'a.'i(-'l! frum the <It'\i l ,(' . For this calculatlou. release
alld su b'il.·lllIl·lIt trdllsft'r ac ross the rectal epithelium an' taken to he seque ntial
jlr11l'('S'iI.'S,

Answers In Stud y Problems art' i ll :\PIK'uc!ix II . p. 579.

 Append ix I-E

AMOUNT OF DRUG IN BODY ON

ACCUMULATION TO PLATEAU

Accu mulauon of <!nJF; ill lin- bod}' is addn-sse...l hen- for Illulliplt' i.v. ant! (·xtm....uscular
doses of furo size and dos i ll~ interval .

MUllIPlIINTRAVINOU5 D05l5

Accum u la ti on. COIIsit!N tht, situation ill whi(-h a do se- o f d Ol~ is ¢ \ l ' U as an l.v. IMllm
dosing Inte rval. t . Rt"t.-.JI that after each tloS(' tilt" Fraction f('lI1ain illg at time , t. is
(' \"('1)'

e - II, 1111' fmt'tiull o f dr ug f('maining at 11ll' end of a dt)si ll~ interva l t . therefore. is e - h .
\ \ l,t'n tim e is e11t1aJ to 2t . the fraction re uillilling is 1' -21<" Till..' amou nt of d m g ill the.' hody
fOI1IJ\\; lIg mulnple doses is snnply the slim of till' amo unts rt'lllluning From each of tht·
previous doses. Tilt, amount of drug ill t1n·IMKly j llsl afh-r tlJ(' next <IuS(' is slln"., . ill Tubh-
E- I for four succe-ssive ("fjlMl doses given I;·W I)· r.
It is apparent fmm Ill(' tahlo that Ill(' maximum amount or <Im~ in tilt' hody just arh' r
til(' rourth do'i.(·, A .......... is til(' rourtlJ dll!W plus till' slim or tln- amounts n ·m;ulling Imm
each or th ree previous doses (slim or te nus in row .. or Tabk- 1':- 1). 111at is. It,lti ll ~ r >=
,- h .

Just artN tilt' Stll dose tilt' amount in the htxly is

AN - Dos.ell + ' + , 2 + , J ... + ,N - 2 + , N-II 2

. ~.

AN........ r .. Dos.e(, + ,2+ , J + r .. ... + ,N_I + ,""l 3

Subtracting ECI' 3 from ECI' 2.

o
2.
•
3.

490
 ..,
AN ."..,,,, · 11 - '•I - Do.. [l - ,'1 4

l1wrt·fort"

II t'lIl't' tilt' amount of d m /ot in tlu- hody 01' ;lIlY lillw t d ll rill~ a doSiJ l ~ int e rval , afte r the .\'t h
d ust" A ,,~ t) is

At til(' end of tilt' dosi n~ interval. when t = r , it follow s that ti ll' minimum amount ill til("
Ixx.J)' afh-r till' Xth dose, t \S..... n is

Stead) ' State . As till" 111111111(" of doses, S . increases , tilt' vahn- of r " approaches zero.
sinn · r is al\\.ll)'s a vallll' It'!\s than I. 11 l( ' maxi mum and minimum amounts of d m g in tilt'
ho dy dllrill~ an 1111<'''111apprtlil(·1. Uppt· ' limits. Then . til(' amou nt lost in {'uch interv al ('(11 1<115
tl.t· amount ~ai lll,,(1. tilt' dose . Fur thi s n-ason dn, ~ in lilt' hOl l), is 111l'1I sa id to h(' al ,\ ' l'fu l lj
statr o r at platt·all. He re tilt' muximum, t\ .......... tilt' minimum . Au ,......' am i till' amount ill
the I)(J(!>' at any lime durin~ the dos in~ inte rval. A ..(t) , an' rea<lily O!Jtailll'tl b). Il'tti ll~ r"
= () in E'Is, 5 and j

10

A
... . . .. . -1-
,
11
Dose I - r

12

;1IIt!

13
. 92 AN\OUNT Of DRUG IN BODY ON ACCUM.UlATlON TO P1.ATEAU APPENDIX I-E

T ime to Hea ch Steady-State. The time to approach plateau, whet her defined with
respect to the maximum o r minimum amou nt of drug in the Ixxl)", depends solely on the
half-life of tilt' d m~. The proof of this state ment is n-adily apparent hy di\idi ng the equa-
lions that define tile' re-spective amou nts after the Xtll dose by the equation s that define
the respective amounts at plateau ,

1 _ ,N
14

As r" equals e - ·\ l . , X · t is the time elapsed. Th us, in one half-life till' [raction remat ntng
eq uals 0.5, and half the plateau value is reached; in two half-lues. three-quarters of the
plate-au va llie is reac hed. and so on. A similar concl usion is drawn when rdating the average
amount during Pilch dostn g inte rval with the average amount at plateau.
MULTIPLIIXTRAVASCULAR DOSIS

Accu m ula tio n. From Eq. 1 in Appendix l-C and kllO\\i ng that .-\ = \ ' . C, it is apparent
that the amount in the body after a single dose is simply the algebraic slim of two expo-
nentf al ter ms with a co mmo n coe ffi cie nt, that is

Amount in
body 15

Usinj?; th e principles of additi \ity and letting r = e - k · r and s = e- k" ·, , the amount in the
bcdv at the ttme the .Yth dose is administered becom es

A _ F · Dose · ko [(1 - r"1 _ II - s"1]

16
N,.'" - (ko kl II - <j (1 'I
Stea dy Sta te . The amount in the hod)' at the beginning (.-\..(0» and end (A ,,( T) of eac h
dosi n~ interval at .steady state ( , S and SS app roach ZNO ) is

17

The amo unt in tIl(' hody at any time within the dosing interval at steady state is

F· Dose ' ko [ e - k l e - k OI ]
A.. I~ ~ (ko kl ~ - n-=>i 18

and thr- time whe n the (le ak concen rranou is reached is

19
kl
T im e to Reach Sl('ad,- State. Th e time to reach ste adv-state is a function of bot h the
ab sorption and t'liminatjo~ half-lives and th e dosing intNval. Thi s can 1)(' seen byexemtnmg
 ~ Of eeoc IN BOOYON ACClWUATlON TO P\ATtAU ..,
the nitio A.\ ,.-.,1A...-... On (1i\;diu F; Eq. )6 by Eq. 17 and rt'arran¢nJ!;, till" amount In tlu-
hud)' lit til(' tirne o f the Xtli dO!ie is

11 - ,'111 - -, - 11 - -'111 - "

20
r s

:\lltt>: To calculate n-lationship s for plasma concentra tion. each o f till" t'llIation .. allllw
for amount ill Iht·lllJlI)' sho uld Ill.' dtvided hy \ '.

STUDY PROBIIMS
No te: nit" areumulunou equations dt'n\l"(1 in this lIpl"N.-udix. partil'ula rly thclSt· fol!u\\; IlJ!;
mult fple i.v. dUM's, art.' applied ill tilt' study problems of Chap. 7, Multiple- DOM' Hq,:in lt'lls.
I . Prun- Ihe identity uf tlu- tW'll funct ions in EfJ. 12.
2. Equatio n 17 for Ill(' amount in tln- !ltJlI)' at tln- end of a dosin g Interval at stt'ady Slllh'
ca n also 1)(· wri tte n as

A.I,' ·
F ·DoiWl ·ko [
II. - " .
,
iT""='! -
-
iT""='j
1

An sw ('rs 10 Study Problems a re in Appt' JI(Ii'l II . p. ,').1)2.

 Appendix I-F

DIST RIBUTIO N OF DRUG S EX TENS IVELY

BOU ND TO PLAS MA PROTEI NS

n it' distri lmlioll of tt... pla.s rna protein to which a d n,~ himls is a majo r t1eh'mlinanl of
tln- dist rihution o f a dm~ with a small (It'Ss than 0 .2 lA g ) volulllt' o f di stributiou. This giVt-S
rise to kim-tjc CUII M"flllt'IWt'S thai an' d iffC'Tt'nl fmm th OSl:' expected for a dmg with a la rgt·
\"011111I(" of d tstrlbutlon when binding to the plasma protelu is altered.
Using albumin a.s a prototypic hinding protein. Ihl' h()d~' can ht' represenn-d a... Im\illg
llin'(' :lflllt'tJIIS compart ments . a." shown in Fig. F-1. The amount of dmg in plusm a is du'
product of \1I11II11e of pl'l..ma ami plasma <lnl!!: couceutratton. The amount of drug in ex-
tracellular fluids uutside plasma is tilt" product uf the a1lut"ous vnlunn- Hr th is Spill't' and rlu-
a\'('mgt' concentration within it. TIll' amount ou tside tilt., extracellula r spat.'t' (in or O il cells
or bou nd to connect ive elenu-nts] is accounted for hy tln- product of tlw , ll i U('O US vol ume
into which dmg distrilm tes oUh idt., the extracellular llujds and all aH' r..l~t.' concentration in
this l'UUI[MrtllU'llt.

Extracellular Space Intracellular

Space
Intravascular Extravascular

(Vp.J (VE! (V,)

Drug Bou nd Drug Bound Drug Bound

to Intravascular to Extravascular to Cell ular
Plasma Proteins Proteins Components

--------1-------- -------- 1-------- --------1------- -

Unbound T Unbound I Unbou nd

Fill;. F_I . l>ruJ( tli.l rihu lt1 "" ""'11: pL...n... (.....t,,"'.. . ",l. Ih.· ...Il'lil't"lI"L., IInitL. " " h itlt· rL...II... (. , 01" " ..• -
' ·l )• .." .11 R·" u&i....It.,.of 1Ilf' hc..1y ...'\dl'r (Yol" "ll" - " ,,). F.tluilihril"n i' .....j.~.....J ..i ..·.. " "I..,,,,.. I .u ...'t"nlro&liurn
in 110.. 110 "I-'" IU't" I....'''''If'. n... t...."..J .n1KT" l r. ti< ill I.... d on... 'I_~ ;on ' (u,.. 1i.. '" urtI... ;offillil;'" of
.In'l:: "II' 110.. " ,I" laI" "" in It - JP"'-" Iu ...bit'" It..· <tAll( hi b. Thr<"'~ "J I II,,· n lr",-'(·llnl;or Huitt. (\', .. ..J \' l )'
,Iru"
...
1'1 1........1 10 IhI' ...." ... r r<lIt-in(l ).