UNIVERSITI PUTRA MALAYSIA

PHARMACOKINETICS OF IMIDOCARB IN NORMAL AND FEBRILE

DOGS AND GOATS





ABDUL SALAM ABDULLAH






FPV 1983 7



This thesis attached hereto, entitled "Pharmacokinetics
of Imidocarb in Normal and Febrile Dogs and Goats" prepared
and submitted by Abdul Salam Abdullah in partial fulfilment
of the requirements for the degree of Doctor of Philosophy,
is hereby accepted.
(PR
(P:OF. DR. MAD /AHD:Al! i\YOB
Chairman, Board of Examiners/
Dean of Graduate Studies
Universiti Pertanian Malaysia
J ' Qh.i L-
(PRO SSOR DR. DESMOND GOT)
External Examiner
School of
S ED SALIM)
nal Examiner
Faculty of Veterinary Medicine and Animal Science
Universiti Pertanian Malaysia
a .
,/ :
(PROFESSOR DR. 'A

UL LATIFF IBRAHIM)
Intei Examiner
Faculty of Veterinary Medicine and Animal Science
Universiti Pertanian Malaysia
PHARNACOKINETICS OF UIIDOCARB IN NOllAL
AND FEBRILE DOGS AND GOATS
by
Abd ul Salam Abdul l ah, D.V.M., M.S.
A Thesis
Submit ted In part ial f ulf ilment of the requirement f o r t he
degree o f Doct or o f Philosophy i n t he Facul ty of Veteri nary
Medicine and Animal Science, Univer s i t i Per tani an Malaysia
Sept ember 1 9 8 3
ABSTRACT
D i spos i t i on ki net ics o f i mi docarb , an ant i pro t ozoan drug,
was s t ud ied i n normal and febr i le dogs and goa t s . Fever was
i nduced us i ng coli endo toxin, Trypano s oma evans i and Inf ect i ous
Bovine Rhi no t rachei t is
(IBR
)
vi rus . The object ives o f t he s t udy
were t o compare t he d i spo s i t i on ki net ics o f i mi docarb in ruminant
and monogas t r ic species, and t he i nfluence of fever of dif ferent
et i ology on t he d i spo s i t i on ki net ics o f thi s drug . The concent ra-
t i on o f i mi docarb in body flu i d s and t i s s ues were meas ured by
spect rophot omet ry .
The d i spos i t i on ki net ics o f i mi docarb i n normal and febr i le
dogs and goat s can be adequat ely descr ibe

by a t wo-compar tmen t
open model. The apparent volume o f t he cent ral compar t ment, V ,
c
was s i gn i f icant ly lower (P<O.Ol) but t he volume o f dis t r ibu t i on,
V was s i gnifi cantly h i gher (P<O.05) i n normal goa t s t han
d
(area )
in dogs . Hi gher volume o f d i s t r ibut i on and t he r a t i o o f i mi docarb
level in per i pheral-t o-cent r al compartment in goa t s ( 6:1 )
prolonged elimi na t i on o f t he d rug, result i ng i n con s i derably
higher levels o f the drug still present i n t he tissues 14 days
af ter a si ngle s ubcu t aneous or i ntramuscular dose . Thus t he
wi thdrawal t i me o f imidocarb was es t imat ed t o be 5-6 weeks i n t hi s
f ood-produci ng species . D i f ferences i n t he ki net i c d i spo s i t i on
of i mi docarb i n dogs and goat s may be largely a t t r i buted t o t he
ana t omical and phy s i ologi cal d i f ferencs in t he ga s t ro i ntes t i nal
t ract between the t wo speci es.
The res ult s of the present s t udy i nd icat e tha t fever of
d i ffe ren t et i ologi es affect ed t he d i sposi t i on ki net ics of imidocarb
11
differently . Plasma concentrations o f imidocarb were higher than
normal during endotoxin-induced fever but lower during Trypanosoma-
induced fever. Although concentrations o f imidocarb in the pl asma
of goats were not af fected by the IBR viral-induced fever, t he
apparent volume o f distribution, V
d ( )
' and the steady-state
area
volume of distribution, V
d ( ss
)
' were significantly l owered as In
the endotoxin-induced fever. Simil arly, the above kinetic
parameters as wel l as o lume o f centra l compartment, V , and the
c
body c learances C1
B
were significantly higher ( P<O . Ol ) in dogs and
goats during Trypanosoma-induced fever than in the normal animals
a lthough the plasma concentrations were substantial ly reduced
during the febrile reaction. The microconstants were also af fected
dif ferentl y by fever o f dif ferent etiology. Nevertheless, ha l f-
life o f imidocarb remained unaf fected during the three febrile
conditions.
Theref ore, it coul d be hypothesized that fever o f dif f erent
etiology af fected the disposition kinetics o f imido carb dif ferently
and the inf luence of fever on pharmacokinetics should be c onsidered
beyond the pl asma c oncentrations and hal f-life o f the drug itsel f.
Furthermore, the pathophysiology of the disease and not just the
febrile state should be considered when eva luating the inf luence
of disease conditions on the disposition kinetics o f a drug .
III
ACKNOIREDGEMENT
I wish t o acknowledge wit h deep gratit ude my indeb t edness t o
Professor J. Desmond Baggo t, Chairman, Depart ment of Pharmacol ogy
and Toxicol ogy, Schoo l o f Vet erinary Medicine, Universit y o f
California, Davis. I have relied t o a great ext ent on his advice
and have benefited from his unriva l led experience in pharmacokinetics.
The enormous guidance, contribll t ion, support and encouragement
glven by Professor Syed Jal a ludin Syed Salim and Professor Abdul
Latif Ibrahim a re deeply appreciat ed. I am also gra t eful t o Dr.
Sheikh Omar Abdul Rahman, Head of t he Depar t ment of Pat hology and
Microbiology and Dr. Law Ah heem, Facu lty o f Fisheries and
Mar ine Science f or t heir hel p . I am a lso indebted t o a l l t echnical
assist ants o f t he Facu l ty of Vet erinary Medicine and Anima l
Science, Universit i Per t anian Malaysia, especially Zainal Abidin
Jamin f or t heir excell ent t echnica l assistance and to Normadiah
Sukaimi f or her accurat e t yping o f the original manuscript.
My gra t it ude t o Universiti Per tanian Mal aysia, Serdang,
Selangor f or funding this project , Schools of Vet erinary Medicine,
Murdoch Universit y, Western Austral ia and University of California,
Davis, U.S.A. f or providing t he labora t ory and library facil it ies
in completing t his project .
Last bu t not l east, I would like t o express my Slncere
gra t it ude t o my wife, Rahmah, daugh t ers, Syazrah Nisydah and
Syazrah Yuanidah for t heir underst anding and patience wit h me lD
compl et ing this project .
iy
TABLE OF CONTENTS
No .
Page
1. T ITLE PAGE . . . . . . . . . . . . . . .. . .. . .. . . . . . . . . . . . . . . . . i
2. AB STRAC T . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
3 . ACKNO HLEDGEMENT . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . .
1 V
4 . TABLE OF CONTENTS . . .. . . . . . . . .. . . . . . . .. . . . . . . . . . .
v
5. L I ST OF TABLES . . . .. .. . .. . .... . . .. . . . . .. . .. . . .. . .
v i i i
6. LIS T O F FIGURES . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . xi v
7 . GENERAL INTRODUC T ION . . . . . . . .. . . . . . . . . . . . . . . . . . . . 1
8. LI TERATURE REVI EH. . . . . . . . .. ... . . . ... . . . . . . . . . . . . . 5
8. 1 Pharmacokine t i c s . . . . . . . .. . . . . . .. . . . . . . . . ... . 5
8 . 1. 1 Int roduc t i on . . . . . . . . . . . . . . . . . . . . . . . . . 5
8. 1. 2 Pr inc i p l e s o f Pharmacoki ne t i c
Ana l ys i s . . . . . . . . . . . .. . . . . . . . . . . . . . . . 6
8. 1. 3 Pharmacoki ne t i c parame t e rs .. . . . .. . . .. 1 2
8. 1. 3 . 1 Act ual pharmac oki ne t i c
ra t e cons t an t s . .. . . . . .. ... . . 12
8. 1. 3 . 2 Vol ume o f d i s t r ib ut i on .. . . . . 14
8. 1. 3 . 3 S t eady-s t a t e vo l ume o f
d i s t r i but i on . . . . . . . . .. ... . .. 18
8. 1. 3. 4 B io lo g i c Hal f - li fe . . . . . . .... 20
8 .1. 3 . 5 Body c learance .. . . . . . . . . . . . . 23
8.1 . 4 Drug dis t ribut i on . . . . . .. . . . . .. . . . . . . . 25
8.1.5 Influence o f dis e as e on d rug
d is t r ibut i on . . . . . . . . . . . . . . . . . . . . . . . . . 30
8. 2 Feve r . . . . . .. . . . . . . .. . . . . ... . .. . . . . . . . . . . . . . 3 1
8. 2 . 1 In t roduc t i on . . . . . . . . . . . . . . . . . . . . .. . . 31
8.2.2 Pathogt.icsis o f feve r .. . . . . . . . . . . . . . . 33
8. 2 . 3 Pat hophys i o l ogy o f f eve r . . . . . . . . . . . . . 34
8.3 Inf l ue nc e of f eve r on pharmacokine t i c s . . . . . . 36
v
No .
9 .
TABLE OF CONTENTS
Page
8 . 4 Inf l u enc e o f f ever on pharmac oki net i c o f
drugs i n dome s t i c animals . . . . . . . . . . . . . . . . . . . 39
TERI ALS AND METHODS . .. . . . . . . . . . . . . . . . .. . . . . . . . 41
9 . 1 Expe r imen t a l Animal s
41
9 . 2 Re s t ra i nt o f Ani ma l s 42
9 . 3 Drug and Chemi c a Is . . . . . . . . . . . . . . . . . . . . . . . . . l\ 2
9 . 4 Feve r I nduc i ng Age nt s . . . . . . . . . . . . . . . . . . . . .. 44
9 . 5
9 . 4. 1 End o t o xi n . . . . . . . . . . . . . .. . . . . . . . . . . . . 44
9 . 4.2 Viruse s . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
9 . 4. 3 Trypanosoma evanSl . . . . . . . . . . . . . . . . . . . 44
Induc t i on o f Fever 44
9 . 5 . 1 Us i ng E . c o l i endo t o xi n . . . . . . . . . . . . . . 44
9 .5. 2 Usi ng Vlrus es 45
9 . 5. 3 Us i ng Trypanos om

evans i . . . . . . . . . . . . . 46
9 . 6 Quan t i t a t ion o f Feb r i l e Respons e . . . . . . . . . . . . 50
9 . 7 Samp l e Co l l e c t i on 52
9 . 8 Ana l yt i ca l Te chniques . . . . . . . . . . . . . . . . . . . . . . . 53
9 .9 Prepar a t i on o f S tandar ds . . . . . . . . . . . . . . . . . . . . 5 5
9 . 1 0 Anal ys i s o f Do t a . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 S
1 0 . E XPERIMENTAL PROCEDURES . . . . . . . . . . . . . . . . . . .. . . . . . . 66
10.1 Pharma coki ne t i c s of Imi docarb in norma l
dogs and goa ts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 6
Expe r i men t 1 : I nt ravenous i nje c t i on of
i mi docarb d i prop i o na te t o no rmal dogs and
goa t s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66
Expe r iment 2 : Subc ut aneous and i nt ramus c ul ar
i nje c t i on o f i mi docarb d ip ro p i ona t e t o
norma l dogs and goa t s . . . .. . . . . . . . . . . . . . . . . . . . 66
Vl
No.
1 1 .
12.
13.
14 .
TABLE OF CONTENTS
Page
10 . 2 Pharmacok i ne t i c s of i mi doc arb i n f ebri le
dogs and goa t s . . .. . .. . . .. .. . . . .. . . . .. . . . . 67
Exp e riment 3 : The i n f l u ence of E. c o l i
endo t o xi n-i nduced f ever . . . . .. . . . - . . . . 67
Experiment 4: The i nf l uence o f Trypanos oma
evans i -induced fever . . . . . . . . . . . . . . . . . . ... . 68
Exp e r imen t 5: The inf luence of I BR vi ral-
i nduced f ever i n goa t s . .. . . ............... 68
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70
11.1 Norma l Dogs and Goa t s . . . . . . . . . . . . .. . . .. . .. 70
Expe riment 1 : Int ra venous admin i s t ra t i on
o f i mi docarb d i prop i onat e to normal dogs
and goats . . ... . . . . . . . . . . . . . . .. . . . .. . . . . . . 70
Expe riment 2 :
admi ni s tra t ion
to norma l dogs
Subc ut aneous and i nt ramu s c ular
o f i mi docarb d i propi onat e
and goat s . . . ..... .. . . . .... . . 83
11 .2 Feb r i l e Dogs and Goa t s . .. . . . . .. . . ... . . . .. . 1 0 1
Exper iment 3 : The i nf luence o f . co l i
end o t o xi n - i nduced fever.. . . . . . . . . . .. .. . .. .
10 1
Expe riment 4:
i nduced fever
Exp e ri ment 5:
i nduced f eve r
The influence of Trypanosoma-
The i nf l uence of IBR v i ral-
DISCUS S ION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
S UHRY OF CONCLUS IONS . . . . . . . . . . . . . . . . . . . . . . . . .
REFERENCES
Vii
llS
128
1 36
154
156
No .
I .
II .
LI S T OF TABLES
Me t hods f or c a l c u l a t i ng vo l ume o f d i s t ri but i on
when d i spos i t i on ki ne t i cs of d rug are d e s c r i bed by
two -comp ar tment open mod e l
Abs o rbance f or d i f fe rent f l u i d s and t i s s ue s
a t a s i ng l e concen t ra t ion ( 1 5 g/ml or gm)
II I. The mean SD obs e rved ( meas ured ) conce nt rat i on
IV.
V.
VI .
o f i mi docarb i n t he p l asma o f dogs ( n= 7 ) and goa t s
( n=8 ) g i ven a s ingl e i nt ravenous d ose ( 4 mg/kg)
of i mi docarb d iprop i onat e
Pharmacoki ne t i c parame t e r s d es c r ib i ng t he
d i sp o s i t i on k i ne t i c s o f i mi doc arb i n norma l dogs
( n=7 ) f o l l owing i ntr av enous i nje c t ion of a s ingl e
d o s e ( 4 mg/kg) o f i mi doc arb d i prop ionat e s o l u t ion
Pharmacoki ne ti c parame t e r s ( mean SD ) d e s c r ib i ng
d i spo s i t i on ki ne t i c s o f i mi docarb i n no rma l goat s
( n =8) f o l l owi ng int ravenous i nj e c t i on of a s ingl e
dos e ( 4 mg/kg) of 12 % i mi docarb d ip rop i ona t e
s olu t i on
Pharmacoki ne t i c paramete r s (me an SD) d e s c rib i ng
t he d i s p o s i t i on ki ne t i c s of i mi docarb i n norma l
dogs ( n= 7 ) and normal goa t s ( n=8) f o l l owi ng
i nt ravenous inj e c t i on of a s ingl e dose ( 4 mg/kg)
of 12 % imi do carb d ipropiona t e s olu t ion
vii i
Page
1 6
64
7 1
7 4
7 5
7 9
No.
VI I .
VIII.
IX.
X.
XI.
LIST OF TABLES
Comp a r i son o f two -and three-compar tment
mode l s us i ng mean conc ent rat i on-t ime d a t a
( 13 p o i n t s ) i n norma l goa t s (n=8)
The mean SD ob s e rved ( meas ured) p l a sma
concent r a t i ons o f i mi docarb ( g/ml ) i n norma l
dogs ( n=7 ) and goa t s ( n=4 ) f o l l owing
s ubc ut aneous i nje c t i on of a s i ngl e dos e
( 4 mg/kg) of 1 2 % i mi docarb d i prop i onate
s o l u t ion
The mean SD o b s e rved ( meas ured ) p l a sma
concent r a t i ons o f imidoc arb ( g/ml ) i n norma l
goa t s ( n=4 ) fol lowi ng i nt ramus cu l ar i nje c t i on
o f a s ingl e dos e ( 4 mg/kg) o f 12 % i mi docarb
d i propi onat e s o l ution
Pharmacok i ne t i c p arame t e rs d e s c ri b i ng the
d i s po s i ti on ki ne t i c s of i mi docarb i n norma l
dogs ( n= 7 ) f o ll owing s ub c u t aneous i nje c t i on
o f a s ingl e do s e ( 4 mg/kg) of 1 2 % imi doc arb
d i propi ona t e s o l ution
Pharmacoki ne ti c parame t e r s d e s c r i b i ng the
d i sp o s i t i o n ki ne t i c s of i mi docarb i n normal
goat s ( n=4) f o l l ow ing s ubc u tane ou s inje c t ion
of a s i ngl e d o s e ( 4 mg/kg) of 1 2% i mi docarb
d ipropi onat e so l u t i on
lX
Page
82
8 4
85
91
9 2
NO.
XI I.
XIII .
XIV .
XV .
LIST OF TABLES
Pharmcoki ne t i c parame te r s d e s c r i b i ng the
d i s pos i t i on ki net i c s of i mi d oc arb i n normal
goa t s (n=4 ) f o l l owi ng i nt ramus c ul a r i nj e c t i o n
of a s ingl e d o s e ( 4 mg/ kg) o f 1 2 % i mi doc arb
d i prop i ona t e so l ut ion
Pharmac oki ne t i c parame t e rs ( mean SD)
d e s c r ib i ng t he d i sp o s i t i on k ine t i c s o f
i mi docarb i n normal d o gs ( n=7 ) a nd normal
goa t s (n=4 ) f o l l owi ng s ubcut aneous in je c t i on
o f a singl e dose ( 4 mg/kg) of 1 2% i mi docarb
d i pro pi onat e s o l u t i on
Pha rmacoki ne t i c parame t e r s (me an SD)
d e s c r i b i ng t he d i s posi t i on k i ne t i cs o f i mi d ocarb
in norma l goa ts f o l l owi ng s ub cu t aneous ( n=4)
and int ramu s c u l a r ( n=4 ) i nje c t i on o f a s i ngl e
do s e ( 4 mg/ kg) of 1 2 % i mi doc arb d i prop i ona t e
solution
The mean SD o bserve d ( measur e d ) pla sma
conc ent rat i on
of
i mi docarb (g/ml) in no rmal
and endo to xi n-induc e d f eb r i l e dogs and goa t s
fol l owi ng in t ravenou s i nje c tion of a s i ngl e
d os e ( 4 mg/ kg) o f 1 2 % imi d o c arb d ip ro p i ona t e
s o l u t i on
Page
93
94
95
102
No .
XVI .
XVII.
XVIII .
XIX.
LIS T OF TABLES
Pharmacoki ne ti c parameter s describ i ng
ki ne t i cs o f imi docarb in febr il e ( e nd o t ox i n
i nduced feve r ) d o gs ( n=6) fol l owing i nt r avenous
inje c t io n o f a.s ingl e d o s e (4 mg/kg) o f 12%
i mido carb d ipropi onate so lut i on
Pharmac o ki ne t i c p arame t e r s d e s c r i b ing
d i spo s i t i o n kine t i c s o f i mi doc arb i n feb r i l e
( endo t o xi n- i nduced feve r ) goat s ( n=6) fo l l o wi ng
i nt r ave nous i n ject i o n o f a s i ngl e dose ( 4 mg/kg)
o f 12% i mi docarb d i p rop i onate s ol u t i on
Pharmac oki ne t ic p ar ame t e rs ( mean SD)
d e s cr ib i ng t he d i s po s i t i o n kine ti c s o f
imido carb i n t he normal ( n=7 ) and feb r i l e
( endot ox i n-ind uced feve r ) dogs ( n=6)
fol l owing int rave nous i nje ct i o n of a s ingl e
do s e (4 mg/kg) o f 12% i mi docarb d i p rop i o nat e
so lution
Pharma c oki ne t ic p arame t e r s ( mean SD)
d e s c rib i ng t he d i s pos i t i o n ki ne t i c s o f
imidocarb i n t h e normal ( n=8) and feb r i l e
( endoto xi n- i nduced f eve r ) goats ( n=6)
fo l l owi ng i nt r avenous i nj e c t i o n o f a s i ngl e
d o s e ( 4 mg/ kg) o f 1 2% i mi docarb d i p rop i onat e
s o l u t i o n
Xl
Page
107
1 0 8
109
1 1 0
No .
xx.
XXI .
XXII.
XXIII.
LIS T OF TABLES
The me an SD obs erved ( meas ured) pl asma
co nce nt r at i ons of i mi docarb ( g/ml) in no rmal
and Trypano soma- i nd uc ed febr i l e dogs and goa t s
fo ll owi ng i nt r avenous inje cti on of a s ingle
d o s e ( 4 mg/kg) o f 12 % i mi docarb d i prop i ona t e
s o l ut i on
Pharmacoki ne t i c p ar ame t e r s d e s cr i b i ng the
d i s p o s i t i on kine t i cs o f i mi docarb i n t he
feb r i l e (Tryp anos oma- induced f e ve r ) dogs (n=6 )
f o llowi ng i nt r aveno us inje cti on o f a s ingle
d ose (4 mg/kg) of 12% imidocarb dipropionat e
s o lut ion
Pharmac okinetic parame t ers ( me an SD)
d e s cr i b i ng t he di s po s i t i on ki ne t i cs of i mi docarb
i n t he nornal ( n= 7 ) and f eb r i le ( Tryp anos omias i s )
d ogs ( n=6) f o l lowi ng i nt r aveno us i nje ct i on o f
a s ingle d o s e ( 4 mg/ kg) o f 1 2 % i mi doca rb
d i propionat e s olution
Pharmacoki ne t i c par ame t e r s d e s cr ib i ng t he
d i s pos it i on kinet i cs of i midocarb in the
feb r i l e ( Tryp ano s oma- induced fe ve r ) go at s
(n=6 ) f o ll owi n g i nt ravenous i nje ct i on o f a
s i ngl e d o s e (4 mg/ kg) o f 12% i mi d oc arb
d i p rop i onat e s o l ut i on
x i i
P age
1 16
121
122
1 23
No .
XXIV.
XXV.
XXVI.
XXVII
LIST OF TABLES
P harmacok i ne t i c parame t e r s ( me an SD)
d e s c r ib i ng t he d i s pos i t i o n k i ne t i c s o f
i mi doc arb in t he normal ( n=8 ) and f eb r i l e
( Trypanosoma-induced f ever ) goa t s ( n= 6)
f o l l owi ng i nt rave nous injec t i on of a
s ing l e dos e ( 4 mg/ kg) of 1 2 % i mi docarb
d iprop i o na t e s o l u t i o n
The mean SD obs erved ( me as ur e d ) p l as ma
c o nc e nt rati ons o f i mi docarb (wg/ml ) in
norma l ( n=8) a nd f eb r i l e ( IBR v i ra l - i nduced
f ever) goa t s ( n= 6) fol l owi ng i nt rave nous
i nje c t i o n o f a s ingl e dos e ( 4 mg/kg) o f
12 % imi docarb d ipropionat e s o l ut ion
harmacok i ne t ic parame t e r s d e s c r ib i ng
t he d i spo s i t i on ki ne t i c s o f imi doc arb
in t he f e br il e ( IBR vra l -i nduc ed feve r )
goat s ( n=6 ) f o l l owi ng int r avenous i nje c t i on
o f a s ing l e dos e ( 4 mg/ kg) o f 1 2% imidocarb
s o l u t i o n
P harmacokine t i c paramet e r s ( me an SD)
d e s c r ib i ng t he d i s pos i t i o n k i ne t i c o f
imidocar b i n t he norma l ( n=8) and f e br il e
( IBR-v i ra l induced f eve r ) goa t s ( n=6) f ol l owi ng
i nt rave nous i nje c t i on of a singl e d ose ( 4mg/ kg)
o f 1 2 % imidocarb d iprop i ona t e s o l u t ion
xi i i
Page
1 2 4
1 2 9
1 3 2
1 3 3
No .
1.
2
LIST OF F IGURES
Inf e c t i o us d i s eas e s ys t em. In the c ourse
o f an i nf ec t i o us d i s eas e and con t inuous
anti b i o t i c t re atment the body o f the ho s t ( H) ,
the mi c robe s (M) and the an t ib ac t e ri al d rug
( D) ar e the i nt e rdependent vari ab l e s o f a
comp l ex s y s t em . The i nt era ct i ons i n the
s ys t em are: 1: Pharmacoki neti c s ( H -- D),
2: D rug tox ic it y ( D H ) , 3 : Host 's
d e f ens e mechani sms (H -- H), 4 : Ba c t e ri a l
t o xi c i ty ( - H ) , 5 : Pharmacodynami c s
( D l), 6 : Bact e ri al d ef ens e mec hani sms
eM - D) (From H inde rl ing, 1 97 8. Si gn i -
Page
2
f i c anc e of t he pharmacoki ne t i cs o f ant imi c rob i al
d rugs. Scand . J . Inf e c t . D i s . Sup p l . 14:2 5 -3 5 ) .
Schemati c d i agram of the two-compa rtment
open mod e l. The d os e o f d rug i s i n t ro d uced
int o t he c e nt ral compartment , whe re i t
d is t rib ut e s i ns t ant ane o us l y . D i s trib ut ion
b e tween cen t ra l and peripheral co mpart ment s
t ake s p l ace mo re s l owl y ; k
12
and k
21
are
f i rs t -o rde r ra t e cons t ant s for d rug t rans fe r
be t ween the t wo comp artment s . E l i mi nat i o n,
whi ch c ompri s e s b i o t rans fo rmat i on and
excre t i on , is a s s umed t o o cc ur exc l us i ve l y
f rom t he cent ra l compa rt ment ; k
e l
i s t h e
XlV
8
No .
2
3 .
4 .
LIST OF FIGURES
f ir s t -orde r r at e con s t an t f or drug e limina t ion
f r om t he c e nt ra l compartm n t . (From B aggot ,
19 7 8 . Some as p ec t s of c linic a l p harma c okin e t ic s
in ve t e rin ary med ic ine . I. J. Ve t . Pharmacol.
The rap . 1, 5-18) .
Semiloga r it hmic graph d e pic t ing t he t ime
cour s e of drug In t he p l a sma a f t e r in t r avenous
admin is t r a t io n of a s in gl e dos e. The equa t ion
whic h d e s c r ibe s t he dis pos it io n curve IS
s hown. ( From Baggo t , 19 7 7 ) . Prin c ip l e s o f
Drug Dis pos it io n in Dome s t ic Animals : The
B a s is o f Ve t e r inary C l in ica l P harmac ol ogy.
Saunde rs , Philad e lp hia .
Expe r imen t al.
o Re s idua l
Analogue compu t e r-gene r at e d curve s s ho wing
kanamycin leve ls (a s f r ac t ion o f int r aven ous
dos e ) i n t he c e nt r al and p e r ip heral c omp a r t-
men t s and the c umu la t ive amount excreted in
t he urIne as a func t i on o f t ime . The curves
are based on microcon s t a nt s whi ch were
de r ived f rom experime nt al p harmac okine t i c
cons t an t s ob t a i ned in s heep . (From Baggo t ,
19 7 8 . S ome asp ec t s of c linica l pharmacoki
ne tic s i n vet erin ary med ici n e I . J. Ve t .
Pha rmacal . The rap . 1, 5-18 ) .
xv
Page
8
10
17
LIST OF F I GURES
No.
Page
5. Graph ica l techni q ue for e stimating the 2 1
ha lf-l i fe of a drug. ( From Baggot, 1 9 77 .
Pr i nci p l es of Drug D i s positi on i n Domestic
Ani ma ls: The Basis of Vete r i nary Cl i n ica l
Pharmacology. Saund e r s, Phi l ade l ph i a).
B = 1 0 gjml; t
l
= 1. 5 h.
2
6. Schematic repre s entati on of the distr i bu t i on 2 9
of drugs i nto d iffe rent compartments ( From
Klotz 19 7 6 . Pathophys i o l ogical and D isease-
i nduced Change s i n Drug D i stri buti on Vo l ume:
Pharmacoki netic Impl ications. C l i nical
Pharmacoki netics 1 :204 - 2 1 8 ) .
7. Postul ated p athway for the pathogenes i s of 35
fever. Endogenous pyrogen circul ates to the
hypotha l amus (POjAH), where it i nduces the
prod uct io n of a metabolite of arachidonic acid.
This substance, i n turn, i ncreases the
synthesi s of nerepiephr i ne , an a lpha-adrene r gic
agonist that i ncr e as e the producti on of cAMP.
This cyclonucl eotide then directl y cau s e s
a lterations i n the activity of temp e rature-
s ensitive neurons that b r i ng about an
increase in heat cons e rvati on or production
XVl
No .
7 .
8.
9.
1 0 .
LI S T OF F IGURES
( or both) . Ag = anti gen; Ag-Ab =ant i gen-
antibody compl exes ; Compl = c o mpl ement; c AHP
= c yc l i c 3 ', 5'-ad enos i n e monopho s phate;
DHS = delayed hyper s ens i tiv i t y ; EP = endogenous
pyrogen ; SHT = s er o toni n; LK = l ymphok i ne;
NE = norepi nephr i ne; PO/AH preoptic area o f
anter i o r hypo thal amus ; RES = r e ti c ulo-
Page
35
endothe l i a l s ys tem i nhib i t o rs ; " activato r s.
( F rom B ernhei m H, B l ock LH , Atki ns E : F ever :
Pa thogenes i s , patho phys i o l ogy , and purpos e.
Ann Intern Med 9 1 :2 61 , 1 9 7 9 ) .
A dog and goa t 1n res trai ning cages 43
lean f eb r i le res pons e o f dogs ( I) and 47
goats (& ) f o l l owi ng i ntravenous i nj ec ti o n
o f LPS E . co l i ( 0 .2 jg/kg) ( f i rs t ar row) and
af ter the i n jec t i on o f imi do c arb d ipro pionate
( s econd a rrow) i n relation to time. Each
point r ep resen t s the mean o f s i x dogs and
s ix goats .
Mean feb ri l e r es pons e o f dogs () and 48
goa t s (e-) f o l l o wing intravenous lnoc u-
l
l ati on o f 10 sanos oma evan sJ and af ter
the
-
i nj ec ti on o f imi docarb d i propi o na t e ( ar ro w)
i n rel ation to t ime. Each po i nt repres ents
the average o f s i x dogs and go at s.
xvi i
No .
1 1.
1
2
.
13.
14.
1 5.
1 6.
17 .
1 8 .
1 9 .
20.
LIS T OF FIGURES
Ne an f eb r i l e re spons e of goats f o l l owing
i ntravenous i nocul ati on o f I nf e c t i ous
Bovi ne Rhi notrache i tis ( IBR) Vi ru s ( f i rs t
arrow) and af te r the i n je c t i on o f i mi docarb
d i pr opi onate ( s e cond arrow) i n r e l ati on to
time . Each po i nt r e pr e s ents the mean o f
s ix goats .
Standard c urve o f i mi docarb in pl asma o f
goat.
Standard c urve o f i mi docarb in u r ine of
goat.
Imi docarb s tandard curve in b i l e
Imi docarb s tandard c u rve in ki dne y
Imi do carb s tandard curve in l ive r
Imi docarb s tandard c urve in he art
Imi docarb s tand ard c urve in mus c l e
Imi d oc arb s tandard c urve in f at
The l e a s t s quares non- l i ne ar regre s s ion l i ne
whi ch b e s t d e s c r ib e s t h e pl a sma concentrati on-
time pro fi le in normal dogs . Data used f o r
xvi i i
Page
49
56
57
58
59
60
61
62
63
72
No.
20.
2 1.
22.
23.
LIST OF F IGURES
construction of graph represents the mean SD
concentration-time data 1n dogs (n=7).
The least squares non-linear regress10n line
Hhich best describes the plasma concentration
time profile 1n normal goats. Data used for
construction of graph represents the mean
SD concentration-time data in goats (n=8).
Computer generated curves, based on m1cro
constants associated with the to-compartment
open model showing the level of imidocarb 1n
copartments of the two-compartment open
model. The fraction of dose in each of the
compartments at 8-hours after a single
intravenous injection (4 mg/kg) in dog is:
6. 3% (central), 14.1% (peripheral), and 79. 6%
(eliminated). The concentrations in plasma
are ShOl,TO.
Computer generated curves, based on m1cro
constants associated with the two-compartment
open model showing the level of imidocarb
in compartments of the two-compartments open
model. The fraction of dose in each of the
compartments at 8-hours after a single
"LX
Page
72
73
77
78
No.
23.
25.
26.
LIST OF FIGURES
intravenous injection (4 mg/kg) 1n goats 1S:
2.8% (central), 18.9% (peripheral), and 78.3%
(eliminated). The concentrations in plasma are
shown.
Cumulative ur1nary excretion (mean + SD) of
unchanged imidocarb in the normal dogs (n=7)
and goats (n=8) folowing intravenous injection
of a single dose (4 mg/kg) of 12% imidocarb
dipropionate solution.
Semilogarithmi plot of the plasma concentra
tion-time profiles for imidocarb which
followed injection of the drug (4 rng/kg) 1n
dogs by the intravenous and subcutaneous
(n=7) routes. The symbols represent the
concentration of imidocarb in the plasma after
the administration of a single intravenous
dose (-) and a single subcutaneous dose
Semilogarithmic plot of the plasma concentra
tion-time profiles for imidocarb which followed
injection of the drug (4mg/kg) 1n goats by
the intravenous (n=8), subcutaneous (n=4) and
intramuscular (n=4) routes. The symbols
xx
Page
78
81
86
87
No.
26.
27.
28.
29.
30.
LIST OF FIGURES
Page
represent the concentrati on of imidocarb 1n
the pla sma after the administration of a
single intravenous dose (), s ubcutaneous dose
() and i ntramuscu l ar dose (=-J).
Concentration of imidocarb (g/ml) 1n pl asma
of norma l d ogs (n=7) a nd goats (n=4) following
subcutaneous injecti on of a single dose
(4 mg/kg) of 12% i mi docarb d iprop ionate
solution.
Concentrati on of imidocarb (g/ml) 1n pl asma
of norma l goats foll owing subcutaneous (n=4)
and i ntramuscul ar (n=4) i njection of a
s ingl e dose (4 mg/kg) of 12% i mi docarb
d ipropionace so lution.
Concentrati on of imidocarb i n var i ous tissues
of normal goats fo l lOlving subcutaneous arrd
intramuscu lar i njecti on of a sing le dose
(4 mg/kg) of 12% imidocarh d iprop i onate
sol uti on.
Cumul ative urlnary excretion (mean + SD) of
unchanged imidocarb in normal goats following
i ntravenous ( n=8) and intramuscular (n=4)
XX1
87
89
90
97
98
No.
30.
31.
32 .
3 3 .
34.
LIST OF FIGURES
i njec tion o f a s i ngle dos e (4 mg/kg) o f
12 % i midocarb d i propi onat e s olu t i on .
Cumula t ive ur 1nar y exc re t i on ( mean + SD) of
unchanged imi d oca rb in n ormal goa t s foll owi ng
i n t ravenous ( n=8) and subcu tane ous ( n=4)
i n j e cti o n of a s i ng l e dos e (4 mg/kg) of 12%
imi docarb d i pr opi onate s oluti on.
Cumula ti ve Ur1l1ary e xc r e ti o n ( mean + SD) of
unchanged imi d ocarb 1n normal d ogs (n=7 )
f ol lowi ng i n t ravenous and s ubcutane ou s
i n j e c t i o n o f a s i ngle dos e (4 mg/kg) of 1 2 %
i mi do carb d i pr opi ona t e solu t ion.
The l ea s t s quare s n on-linear regre s s i on l i ne
whi ch b e st de sc r ib e s t he pl asma conc e nt ra tion-
t i me pro fi le i n end otoxi n-i nd uc e d fe br i le
dogs. Data used for construction of graph
r e pr e s e nts t he mean SD c on c e n t r a t ion-ti me
d a t a i n f eb r i l e dogs ( n=6).
The least squar e s n o n-li n ear regre s s lon line
whi c h bes t describes the plas ma concentra t ion
t ime pro fi l e i n endotox i n -i n duced febrile
goats . Dat a us ed f or c on s truc t i on o f graph
re pre s e n t s the mean SD conc e ntra ti o n-t i me
data i n f ebr i le goa t s (n =6).
XXll
Page
9 8
99
100
103
104
No .
35 .
36.
3 7 .
3 8 .
LIST OF FIGURES
The leas t squar e s non-l i near regre ssl0n l i ne s
which b e s t descr ibes the p lasma concent rat i on
time p ro f i l e i n norma l and endotox i n-i n duced
f e br i l e dogs. Da ta used for cons tructi on o f
graphs repres ents the mean SD concentrati on
ti me data in n' ormal ( n=7) and f e bril e dogs
( n= 6 ) .
The leas t s quare s non-l i near regresslon l i ne s
wh i ch b e s t d e s cr i b e the p l a sma concentrati on
time p ro f ile s in norma l and endo to xin-i nduced
f eb r i l e goats . Dat a used f or con s truc ti on o f
graphs r e pr e s ents the mean SD con centra ti on
ti me data i n normal ( n=8 ) and f ebril e goa ts
( n=6 ) .
Cumula ti ve urlnary excreti on (mean + SD) o f
unchanged i mi doca rb i n the no rmal ( n=7 ) and
feb r i l e ( endotoxin-induced fever) dogs ( n=6 )
f ollowing intravenous injection of a s i ngle
d o s e ( 4 mg/kg) of 12% imi doc a rb d i p ropi onate
s o l ution .
Cumulative urlnary excr e ti on ( mean + SD) o f
unchanged i mid oca rb i n the norma l (n= 8 ) a nd
f ebr i l e ( Endo toxi n- i nduced f e ve r ) goa ts ( n=6 )
x x 111
Page
1 0 5
106
1 13
1 1 4