Professional Documents
Culture Documents
(DILI)
Drug-Drug
Drugs Interactions
LIVER
Drug Elimination
Drug Metabolites
(the good, the bad and the ugly)
Why Study Drugs and the Liver?
ClH = Q
High Extraction Drugs/
Xenobiotics/ Endogenous Compounds
Nitroglycerine
Lidocaine
Propranolol
Bile Acids
Hepatic Drug Clearance
Diazepam
Phenytoin
Theophylline
Bilirubin
Phase 1 Biotransformation and
Phase 2 Conjugation in Liver
O Sugar
OH
OH
Glucuronyl
CYP transferase
ER ER
Phase 1 Phase 2
Oxidative Conjugation to polar ligand
reactions Glucuronyl transferases
CYP-mediated Sulfotransferases
Glutathione-S- transferases
Contributions of Specific P450s to
Drug Metabolism
CYP3A4
CYP3A4
CYP2E1
CYP2D6
CYP2C*
CYP1A2
unknown
* multiple subfamily
members exist
Role: Production of an active drug
Biotransformation of an inactive pro-drug) to an active drug
pro-drug
active drug
Glucuronyl
OH transferase
CYP3A4
ER ER
Phase 2: Conjugation
NH-CO-CH3
NH-CO-CH3
UDP
+ Glucuronic acid O Glucuronic acid
OH UDP-glucuronyl
transferase
ER
CYP
ER
Drug Elimination
Biliary Excretion
Renal Excretion
Common Theme
Liver uses similar mechanisms to handle
endogenous and xenobiotic compounds
Drug-Drug Interactions:
Various Issues
ENDOPLASMIC RETICULUM
Case Presentation
23 year old man underwent cardiac
transplantation.
Begun on usual doses of cyclosporin A (6
mg/kg/day) and levels were therapeutic for 2
days.
Also given ketoconazole for suspected fungal
infection.
Then developed renal failure and seizures
consistent with acute cyclosporin A toxicity -
blood levels of CsA were high.
Case Continued
Dose was reduced and therapeutic blood levels
were re-established
However, 6 weeks after surgery his blood levels
had fallen to subtherapeutic levels and dose had
to be increased again.
WHY?
Drug Interactions and CYP3A4
Absence of competition -
CYP3A4
Drug: Unaltered
Cyclosporin
Cyclosporin A
Cyclosporin
Metabolites
Cytochrome P450 Metabolism
A B CsA Keto
ENDOPLASMIC RETICULUM
Our Case: Subtherapeutic cyclosporin
levels 6 weeks after discharge
Ketoconazole
CYP3A4
Unaltered
Drug
Cyclosporin A
Cyclosporin A
Metabolites
Our Case
Patient has Cyclosporin A toxicity and high blood
levels 2 days after transplant.
Not likely due to genetically low levels of CYP3A4
as six weeks later his blood levels were low.
More likely high levels due to simultaneous
administration of a competing drug - ketoconazole
for suspected fungal infection.
Induction of CYP Enzymes
Hepatocellular injury
toxic metabolite: isoniazid, acetaminophen
Autoimmune hepatocellular injury
halothane hepatitis
Cholestatic liver injury
estrogen
DILI Incidence
10 fold increase in No. of reported cases between 1964-
1973 in Japan
Unpredictable
Not dose related
Rare 0.01-1.0 %
Weeks to months after ingestion of drug
Idiosyncratic
Immune mediated idiosyncrasy (Hypersensitivity)
Rash
Fever
Arthragia
Eosinophilia
Example: Phenytoin, Sulfonamides, Valproate
Extrahepatic manifestations
Hypersensitivity reactions
Fever
Rash
Arthralgias
Esinophelia
Methotrexate Acetaminophen
Alcohol Alcohol
Obesity Fasting
D.M INH
Chronic hepatitis
Valproate
INH Young age
HBV,HCV,HIV Anticonvulsants
Alcohol
Older age Diclofenac
Female Female
Osteoarthritis
Risk Factors For Susceptibility to DILI
Sulfonamide Rifampicin
HIV Slow acetylators
Slow acetylator INH
Genetic defect in defense
Pyrazinamide
Anticonvulsats Slow acetylators
Genetic defect in INH
detoxification
Acetaminophen Metabolism
Glucuronidation
Sulfation
Acetaminophen Stable
Excretion
Metabolites
CYP2E1 Glutathione
(CYP3A4, CYP1A2) conjugation
Covalent binding
oxidative stress
Hepatocyte damage
Acetaminophen Metabolism:
High Dose
Glucuronidation
Acetaminophen Sulfation
Stable
Overdose Saturated Metabolites
Excretion
Glutathione
CYP2E1 conjugation
N-acetylcysteine
Covalent binding (antidote to overdose)
oxidative stress
Hepatocyte damage
Therapeutic Misadventure
CYP2E1 Glutathione
(CYP3A4, CYP1A2) conjugation
Covalent binding
oxidative stress
Hepatocyte damage
A Potentially Lethal
Combination
CYP2E1 Glutathione
conjugation
EtOH
Fasting
Covalent binding
oxidative stress
Hepatocyte damage
Drugs that Induce CYP2E1
Isoniazid (INH)
Phenobarbital
Ethanol !!!
Approach to Drug-Induced Liver
Disease