Hepatic Drug Metabolism Eva Brittebo Dept Pharmaceutical Biosciences Background Cytochrome P450 (CYP) Liver metabolism Liver toxicity Inhibition and induction Polymorphism 15-05-13 2 Plasma concentration of a medicine Medicines in plasma Absorption Distribution Metabolism Excretion Dosing interval = ADME 3 Phase I metabolism Introduction of a functional group OH - OH - NH 2 - SH - epoxid - COOH Phase II metabolism Conjugation of an endogenous water-soluble compound Drug metabolism enzymes Cytokrom P450 (CYP) CYP OH -glutathione -glucuronic acid -acetyl -sulfate Guengerich, Chem. Res. Toxicol. 2008, 21, 70 83
CYP (cytochrome 450) a superfamily of drug metabolism enzymes Major hepatic CYPs Metabolism of drugs, other xenobiotics and endogenous substrates CYP1 family (> 40 % identity) CYP1A subfamily (> 55% identity) CYP1A1 individual gene/protein CYP1A1*1 allele variant CYP 1A2 CYP 2C9 CYP 2C19 CYP 2D6 CYP 3A4 >90% of currently used drugs 15-05-13 7 15-05-13 8 CYP3A4 Interindividual differences in hepatic drug metabolism A major hepatic CYP metabolizes more than 120 drugs can be inhibited and induced 15-05-13 9 Polymorphism Exposure to CYP-inducing chemicals F. Peter Guengerich, The AAPS Journal 2006; 8 (1) The plant-animal warfare CYP developed in response to toxic substances in plants that had to be detoxified by animals From Boelsterli: Mechanistic Toxicology
CYP and drug-induced liver damage CYP bioactivation of paracetamol (Alvedon) Overdose! heptatotoxicity and acute liver failure 0-24 h nausea, abdominal pain 18-24 h less symptoms, ALAT/ASAT 72-96 h liver encephalopathy, jaundice, coagulation disturbance Risk factors: Alcohol, CYP-inducing drugs Antidote: N-acetylcysteine (NAC) Low dose paracetamol - detoxication Overdose paracetamol Saturated Overdose paracetamol - metabolic activation Overdose paracetamol - metabolic activation CYP2E1 CYP2E1 saturated Liver damage
Overdose paracetamol - metabolic activation Drug-related problems due to CYP CYP2E1 CYPs are Saturable -> dose-dependent kinetics Inhibitable -> drug-drug (food) interactions Inducible -> drug-drug (food) interactions Polymorphic -> interindividual metabolism antidot N-acetylcysteine Read FASS Liver damage A patient s medication Drug-drug interactions due to hepatic CYP inhibition hormone antifungal drug antibiotic Medroxyprogesterone Cefaclor Ketoconazole antihistamine Terfenadine 15-05-13 21 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Day of treatment Monahan BP et al. JAMA From 1990;264:2788 2790 Centers for Education & Research on Therapeutics Medroxyprogesterone Medroxyprogesterone Not associated with arrhythmia Cefaclor Ketoconazole Cefaclor Ketoconazole Terfenadine First non-sedating antihistamine Terfenadine 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Day of treatment Monahan BP et al. JAMA 1990;264:2788 2790 From Centers for Education & Research on Therapeutics 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Day of treatment Monahan BP et al. JAMA 1990;264:2788 2790 From Centers for Education & Research on Therapeutics
Ketoconazole + Terfenadine " ketoconazole inhibits liver CYP3A4 " decreased liver metabolism of terfendine " increased plasma concentrations of terfenadine " K + channel is blocked " prolonged QT intervals Drug withdrawals due to drug drug interactions Withdrawn Drug Use Drug-drug interaction via CYP inhibition 1998 Terfenadine Antihistamine Arrhythmias 1998 Mibefradil Calcium-channel blocker Arrhythmias 1999 Astemizole Antihistamine Arrhythmias 1999 Grepafloxacin Fluoroquinolone antibiotic Arrhythmias Monahan et al., JAMA 1990 Torsades de Pointes (twisting the points) 2000 Cisapride Gastroesophageal reflux disease Arrhythmias 80 deaths Food - drug interactions due to hepatic CYP inhibition Grape fruit drug interaction Dihydroxybergamottin in grape fruit CYP3A4 inhibitor 12-fold increase of some drug plasma concentrations 15-05-13 27 15-05-13 28 Hepatic CYP enzyme induction and drugs CYP gene regulation CYP genes can be upregulated by drugs and chemicals via ligand-receptor interaction CYP3 is induced by dexamethasone, phenobarbital, phenytoin, rifampicin, St John s wort etc CYP1 is induced by dioxin, PCB, DDT etc 15-05-13 29 15-05-13 30
Drug-drug interaction due to induction of CYP3A Induction of hepatic CYP3A4 and drug-drug interaction " increased metabolism of oral contraceptives decreased plasma level! pregnancy " increased metabolism of HIV-protease inhibitors decreased plasma level! resistance 15-05-13 31 CYP polymorphism and drugs CYP2D6 polymorphism Poor metabolizers (PM) Absent in 7% of Caucasians* Absent in 1 2% non-caucasians Ultrarapid metabolizers (URM) Hyperactive in up to 30% of North Africa, East Africa and Middle East 15-05-13 33 * In the United States, "Caucasian" is used primarily as a distinction loosely based on skin color alone for a group commonly refered to as Whites. In Britain, "Caucasian" follows the North American definition, but in continental Europe, "Caucasian" currently refers exclusively to people who are from the Caucasus Hepatic CYP2D6 and nortriptyline Preclinical drug development antidepressant drug 5-10 % of the Europeans lack CYP2D6 nortriptyline cannot be metabolized! 100% increased plasma concentration dose adaptation Approval or rejection of new drug candidates metabolized by polymorphic CYP forms? Consider the potential drug-drug interactions!