英国纽卡斯尔大学药理学课件.pptVIP

Drug Elimination (I) Professor F Kamali Wolfson Unit of Clinical Pharmacology Drug Elimination Drugs eliminated by biotransformation and/or excretion into urine or bile. Liver major site for drug metabolism Kidney major organ for drug excretion Why the body needs to metabolise drugs? Water soluble drugs:- excreted unchanged through the kidneys Lipid soluble drugs ? filtered in glomeruli ? reabsorbed on the distal portion of nephron Metabolism to more polar compounds ? excretion in urine Two phases of drug metabolism Drug ?phase I ? drug* (reactive functional group) ? phase II “detoxification” ? inactive drug ? excretion into urine Enzymes in drug metabolism, capable of metabolism of endogenous compounds e.g. hormones Evolutionary function! Drugs and endogenous compounds can interfere with each other’s metabolism Phase I PathwayCytochrome P450 Cycle Sub-classification of phase 1 reactions Oxidation involving Cytochrome P450: Oxidation (hydroxylation , dealkylation, deamination) Other Non-P450 reactions: Reduction Hydrolysis Hydration Isomerisation Miscellaneous Oxidations involving cytochrome P450 (microsomal mixed-function oxidase) Hydroxylation Aliphatic hydroxylation Side chain hydroxylation of pentobarbitone Dealkylation N-demethylation of diazepam Oxidative deamination e.g. amphetamine Non-P450 reactions Non-P450 reactions Hydrolysis Non-P450 reactions ?Xanthine Oxidase Phase II pathways Conjugation reactions: If phase 1 metabolite(s) too lipophilic to be retained in kidney tubular fluid ?conjugation with an endogenous substrate:- Glucuronic acid, sulphuric acid, acetic acid or an amino acid, (glutathione) Drug conjugation ? More water soluble metabolites (often therapeutically inactive) Glucuronidation:- most common and important Neonates deficient:- chloramphenicol toxicity? Compoun