药物代谢PPTDrugMetabolism5.pptVIP

Drug Metabolism Most metabolic products are less pharmacologically active Important exceptions: Where the metabolite is more active (Prodrugs, e.g. Erythromycin-succinate (less irritation of GI) -- Erythromycin) Where the metabolite is toxic (acetaminophen) Where the metabolite is carcinogenic Close relationship between the biotransformation of drugs and normal biochemical processes occurring in the body: Metabolism of drugs involves many pathways associated with the synthesis of endogenous substrates such as steroid hormones, cholesterol and bile acids Many of the enzymes involved in drug metabolism are principally designed for the metabolism of endogenous compounds These enzymes metabolize drugs only because the drugs resemble the natural compound Phases of Drug Metabolism Phase I Reactions Convert parent compound into a more polar (=hydrophilic) metabolite by adding or unmasking functional groups (-OH, -SH, -NH2, -COOH, etc.) Often these metabolites are inactive May be sufficiently polar to be excreted readily Phase II Reactions Conjugation with endogenous substrate to further increase aqueous solubility Conjugation with glucoronide, sulfate, acetate, amino acid Phase I usually precede phase II reactions Liver is principal site of drug metabolism: Other sites include the gut, lungs, skin and kidneys For orally administered compounds, there is the “First Pass Effect” Intestinal metabolism Liver metabolism Enterohepatic recycling Gut microorganisms - glucuronidases Drug Metabolism Drug Metabolism - Phase I Phase I Reactions Oxidation Reduction Hydrolytic cleavage Alkylation (Methylation) Dealkylation Ring cyclization N-carboxylation Dimerization Transamidation Isomerization Decarboxylation Drug Metabolism - Oxidation Two types of oxidation reactions: Oxygen is incorporated into the drug molecule (e.g. hydroxylation) Oxidation causes the loss of part of the drug molecule (e.g. oxidative deimination, dealkylation) Microsomal Mixed Function Oxidases (MF