药物体外代谢研究III- PHASE II酶研究.pdf

药物体外代谢研究III 药物体外代谢研究III —Phase II酶研究 —Phase II酶研究 刘慧鑫 Outline • Background research significance； • Classification Nomenclature; • Catalytic Mechanisms; • Substrate specificity; • Distribution; • Species differences examples; • Metabolic stability studies (UGTs) 1 药物代谢酶 药物代谢酶 Elimination pathways of top 200 drugs 清除机制 可能参与代谢的酶/蛋白 氧化代谢 CYP，FMO，MAO，Mo-CO，过氧化物酶 水解代谢 酯酶，酰胺酶，环氧化物水解酶 结合代谢 UGT，ST，甲基转移酶，乙酰转移酶 以不变形式清除 转运蛋白 FMO，黄素单加氧酶；MAO，单胺氧化酶；UGT，UDP-葡糖醛酸转移 酶；ST ，磺基转移酶；Mo-CO，含钼氧化酶 Wieners et al. (2005) Nature Rev Drug Discov 4:825-833 Background 研究意义 代谢稳定性(代谢通路及速率）； 揭示药物（或毒物）的作用机制(如解毒）； 种属差异研究； 前药设计与评价； 结构改造及新药研发 2 Phase II代谢酶  Catalyze both detoxification as well as bioactivation reactions  Generally considered to be “antioxidant” enzymes when reactions catalyzed lead to detoxification.  partly because they remove metabolites capable of causing oxidative stress via redox cycling  Conjugation reactions also detoxify reactive intermediates of phase I reactions  Conjugatin reactions requires the presence of a reactive group (R-OH, R-NH , R-COOH, R-SH, and some others) 2 实 例 Bile Urine Conjugation with phase II enzymes Detoxification Antioxidant