一、药物代谢发展简史解决方案.ppt

浙江大学药学院 曾苏/药物分析与药物代谢研究室 药物大多是外来分子，进入人体后生物体的防御系统必然对这些外源物有所反应。一些药物以原形从人体排泄，然而大多数药物为了易于排泄需要进行结构修饰。这些结构修饰的过程称为“药物代谢”（drug metabolism）, 也称为“生物转化”（biotransformation）。 In the urine eliminated the next morning was found to be unusually acidic, even after being allowed to stand 12 hours after evaporation ...after the residue was mixed with hydrochloric acid and allowed to stand, a large amount of long prismatic brown crystals was formed, which did look like benzoic acid. Another portion, which had been concentrated to a syrupy thickness, formed a magma乳浆状of crystalline plates after being mixed with hydrochloric acid. ...Long, colorless prismatic crystals were then isolated . These crystals consisted of pure hippuric acid. ... As long as I continued to ingest benzoic acid, I could very easily continue to produce quantities of hippuric acid, without any apparent unhealthy effects, so it would be quite easy to produce in such a way great quantities of hippuric acid. . 肝微粒体的制备 肝微粒体是肝细胞经破碎得到的内质网（Endoplasmic reticulum）碎片，主要由脂类及蛋白质构成，可分为粗内质网和平滑内质网 。内质网中的主要酶有： 胆固醇合成酶，甾体水解酶，药物代谢酶，葡萄糖-6-磷酸酶，腺苷三磷酸酶，细胞色素b5还原酶，核苷二磷酸酶，?-D-葡糖苷酸酶等和蛋白质合成。 肝微粒体蛋白质浓度测定（Lowry法） 试管编号 0 1 2 3 4 5 6 标准蛋白质（ml） 0 0.1 0.2 0.3 0.4 0.5 / 微粒体溶液（ml） 0.1 0.9%NaCl（ml） 0.5 0.4 0.3 0.2 0.1 0 0.4 D试剂 （ml） 4.0 4.0 4.0 4.0 4.0 4.0 4.0 左：CYP2C9晶体结构图，右：CYP2C9与华法令形成的复物 Drug Interaction Studies —Study Design, Data Analysis, and Implications for Dosing and Labeling，September 2006 SFDA, 化学药物非临床药代动力学研究技术指导原则,2005 International Society for the Study of Xenobiotics (ISSX) Studying xenobiotics is the vocation of our profession Founded in 1981 2500 members from 50 countries Therapeutic drugs Man-made chemicals Natural products Food consti