《复旦大学药物代谢及其动力学在新药研发中的应用》.pptVIP

Transport Pathways药物吸收机制 Probes for Transport Pathways肠道吸收标准对照药物 Transcellular （被动吸收） Propranolol, Testosterone Paracellular （细胞间渗透） Mannitol, Inulin Carrier mediated （主动吸收） Glucose P-Glycoprotein mediated （P－糖蛋白调节） 底物 Vinblastine 抑制物 Verapamil Glucose （蔗糖） vs Inulin （木香素）主动吸收 vs 细胞间渗透 Propranolol vs Mannitol被动吸收 vs 细胞间渗透 由P－蛋白所调节的药物吸收－使用P－糖蛋白抑制剂 Verapamil In Vitro Models of the Liver体外肝模型 Hepatocytes 肝细胞 Liver slices 肝切片 Liver microsomes 肝微粒体 Liver S-9 Fraction 肝S-9组分 USFDA Guidance for Industry美国药物和食品管理局关于药物代谢实验的指南 HPLC profiles of BCH-3840 and its metabolite (BCH-6440) BCH-3840 metabolite? In vitro metabolic stability by rat hepatic S9 Efficacy Hits Optimized Lead Go or no go decision Compound for Development (CD) NEW DRUG IND NDA RD 临床实验 临床前实验 研究和发现 研究和发现阶段 能否被吸收？ permeability 是否被代谢？ metabolic stability 代谢产物？ metabolite identification 代谢途径？ pathway identification 对其它药物的影响？ drug-drug interaction Liquid Chromatography / Mass Spectrum of BCH-3840 and its metabolite (BCH-6440) Hydroxylation or Oxidation MH+ = 310 MH+ = 294 Mass Identification HPLC profiles of BCH-3840 and its metabolite (BCH-6440) Preparation of metabolite by bulk incubation M M P P 10 mg microsomal protein 2 mg BCH-3840 Fraction collection of metabolite fractionation concentration Nuclear Magnetic Resonance profiles of BCH-3840 and its metabolite (BCH-6440) C5-H BCH-3840 Metabolite Structure Elucidation In vitro therapeutic index of BCH-6440 Efficacy Hits Optimized Lead Go or no go decision Compound for Development (CD) NEW DRUG IND NDA RD 临床实验 临床前实验 研究和发现 研究和发现阶段 能否被吸收？ permeability 是否被代谢？ metabolic stability 代谢产物？ metabolite identification 代谢途径？ pathway identification 对其它药物的影响？ drug-drug interaction Inhibitors for CYP Isoform Conc (mM) Furafulline (CYP1A2) 10 Tranylcypromine (CYP2A6) 50 Sulfaphenazole (CYP2C9) 25 Omeprazole (CYP2C19) 20 Quinidine (CYP2D6) 2 4-methylpyrazole (CYP2E