药物代谢介绍与其动力学在新药研发中应用.pptVIP

药物代谢介绍和其动力学在新药研发中的应用;;药物代谢动力学的任务;药效;;;;;二五原则 5 毫克 5 天;临床前实验药物代谢动力学的生物模型 体外和离体模型 (in vitro / in situ models) 吸收模型 absorption/permeability 代谢模型 metabolism 体外推测和体内 (in vitro / in vivo correlation) 动物模型 (in vivo animal models) 动物推测人 (species extrapolation);排出太快/药效时间太短;Plasma concentrations of BCH-3840 and its metabolite (BCH-6440) in mice dosed 50 mg/kg orally;药物吸收模型 ;absorption/distribution model 脂层转移模型;in vitro absorption/distribution model;Caco-2 Transport Pathways人大肠癌细胞模型;;;;;;Chong, Dando Morrison; Pharm. Res. 1997;False Positive 假阳性 ＝ 低;in situ rat intestinal perfusion (single pass) 离体大鼠十二指肠灌流模型（单循环）;Perfusion Procedures: rat is put on a heating pad to maintain body temperature jejunum is exposed via a middle line incision sutures: 1st is made at 5 cm distal to the ligament of Treitz 2nd is made at about 20 cm distal to 1st one the inlet of cannula - a syringe infusion pump the outlet of cannula - a fraction collector the perfusion segment is precleaned by passing 10 ml of blank perfusate buffer perfusion time and rate = 0.1 ml/min for 120 min outlet perfusion samples are collected every 10 min plasma samples are collected at 30, 60, 90 and 120 min after perfusion Calculations: Permeability (Peff, cm/min) = (Q/2RLp) x (1- C’out / C’in ) C’out / C’in = (Cout / Cin) x [ phenol red ] in / [ phenol red ] out;In situ rat intestinal permeability (single pass);Plasma concentrations of BCH-3840 and its metabolite (BCH-6440) in mice dosed 50 mg/kg orally;排出太快/药效时间太短;;Enhanced Throughput Screening Perfusion: 4 compounds per day (4 animals) Sample size: time points 7 duplicate x 2 control/drug x 3 sample/perfusion 42 Total samples/day 168 Bioanalysis: no extraction no standard curve (peak area) machine time/2 LCs 24 hrs Total manpower: animal tech x 1 PKDM tech x 2 Test article amount: 1 mg / test article Screening rate: one chemotypes with 30 compounds / 2 weeks ;pKa = 10 pKa = 8.4 pKa