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1、药物代谢及其动力学在新药研发中的应用,胡卓汉 博士 瑞德肝脏疾病研究(上海)有限公司 复旦大学药学院,2004年12月30日 中国.北京,Efficacy Hits,Optimized Lead Go or no go decision,Compound for Development (CD),NEW DRUG,IND,NDA,R&D,临床实验,临床前实验,研究和发现,药物研发的三大任务 药效 Efficacy/ Pharmacodynamics 安全 Safety / Toxicology 药物代谢动力学 Drug Metabolism/Pharmcokinetics,药物代谢动力学的任务
2、,（最大无毒性浓度）,(最小有效浓度）,(最小药效时间）,血浆浓度,时间,药效,毒理,药代,最佳 血浆浓度,Efficacy Hits,Optimized Lead Go or no go decision,Compound for Development (CD),NEW DRUG,IND,NDA,R&D,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？ dr
3、ug-drug interaction,Efficacy Hits,Optimized Lead Go or no go decision,Compound for Development (CD),NEW DRUG,IND,NDA,R&D,临床实验,临床前实验,研究和发现,临床前阶段 生物利用度 bioavailability 血浆浓度的线性和非线性 dose escalation & proportionality 多次给药和体内积蓄 multiple doses & accumulation 吸收和排泄模式 mass balance 体内分布 distribution 从动物代谢推算人体
4、代谢 extrapolation,Efficacy Hits,Optimized Lead Go or no go decision,Compound for Development (CD),NEW DRUG,IND,NDA,R&D,临床实验,临床前实验,研究和发现,临床阶段 长期毒性实验的动物选择 metabolism profiling in animals and humans,Efficacy Hits,Optimized Lead Go or no go decision,Compound for Development (CD),NEW DRUG,IND,NDA,R&D,临床实验
5、,临床前实验,研究和发现,临床实验准则 Good Clinical Practice (GCP),非临床实验准则 Good Laboratory Practice (GLP),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)
6、,排出太快/药效时间太短,口服吸收差/血浆浓度太低,分布,排泻,代谢问题,吸收问题,蛋白质相互作用,分布体积,肾脏排泄,肝脏代谢,溶解度,肠道吸收膜通透性,肠道消化,早期研发阶段,后期研发阶段,Situation Analysis,in vitro体外 metabolism,in situ离体 permeability,in vivo体内 bioavailability,Plasma concentrations of BCH-3840 and its metabolite (BCH-6440) in mice dosed 50 mg/kg orally,Poor oral bioavaila
7、bility,药物吸收模型,计算机,脂溶度,脂层转移,细胞层转移,十二指肠灌流,14,absorption/distribution model 脂层转移模型,水相 Aqueous phase,水相 Aqueous phase,有机相 Organic phase,pH=6.5,pH=7.4,Permeability Evaluation in vitro,15,in vitro absorption/distribution model,Caco-2 Transport Pathways 人大肠癌细胞模型,Transport Pathways 药物吸收机制,被动,细胞间,主动,P糖蛋白,Pro
8、bes 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
9、蛋白所调节的药物吸收 使用P糖蛋白抑制剂 Verapamil,Chong, Dando Pharm. Res. 1997,False Positive 假阳性 低,False Negative 假阴性 高,Caco-2 Transport Pathways 人大肠癌细胞吸收模型,in situ rat intestinal perfusion (single pass) 离体大鼠十二指肠灌流模型（单循环）,METHOD Animal: Male Sprague-Dawley rats (250 - 350 g), fasted overnight. Rat is anesthetized by
10、 urethane 1.5g/kg, im. before perfusion starts. Perfusate: Phosphate buffer, pH = 6.5 10 mM glucose Phenol red (negative control) Acetaminophen (positive control) Final concentrations of test article = 0.05-0.30 mg/mL,Perfusion Procedures: rat is put on a heating pad to maintain body temperature jej
11、unum 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 bl
12、ank 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- Cout / Cin ) Cout / Cin = (Cout / Cin) x phenol
13、red in / phenol red out,in situ rat intestinal perfusion (single pass),In situ rat intestinal permeability (single pass),Prediction within 90% interval = 19/31 (61.3%),In-house validation,假阳性,假阴性,Plasma concentrations of BCH-3840 and its metabolite (BCH-6440) in mice dosed 50 mg/kg orally,Poor oral
14、bioavailability,排出太快/药效时间太短,口服吸收差/血浆浓度太低,分布,排泻,代谢问题,吸收问题,蛋白质相互作用,分布体积,肾脏排泄,肝脏代谢,溶解度,肠道吸收膜通透性,肠道消化,早期研发阶段,后期研发阶段,Situation Analysis,in vitro体外 metabolism,in situ离体 permeability,in vivo体内 bioavailability,In Situ Rat Intestinal Permeability: Good,阳性对照,阴性对照,受试药物,Enhanced Throughput Screening Perfusion:
15、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 articl
16、e Screening rate: one chemotypes with 30 compounds / 2 weeks,pKa = 10 pKa = 8.4 pKa = 6.5 Preduced%= 0% Preduced%= 7% Preduced%= 12%,SAR: pKa vs. permeability 实例：结构优化和吸收率分析,SAR: permeability vs. efficacy 实例：结构优化和吸收率和活性的分析,IC50 = 2 uM Preduced%= 0%,IC50 = 0.012 uM Preduced%= 0%,IC50 = 1.1 uM Preduced%= 17%,IC50 = 0.025 uM Preduced%= 15%,小结：体外和离体药物吸收实验系统 体外人大肠癌细胞模型 (in vitro Caco-
