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1、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.北京,2,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,3,药物代谢
2、动力学的任务,（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,4,药效,毒理,药代,最佳 血浆浓度,5,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
3、它药物的影响？ drug-drug interaction,6,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 distributi
4、on 从动物代谢推算人体代谢 extrapolation,7,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,8,Efficacy Hits,Optimized Lead Go or no go decision,Compound for Development (CD),NEW DRUG,
5、IND,NDA,R&D,临床实验,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),9,二五原则 5 毫克 5 天,10,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 (s
6、pecies extrapolation),11,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,12,Plasma concentrations of BCH-3840 and its metabolite (BCH-6440) in mice dosed 50 mg/kg
7、 orally,Poor oral bioavailability,13,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,16,Caco-2 Transport Pathways人大肠癌细胞模型,17,Transport
8、 Pathways药物吸收机制,被动,细胞间,主动,P糖蛋白,18,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,19,Glucose （蔗糖） vs Inulin （木香素）主动吸收 vs 细胞间渗透,20,
9、Propranolol vs Mannitol被动吸收 vs 细胞间渗透,21,由P蛋白所调节的药物吸收使用P糖蛋白抑制剂 Verapamil,22,Chong, Dando Pharm. Res. 1997,23,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,24,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
10、- 350 g), fasted overnight. Rat is anesthetized by 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,25,Perfusion Procedures: rat is
11、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 p
12、erfusion 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
13、 (1- Cout / Cin ) Cout / Cin = (Cout / Cin) x phenol red in / phenol red out,in situ rat intestinal perfusion (single pass),26,In situ rat intestinal permeability (single pass),Prediction within 90% interval = 19/31 (61.3%),In-house validation,假阳性,假阴性,27,Plasma concentrations of BCH-3840 and its met
14、abolite (BCH-6440) in mice dosed 50 mg/kg orally,Poor oral bioavailability,28,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,29,In Situ Rat Intestinal Permeabili
15、ty: Good,阳性对照,阴性对照,受试药物,30,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/day168 Bioanalysis: no extraction no standard curve (peak area) machine time/2 LCs24 hrs Total manpower:anim
16、al tech x 1 PKDM tech x 2 Test article amount:1 mg / test article Screening rate:one chemotypes with 30 compounds / 2 weeks,31,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,32,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%,33
