PPI药物代谢机理及临床相互作用

如何抉择？,PPI 止血 凝血风险=死亡抗凝 ClopidogrelGI出血=死亡,心内科,消化科,最近的一个热点问题,急性冠脉综合征患者在合并使用波利维和PPI的不良转归风险,在服用氯吡格雷的8205出院患者中，有63.9%(5244人)服用氯吡格雷和PPI，有36.1%（615人）单独服用氯吡格雷。单独用药的不良转归率为20.8%，合并用药的不良转归率为29.8%。,Risk of Adverse Outcomes Associated With Concomitant Use of Clopidogrel and PPI Following ACSJAMA 2009;301(9):937-944(doi: 10,1001/JAMA2009,261),Cumulative Risk of All-Cause Mortality and Recurrent ACS Among Patients Taking Clopidogrel After Hospital Discharge for ACS and Prescribed a PPI at Hospital Discharge or During Follow-up (n=5244),POINTS,PPI 好心办坏事,变量分析显示，合并使用PPI与单独使用氯吡格雷，前者会增加ACS患者的不良转归（死亡或重新入院）【校正风险1.25倍，95%可信区间：1.11-1.41】,Risk of Adverse Outcomes Associated With Concomitant Use of Clopidogrel and PPI Following ACSJAMA 2009;301(9):937-944(doi: 10,1001/JAMA2009,261),结论：在ACS出院患者中，合并使用PPI+氯吡格雷比不使用PPI而只用氯吡格雷会引发更高的不良转归风险，提示PPI的合并使用与减弱氯吡格雷对ACS的疗效有一定关系。,Risk of Adverse Outcomes Associated With Concomitant Use of Clopidogrel and PPI Following ACSJAMA 2009;301(9):937-944(doi: 10,1001/JAMA2009,261),POINTS,PPI与安慰剂风险对比,Gilard M et al. J Thromb Haemost 2006;4(11):25082509. Gilard M et al. JACC 2008;51:256260.,血小板再活化指数 (PRI),Placebo,奥美拉唑,100 80 60 40 20 0,Mean PRI Day 7,Regimens: OME + Clopid + ASA Placebo + Clopid + ASA,p 3A4 埃索美拉唑: 3A4 C19兰索拉唑: 2C19 and 3A4泮托拉唑: 2C19, 3A4, 及2相代谢，通过硫酸及葡萄糖醛酸结合形成代谢产物雷贝拉唑: 转化为硫醚前为非酶代谢， 2C19, 3A4，雷贝拉唑硫醚通过2C19代谢CYP2C19 呈现基因多态性立体选择性代谢,Welage LS, Berardi RR. J Am Pharm Assoc (Wash). 2000;40:5262.Spencer CM, Faulds D. Drugs. 2000;60:321329.,PPIs的代谢途径,Ishizaki T et al. Aliment Pharmacol Ther. 1999;13:27-36. Product labeling of esomeprazole (Astra Zeneca).,雷贝拉唑,2C19,3A4,Not CytochromeMediated,demethylated,thioether,sulfone,奥美拉唑,2C19,3A4,3A4,2C19,sulfone,5-hydroxy,3-hydroxy,5-O-desmethyl,2C19,3A4,demethylated,sulfone,兰索拉唑,2C19,3A4,sulfone,hydroxy,2C19 (Major),埃索美拉唑,3A4 (Remaining),sulfone,Hydroxy and desmethyl,85.5%,90%,50%,73%,10%,潘妥拉唑,OS,N,OCH3,H3C,H3CO,经由CYP3A4降解/氧化,经由CYP2C19 及 CYP3A4 (极少)羟基化,经由CYP2C19 及 CYP2D6 (极少)O-反甲基化,CH3,I 相代谢,N,N,O=S=O,OH,OH,人体内奥美拉唑的代谢,Maton PN and Burton ME. Clinicians Manual on Drug Interactions in Gastroenterology. London: Life Sciences Communications Ltd, 1996,OS,N,CH3,H3C,H3CO,CH3,N,N,I 相系统,代谢物,联合用药(如安定),人体内奥美拉唑的代谢,Maton PN and Burton ME. Clinicians Manual on Drug Interactions in Gastroenterology. London: Life Sciences Communications Ltd, 1996,无II 相系统可用,OS,N,OCH3,H3CO,HF2CO,经由CYP3A4降解/氧化,经由CYP2C19脱烷,I 相代谢,II 相代谢,结合反应,N,N,O=S=O,OH,OSO3H,人体内泮托拉唑代谢,Maton PN and Burton ME. Clinicians Manual on Drug Interactions in Gastroenterology. London: Life Sciences Communications Ltd, 1996,II 相系统,OS,N,OCH3,H3CO,HF2CO,N,N,I 相系统,联合用药(如安定),代谢物,人体内泮托拉唑代谢,Maton PN and Burton ME. Clinicians Manual on Drug Interactions in Gastroenterology. London: Life Sciences Communications Ltd, 1996,PPI对CYP2C19的抑制作用,Data are presented as mean Ki M (+/- STD),Ki（表观抑制常数）的倒数提示药物相互作用潜在可能Ki值越大说明药物相互作用潜在可能性越小,Li XQ, et al. Drug Met Disp 2004;32(8):821-827,联合用药时与细胞色素 P450 系统的相互作用,Adapted from Blume H, et al. Drug Safety 2006; 29(9): 769-84.; Welage LS, Berardi RR. J Am Pharm Assoc (Wash). 200C0;40:5262; Andersson T. Clin Pharmacokinet 2001;40:523537., No interaction? No data CL Clearance,5种PPI药物相互作用概要,本品可能减少生物利用度取决于胃内pH值的药物（如酮康唑）的吸收。请注意，这也适用于口服本品之前的短暂时间内所应用的药物。泮托拉唑的活性成份在肝脏内通过细胞色素P450酶系代谢，因此凡通过该酶系代谢的其它药物均不能除外与之有相互作用的可能性。然而对许多这类药物进行专门检测，如卡马西平、咖啡因、安定、双氯芬酸、地高辛、乙醇、格列本脲、美托洛尔、萘普生、硝苯地平、苯丙香豆素、苯妥英、吡罗昔康、茶碱、华法林和口服避孕药等，却未观察到泮托拉唑与之有明显临床