PPI药物代谢机理及临床相互作用.ppt

Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,如何抉择？,PPI,止血,凝血风险,=,死亡,抗凝,Clopidogrel,GI,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 ACS,JAMA 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 ACS,JAMA 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 ACS,JAMA 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 AssocWash).,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,Cytochrome,Mediated,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,O,S,N,OCH,3,H,3,C,H,3,CO,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,CH,3,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,O,S,N,CH,3,H,3,C,H,3,CO,CH,3,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,O,S,N,OCH,3,H,3,CO,HF,2,CO,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,OSO,3,H,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,O,S,N,OCH,3,H,3CO,HF,2,CO,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,奥美拉唑,埃索美拉唑,兰索拉唑,泮托拉唑,雷贝拉唑,雷贝拉唑硫醚,S-C19,美酚妥英,HLM,6.2,(0.8),8.6,(1.0),0.45,(0.007),69.4,(9.2),21.3,(2.8),24,(0.1),4,羟基化,r2C19,2.4,(0.005),7.9,(0.5),0.74,(0.09),15.3,(1.1),18.8,(1.3),2.8,(0.1),R-,奥美拉唑,HLM,NA,NT,1.5,(0.2),17.4,(1.0),16.8,(1.9),3.1,(0.2),5-,羟基化,r2C19,NA,NT,0.91,(0.005),13.9,(0.9),17.3,(1.4),8.3,(0.8),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,奥美,埃索,兰索,潘妥,雷贝,苯妥英,CL,CL,nn,n,安定,CL,CL,n,n,n,安替比林,CL,?,CL,n,?,咖啡因,Conflicting,?,n,n,?,卡马西平,CL,?,?,n,?,环孢霉素,Conflicting,?,?,n,?,口服避孕药,?,?,Conflicting,n,?,氨茶碱,n,?,Conflicting,n,n,乙醇,n,?,n,n,?,华法林,CL,CL,n,n,n,美托洛尔,n,?,?,n,?,合用药物,埃索美拉唑,兰索拉唑,奥美拉唑,泮托拉唑,雷贝拉唑,抗酸药,未知,矛盾的结论,无,44,无,45,无,46,安替比林,未知,消除率,消除率,无,48,未知,咖啡因,未知,无,49,矛盾的结论,无,49,、,51,未知,卡马西平,未知,未知,消除率,无,53,未知,口服避孕药,未知,矛盾的结论,矛盾的结论,无,55,未知,环孢素,未知,未知,矛盾的结论,无,59,未知,安定,消除率,无,64,消除率,无,67,无,a68,双氯芬酸,未知,未知,无,69,无,39,未知,地高辛,未知,未知,吸收,70,无,b,吸收,72,乙醇,未知,无,73,无,73,无,74,未知,格列本脲,未知,未知,未知,无,75,未知,左甲状腺素,未知,未知,未知,无,76,未知,美托洛尔,未知,未知,无,77,无,78,未知,萘普生,未知,未知,无,69,无,79,未知,硝苯地平,未知,未知,吸收消除率,无,c81,未知,苯妥英,消除率,无,40,消除率,无,86,无,87,吡罗昔康,未知,未知,无,69,无,88,未知,他克莫司,未知,消除率,89,未知,无,90,无,89,茶碱,未知,矛盾的结论,无,91,、,93,无,91,、,94,无,95,华法林,未知,无,43,消除率,无,98,无,95,5,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意义的相互作用。泮托拉唑与同时使用的抗酸药也没有相互作用。对泮托拉唑与同时服用的抗生素（,克拉霉素，甲硝唑，阿莫西林,）进行人体动力学研究，未发现有临床意义的相互作用。,潘妥洛克说明书,Egan LJ,Clinical Gastroenterol Hepatol,2004;2:725730.,讨论,2C19,亚型,慢代谢,PM,强代谢,EM,纯合子,EM,杂合子,