质子泵抑制剂与氯吡格雷的药物相互作用解析

近年来,临床研究发现氯吡格雷合用质子泵抑制剂（proton pump inhibitors,PPI）可能会增加急性冠脉综合征（acute coronary syndrome,ACS）或经皮冠状动脉介入（percutaneous coronary intervention,PCI）术后患者心血管不良事件发生的风险,因此,联合用药存在争议。本文从氯吡格雷与CYP2C19多态性、PPI与氯吡格雷在药理及临床作用上的相互影响、相关临床研究来深入解析药物相互作用。药代动力学研究的Meta分析结果显示,PPI可能削弱了氯吡格雷抗血小板的效应。10个临床观察性研究都体现了这个观点,但文献质量偏低,而其余3篇低质量的观察性研究、5篇中等质量的观察性研究和1篇高质量的RCT均未发现氯吡格雷合用PPI会显著增加患者心血管不良事件的发生风险。     

氯吡格雷、质子泵抑制剂、他汀类药物的代谢途径及其相互影响的机制

近年来,越来越多的冠心病患者需要同时服用除抗血小板、调脂、扩血管药物外预防和治疗其他疾病的药物,如质子泵抑制剂.但就这些药物间的相互作用是否有临床意义,尚未达成统一认识.该文应用药理学理论,对他汀类药物和质子泵抑制剂对氯吡格雷代谢的影响进行分析.但药物间的相互作用是复杂的多对体系统,简单地就两种药物的相互作用进行试验、分析是不全面的,结果的实用性也很有限.     

氯吡格雷与质子泵抑制剂的相互作用

氯吡格雷能够降低冠心病患者再次发生心肌梗死的风险,故广泛用于急性冠脉综合征和经皮冠脉介入术后的患者。临床相关指南建议,氯吡格雷应与质子泵抑制剂（proton pump inhibitor,PPI）合用以减少氯吡格雷的胃肠道不良反应。但是,氯吡格雷需经肝脏细胞色素P450酶的同功酶CYP2C19代谢才能转化为活性产物发挥作用,而PPI同样主要由CYP2C19代谢。药代动力学研究显示,氯吡格雷与奥美拉唑合用会发生药物相互作用、由此降低氯吡格雷的抗血小板作用,而泮托拉唑与氯吡格雷的相互作用不明显。发表于2009年的系列回顾性病例对照研究表明,氯吡格雷与PPI合用会增加心血管不良事件的发生风险。但这一研究结果并未得到前瞻性的随机、对照研究和荟萃分析的证实。因此,目前仍需进行大规模的前瞻性的随机、对照试验来分析氯吡格雷和PPI合用与心血管不良事件风险间的相关性。鉴于临床上有大量服用氯吡格雷的患者需合用PPI来降低胃肠道出血风险,建议现最好选用与氯吡格雷相互作用较小的泮托拉唑。     

分析氯吡格雷与质子泵抑制剂的相互作用

目的总结氯吡格雷与质子泵抑制剂的相互作用。方法分析并总结相关研究文献,对氯吡格雷与质子泵抑制剂的相互作用进行阐述。结果与结论氯吡格雷联合阿司匹林能强化抗血小板作用,降低心血管事件发生率,是目前冠状动脉介入术(PCI)后标准的抗血小板治疗方案[1]。但双联抗血小板治疗常引起胃肠道不适,甚至可能增加出血风险。临床常通过合用质子泵抑制剂来预防上消化道出血的发生。近年来,关于质子泵抑制剂对抗血小板治疗的拮抗作用,以及这种拮抗作用能否明显增加PCI后不良心血管事件的发生,成为心血管医师研究的热点。     

氯吡格雷与质子泵抑制剂是非曲折的这些年

氯吡格雷是噻吩类血小板聚集抑制剂。氯吡格雷本身不具有抗血小板活性,但它能通过在肝脏内的CYP450酶系（主要是CYP2C19）氧化水解成活性代谢产物产生抗血小板作用。而质子泵抑制剂（PPIs）在肝脏中氧化代谢也是由CYP450酶系（主要是CYP2C19、CYP3A4）催化。由于二者代谢都通过CYP2C19酶,所以理论上同时使用氯吡格雷和PPIs会产生竞争性抑制。     

氯吡格雷与质子泵抑制剂合用易增加副作用

最新研究表明,将质子泵抑制剂（PPIs）与血小板聚集抑制剂氯吡格雷（商品名：波立维）合用于急性冠脉综合征（ACS）时,不但会降低血小板聚集抑制剂的疗效,而且会增加不良反应发生的风险。这一研究结果发表在2009年3月4日的JAMA杂志上。该发现虽然是基于回顾性分析结果,但由于PPIs常被用来降低那些为减少心血管事件的复发率而接受氯吡格雷和阿司匹林双重抗血小板聚集治疗的患者胃肠道出血的风险,从而可能影响到PPIs在这些人群中的使用。     

氯吡格雷与质子泵抑制剂相互作用的研究进展

急性冠状动脉综合征患者被推荐服用氯吡格雷时合用质子泵抑制剂(PPIs),以降低患者胃肠道出血的发生率。近年来有些学者关注氯吡格雷与PPIs之间的相互作用,众多研究的结论也是矛盾的,因此给服用氯吡格雷的患者开PPIs处方之前,强化消化道出血风险及心血管风险的个体化危险评估仍是非常必要的。     

氯吡格雷与质子泵抑制剂合用对亚急性支架内血栓形成的影响

目的探讨氯吡格雷与质子泵抑制剂(PPIs)合用对PCI术后1个月内亚急性支架内血栓形成的影响。方法观察6 209例PCI术后接受氯吡格雷治疗的患者,分为使用PPIs组(1 182例)及未使用PPIs组(5 027例)。比较两组PCI术后1个月内亚急性支架内血栓发生情况,分析氯吡格雷与PPIs合用对亚急性支架内血栓形成的影响。结果两组患者的一般资料、相关检查化验、合并用药及冠脉病变等比较差异无统计学意义(P>0.05)。发生亚急性支架内血栓形成情况:未使用PPIs组34例(0.68%),使用PPIs组4例(0.37%),两组比较差异无统计学意义(χ2=1.797,P=0.18)。结论 PCI术后1个月内接受氯吡格雷联合PPIs治疗,未观察到有增加亚急性支架内血栓形成的风险。     

北京医院老年患者质子泵抑制剂与氯吡格雷合用情况调查分析

目的 :调查并评价北京医院老年患者氯吡格雷与质子泵抑制剂合用现状。方法:检索北京医院治疗药物监测系统,查阅2012年1月至2016年12月的合用氯吡格雷和质子泵抑制剂的老年住院患者(≥65岁),对病例进行系统的回顾性分析,并对调查结果进行统计分析。结果:共纳入患者6 376例,其中男性3 619例(56.8%),女性2 757例(43.2%);平均年龄(77.2±6.8)岁。患者分布在33个科室,主要集中在心血管科(包括心内科,心外科和心血管重症监护室),占49.5%。氯吡格雷与5种质子泵抑制剂均有联用,合用例数排序为艾司奥美拉唑>泮托拉唑>奥美拉唑>兰索拉唑>雷贝拉唑;合理联用的总比例为39.2%。结论:尽管北京医院老年患者氯吡格雷与质子泵抑制剂合理联用的比例呈上升趋势,但总合理联用率仍偏低,且各科室差异较大,需要进一步规范。     

经CYP3A4代谢的他汀类药物对氯吡格雷抗血小板作用影响的系统评价

目的系统评价经CYP3A4代谢的他汀类药物对氯吡格雷抗血小板作用的影响。方法检索Cochrane图书馆、PubMed、Embase、SCI数据库和中国生物医学文献数据库(CBM)、维普中文科技期刊数据库(VIP)、中国期刊全文数据库(CNKI),对纳入的随机对照试验(RCT)进行质量评价,采用RevMan 5.1软件对满足纳入标准的有关他汀类药物对氯吡格雷抗血小板作用的RCT研究进行Meta分析。选取最大血小板聚集率(MPAR)等作为观察指标,得出合并后的均数差值(MD)及其95%可信区间(CI)进行定量综合评估。结果共检索出1 511篇文献,符合标准的14篇RCTs研究进入Meta分析,结果显示不同他汀类药物联用氯吡格雷的主要心脑血管缺血事件组间无显著差异[RR=0.73,95%CI(0.47,1.12),P=0.15]。MPAR组间亦无显著差异[MD=0.04,95%CI(-1.26,1.35),P=0.95]。血小板颗粒膜糖蛋白CD62P表达组间差异不显著(P=0.31)。结论经CYP3A4途径代谢的阿托伐他汀并不影响氯吡格雷的抗血小板作用。     

质子泵抑制药药动学的研究进展

质子泵抑制药(PPIs)是临床中主要的抑酸药,奥美拉唑、埃索美拉唑、兰索拉唑、泮托拉唑、雷贝拉唑等PPIs在药动学方面存在很大的差异(如生物利用度、代谢型、药物的相互作用、生物特异性等方面)。近年来,有很多文献报道了P450酶(CYP)代谢对PPIs的药动学影响。临床证据证明PPIs安全有效,但仍有很多患者对PPIs耐药,所以在实践中应该选择性应用PPIs。     

Effects of drug interactions on biotransformation and antiplatelet effect of clopidogrel in vitro

BACKGROUND AND PURPOSE

The conversion of clopidogrel to its active metabolite, R-130964, is a two-step cytochrome P450 (CYP)-dependent process. The current investigations were performed to characterize in vitro the effects of different CYP inhibitors on the biotransformation and on the antiplatelet effect of clopidogrel.

EXPERIMENTAL APPROACH

Clopidogrel biotransformation was studied using human liver microsomes (HLM) or specific CYPs and platelet aggregation using human platelets activated with ADP.

KEY RESULTS

Experiments using HLM or specific CYPs (3A4, 2C19) revealed that at clopidogrel concentrations >10 µM, CYP3A4 was primarily responsible for clopidogrel biotransformation. At a clopidogrel concentration of 40 µM, ketoconazole showed the strongest inhibitory effect on clopidogrel biotransformation and clopidogrel-associated inhibition of platelet aggregation with IC₅₀ values of 0.03 ± 0.07 µM and 0.55 ± 0.06 µM respectively. Clarithromycin, another CYP3A4 inhibitor, impaired clopidogrel biotransformation and antiplatelet activity almost as effectively as ketoconazole. The CYP3A4 substrates atorvastatin and simvastatin both inhibited clopidogrel biotransformation and antiplatelet activity, less potently than ketoconazole. In contrast, pravastatin showed no inhibitory effect. As clopidogrel itself inhibited CYP2C19 at concentrations >10 µM, the CYP2C19 inhibitor lansozprazole affected clopidogrel biotransformation only at clopidogrel concentrations ≤10 µM. The carboxylate metabolite of clopidogrel was not a CYP substrate and did not affect platelet aggregation.

CONCLUSIONS AND IMPLICATIONS

At clopidogrel concentrations >10 µM, CYP3A4 is mainly responsible for clopidogrel biotransformation, whereas CYP2C19 contributes only at clopidogrel concentrations ≤10 µM. CYP2C19 inhibition by clopidogrel at concentrations >10 µM may explain the conflicting results between in vitro and in vivo investigations regarding drug interactions with clopidogrel.     

Influences of different proton pump inhibitors on the anti-platelet function of clopidogrel in relation to CYP2C19 genotypes

AIMS

The efficacy of clopidogrel is influenced by CYP2C19 genotypes and substrates of CYP2C19, such as proton pump inhibitors (PPIs). We assessed the influence of three different PPIs on the anti-platelet function of clopidogrel in relation to CYP2C19 genotype status.

METHODS

Thirty-nine healthy volunteers with different CYP2C19 genotypes took clopidogrel 75 mg with or without omeprazole 20 mg, lansoprazole 30 mg or rabeprazole 20 mg in the morning for 7 days. The influence of the three PPIs on the anti-platelet function of clopidogrel was determined. A less than 30% inhibition of platelet aggregation (IPA) during clopidogrel dosing was defined as a ‘low responder’. We also examined whether evening dosing of omeprazole could prevent the interaction with clopidogrel dosed in the morning.

RESULTS

In rapid metabolizers (RMs, *1/*1, n = 15) of CYP2C19, omeprazole and rabeprazole significantly attenuated the anti-platelet function of clopidogrel. In decreased metabolizers (DMs, carriers of *2 and/or *3, n = 24), there was a large variation in IPA and there was a trend but no significant decrease in IPA when placed on a concomitant PPI. Some DMs became ‘low-responders’ when placed on a concomitant PPI. Evening omeprazole dose in RMs did not seem to cause a significant decrease in IPA in contrast to morning dosing, but did so in DMs.

CONCLUSIONS

The three PPIs affected the efficacy of clopidogrel to different degrees. Both omeprazole and rabeprazole significantly decreased IPA in RMs but not DMs, although there was a trend towards lower IPA in DMs. Morning and evening dosing of omeprazole were both associated with lower IPA in DMs.     

雷公藤活性成分对大鼠体内P450酶活性的影响

目的用Cocktail探针药物法,研究雷公藤片对大鼠肝CYP450的影响。方法分别以奥美拉唑和咪达唑仑作为CYP2C19和CYP3A4的探针药,将大鼠随机分为低剂量和高剂量两组,每日早晚灌胃雷公藤片,采用液质联用法测定连续使用雷公藤片前后大鼠血浆中相应的探针药物的浓度及其药代动力学参数。结果连续灌胃10 d后,与用药前比较,奥美拉唑、咪达唑仑的血药浓度及其药代动力学参数有明显改变;低剂量组和高剂量组中咪达唑仑的AUC明显增加,CL/F明显降低,T12增大,Vd/F和Tmax变化不明显,高剂量组中Cmax有所增大;低剂量组中奥美拉唑的T21和Vd/F有所增大,高剂量组中AUC增加(P<0.05)。结论连续灌胃雷公藤片10 d后,雷公藤片对大鼠体内CYP3A4酶具有抑制作用;对CYP2C19酶具有一定的抑制作用。     

CYP2C9、CYP2C19、CYP3A4基因多态性对磺脲类降糖药代谢的影响

磺脲类口服降糖药在人体内主要经过肝脏代谢。肝脏中的细胞色素氧化酶P450是一种重要的药物代谢酶系统,在人群中存在基因多态性,导致药物疗效和不良反应在个体间存在着较大的差异。本文将对CYP450中的几种重要的代谢酶亚型CYP2C9、CYP2C19、CYP3A4的基本结构、基因多态性、种族差异及其对磺脲类降糖药代谢的影响作一综述。     

细胞色素P450的工具药选择及种属差异的研究进展

药物对代谢酶的影响以及代谢产生的药物相互作用与药物安全性密切相关。细胞色素P450(CYP)是参与内、外源性化合物I相代谢反应的重要超家族酶系。特异性探针、诱导剂、抑制剂以及实验动物模型广泛应用于CYP介导的代谢途径以及药物相互作用研究。已知CYP底物存在明显重叠性,且表达调控机制种属差异显著,故研究中选择适当的实验动物以及特异性的探针、诱导剂和抑制剂,成为影响数据外推的关键问题。本文简要综述了CYP1A2,CYP2C9,CYP2C19,CYP2D6,CYP3A4/5的常用体内外探针、诱导剂、抑制剂以及动物种属表达调控的差异。     

Effect of CYP2C19*2 and *17 mutations on pharmacodynamics and kinetics of proton pump inhibitors in Caucasians

AIMS

To investigate the impact of CYP2C19 mutations *2-*6 and *17 on acid-inhibition and pharmacokinetics of lansoprazole (L15), omeprazole (O10, O20) and pantoprazole (P40) in Caucasians.

METHODS

CYP2C19 genotyping for *2–*6 and *17 mutations was assessed in subjects who were H. pylori negative in two randomized crossover trials. The influence of CYP2C19 mutations on single and repeated administration of L15 and O10 (study A) and O20 and P40 (study B) was investigated. Pharmacokinetics and the cumulative percentage of time with intragastric pH above 4 (% > pH 4) were assessed on day 1 and 6.

RESULTS

For study A CYP2C19 genotyping found five *1/*1, four *1/*2, one *1/*17 and one *2/*17. For study B the results were six *1/*1, two *1/*2, six *1/*17, one *2/*2 and one *2/*17. For all PPIs AUC was highest in *2/*2 and lowest in *1/*17. On day 1, all PPIs significantly increased percentage >pH 4 compared with baseline. *1/*1 genotype showed no significant acid-inhibition after L15, O10 and O20. *1/*17 genotype showed no significant acid-inhibition after O20 and P40. *1/*2 genotype showed significant acid-inhibition after L15 and O10. On day 6, all four PPIs showed significantly increased acid-inhibition. *1/*1 and *1/*17 showed a significantly increased percentage > pH 4 after treatment with O20 and P40. However, in *1/*1 subjects percentage > pH 4 was not significantly increased after L15 and O10. *1/*2 genotype showed a significant acid-inhibitory effect after repeated dosing with L15 and O10.

CONCLUSIONS

Caucasian subjects with *1/*1 and *1/*17 genotype need stronger acid-suppression therapy, especially during the first days of treatment or with on-demand therapy.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• The influence of CYP2C19 on the kinetics and dynamics of omeprazole, lansoprazole and rabeprazole has been studied in Japanese subjects.
• It has been suggested that subjects with *1/*1 genotype might need stronger acid suppression than *1/*2 and *2/*2 subjects. This suggestion comes from data in Japanese subjects and has not been confirmed in Caucasians.
• Furthermore, a novel CYP2C19 mutation, *17, which mainly occurs in Caucasians has been discovered. This mutation has been associated with clinical failure, but its relevance for therapy with PPIs has not been studied yet.

WHAT THIS STUDY ADDS

• In this study, the influence of CYP2C19 on both the pharmacokinetics and dynamics in Caucasian subjects after single and repeated dosing has been investigated.
• This is the first study showing that Caucasian subjects with *1/*1 and *1/*17 mutations need stronger acid-inhibition. In this study three proton pump inhibitors (omeprazole, lansoprazole and pantoprazole, in different doses) were studied of which pantoprazole had not been studied before in this setting, not even in Japanese.

     

盐酸小檗碱对大鼠肝微粒体细胞色素P450酶含量及活性的影响

目的考察盐酸小檗碱对大鼠肝微粒体的蛋白含量、CYP450酶总量和主要CYP450酶亚型(CYP1A2、CYP2D6、CYP3A4和CYP2C19)活性的影响。方法以溶剂为空白对照灌胃给予盐酸小檗碱250 mg/(kg·d),连续7 d,测定其肝微粒体蛋白含量、CYP450蛋白含量以及CYP1A2、CYP2D6、CYP3A4和CYP2C19活性。结果与空白对照组比较,盐酸小檗碱给药组大鼠肝微粒体蛋白含量及肝微粒体CYP450含量无明显差异(P>0.05)。盐酸小檗碱给药后,给药组大鼠的平均CYP3A4活性是空白对照组的1/2;而两组之间CYP1A2、CYP2D6和CYP2C19的活性相当。结论盐酸小檗碱对大鼠CYP3A4活性有一定抑制作用,对CYP1A2、CYP2D6和CYP2C19的活性没有影响。