Center for Clinical Research, Department of Pharmacology, Hamamatsu University School of Medicine, Hamamatsu 431-3192, Japan.
Br J Clin Pharmacol. 2010 Sep;70(3):383-92. doi: 10.1111/j.1365-2125.2010.03717.x.
Active metabolism of clopidogrel is mainly mediated by CYP2C19. There are genetic differences in the activity of CYP2C19. Therefore, active metabolism of clopidogrel is affected by CYP2C19 genotypes. The main metabolizing enzyme of proton pump inhibitors (PPIs) is CYP2C19. Therefore, the anti-platelet function of clopidogrel is attenuated by concomitant use of PPIs. There are differences in the metabolic disposition among different PPIs. Affinity to CYP2C19 differs among different PPIs.
Whether a PPI attenuates the efficacy of clopidogrel depends on CYP2C19. Individuals who are decreased metabolizers, i.e. carriers the allele of CYP2C192 and/or 3, are more likely to convert from 'responder' to 'non-responder' to clopidogrel when placed on a concomitant PPI. We found that rabeprazole, whose affinity to CYP2C19 has been considered lower, attenuated the efficacy of clopidogrel. * We tested whether the separate dosing of a PPI and clopidogrel decreased the risk of attenuation of clopidogrel efficacy. We unfortunately found that separate dosing did not avoid the problematic interaction between clopidogrel and a PPI in subject's with CYP2C192 and/or CYP2C193.
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.
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.
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.
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.
氯吡格雷的活性代谢主要由 CYP2C19 介导。CYP2C19 的活性存在遗传差异。因此，氯吡格雷的活性代谢受 CYP2C19 基因型的影响。质子泵抑制剂（PPIs）的主要代谢酶是 CYP2C19。因此，同时使用 PPI 会减弱氯吡格雷的抗血小板功能。不同的 PPI 在代谢处置上存在差异。不同的 PPIs 对 CYP2C19 的亲和力不同。
PPI 是否会减弱氯吡格雷的疗效取决于 CYP2C19。当处于同时使用 PPI 的状态时，代谢能力下降的个体（即携带 CYP2C192 和/或3 等位基因的个体）更有可能从“反应者”转变为“无反应者”。我们发现，其对 CYP2C19 的亲和力被认为较低的雷贝拉唑会减弱氯吡格雷的疗效。我们测试了单独给 PPI 和氯吡格雷给药是否会降低减弱氯吡格雷疗效的风险。不幸的是，我们发现对于 CYP2C192 和/或 CYP2C193 的个体，单独给药并不能避免氯吡格雷和 PPI 之间的问题相互作用。
氯吡格雷的疗效受 CYP2C19 基因型和 CYP2C19 底物（如质子泵抑制剂（PPIs））的影响。我们评估了三种不同的 PPI 对氯吡格雷抗血小板功能的影响与 CYP2C19 基因型状态有关。
39 名具有不同 CYP2C19 基因型的健康志愿者每天早上服用氯吡格雷 75mg，同时服用或不服用奥美拉唑 20mg、兰索拉唑 30mg 或雷贝拉唑 20mg，连续 7 天。测定三种 PPI 对氯吡格雷抗血小板功能的影响。氯吡格雷给药期间血小板聚集抑制率（IPA）小于 30%定义为“低反应者”。我们还检查了奥美拉唑在晚上给药是否可以预防与早上给予的氯吡格雷的相互作用。
在快速代谢者（RMs，1/1，n=15）中，奥美拉唑和雷贝拉唑明显减弱了氯吡格雷的抗血小板功能。在代谢能力下降的个体（DMs，携带2 和/或3，n=24）中，IPA 存在较大差异，同时使用 PPI 时 IPA 呈下降趋势，但无统计学意义。一些 DMs 在同时使用 PPI 时成为“低反应者”。与早上给药相比，RMs 中晚上给予奥美拉唑似乎不会导致 IPA 明显下降，但在 DMs 中会导致 IPA 下降。
三种 PPI 对氯吡格雷的疗效影响程度不同。奥美拉唑和雷贝拉唑均可显著降低 RMs 的 IPA，但不能降低 DMs 的 IPA，尽管 DMs 的 IPA 呈下降趋势。奥美拉唑的早上和晚上给药都会导致 DMs 的 IPA 降低。
