Influences of different proton pump inhibitors on the anti-platelet function of clopidogrel in relation to CYP2C19 genotypes
Influences of different proton pump inhibitors on the anti-platelet function of clopidogrel in relation to CYP2C19 genotypes
复制标题
DOI：
10.1111/j.1365-2125.2010.03717.x
复制
发表时间：
2010-09-01
影响因子：
3.4
通讯作者：
Umemura, Kazuo
中科院分区：
文献类型：
--
作者：
Furuta, Takahisa;Iwaki, Takayuki;Umemura, Kazuo
中心点氯吡格雷的活性代谢主要由CYP 2C 19介导。CYP 2C 19的活性存在遗传差异。因此，氯吡格雷的活性代谢受CYP 2C 19的影响。质子泵抑制剂（PPI）的主要代谢酶是CYP 2C 19。genotypes.center因此，合并使用PPIs.center dot可减弱氯吡格雷的抗血小板功能。不同PPI之间的代谢分布存在差异。不同的PPI与CYP 2C 19的亲和力不同。本研究补充的内容PPI是否减弱氯吡格雷的疗效取决于CYP 2C 19。代谢减少的个体，即携带CYP 2C 19 *2和/或 *3等位基因的个体，在接受伴随治疗时更有可能从氯吡格雷的“应答者"转变为”非应答者“。我们发现，与CYP 2C 19的亲和力被认为较低的雷贝拉唑减弱了clopidogrel.center的疗效。我们测试了PPI和氯吡格雷单独给药是否降低了氯吡格雷疗效减弱的风险。PPI.center不幸的是，我们发现单独给药并不能避免氯吡格雷和质子泵抑制剂（PPI）在CYP 2C 19 *2和/或CYP 2C 19 * 3受试者中的相互作用。目的氯吡格雷的疗效受CYP 2C 19基因型和CYP 2C 19底物（如质子泵抑制剂（PPI））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CYP 2C 19基因型status. METHODSThirt-nine不同CYP 2C 19基因型的健康志愿者服用氯吡格雷75 mg或不服用奥美拉唑20 mg，兰索拉唑30 mg或雷贝拉唑20 mg在早晨7天。测定三种PPI对氯吡格雷抗血小板功能的影响。在氯吡格雷给药期间，血小板聚集（IPA）抑制低于30%被定义为“低应答者”。我们还研究了晚上给药奥美拉唑是否可以防止与早上给药的氯吡格雷的相互作用。在CYP 2C 19的快速代谢者（RM，*1/*1，n = 15）中，奥美拉唑和雷贝拉唑显著减弱氯吡格雷的抗血小板功能。在代谢减少者（DM，*2和/或 *3携带者，n = 24）中，IPA存在较大变化，当与PPI合并使用时，IPA存在趋势但无显著降低。一些DM在接受伴随PPI治疗时变为“低应答者”。晚上奥美拉唑剂量在RM似乎并没有引起显着降低IPA在上午的剂量，但这样做在DMs.CONCLUSIONSThe三个PPI影响氯吡格雷的疗效不同程度。奥美拉唑和雷贝拉唑均显著降低了RM中的IPA，但对DM无影响，尽管DM中的IPA有降低的趋势。奥美拉唑早晨和晚上给药均与DM中IPA较低相关。
center dot 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.center dot 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.center dot There are differences in the metabolic disposition among different PPIs. Affinity to CYP2C19 differs among different PPIs.WHAT THIS STUDY ADDScenter dot Whether a PPI attenuates the efficacy of clopidogrel depends on CYP2C19. Individuals who are decreased metabolizers, i.e. carriers the allele of CYP2C19 *2 and/or *3, are more likely to convert from 'responder' to 'non-responder' to clopidogrel when placed on a concomitant PPI.center dot We found that rabeprazole, whose affinity to CYP2C19 has been considered lower, attenuated the efficacy of clopidogrel.center dot 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 CYP2C19 *2 and/or CYP2C19 *3.AIMSThe 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.METHODSThirty-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.RESULTSIn 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.CONCLUSIONSThe 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.