Cytochrome P450 Genetic Polymorphisms and the Response to Prasugrel Relationship to Pharmacokinetic, Pharmacodynamic, and Clinical Outcomes
Cytochrome P450 Genetic Polymorphisms and the Response to Prasugrel Relationship to Pharmacokinetic, Pharmacodynamic, and Clinical Outcomes
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DOI：
10.1161/circulationaha.109.851949
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发表时间：
2009-05-19
期刊：
影响因子：
37.8
通讯作者：
Sabatine, Marc S.
中科院分区：
文献类型：
--
作者：
Mega, Jessica L.;Close, Sandra L.;Sabatine, Marc S.
背景-氯吡格雷和普拉格雷都需要通过细胞色素P450（CYP）酶生物转化为活性代谢物。在接受氯吡格雷治疗的患者中，功能降低的CYP 2C 19等位基因携带者的活性代谢物水平显著降低，血小板抑制作用减弱，不良心血管事件发生率较高。Prasugrel治疗的患者的临床结局的影响的α多态性仍然unknowed.Methods和结果之间的关联在α基因的功能变异，活性药物代谢产物的血浆浓度和血小板抑制反应普拉格雷在238名健康受试者进行了测试。然后，我们研究了这些遗传变异与心血管结局的关系，在一项名为“通过优化血小板抑制与普拉格雷溶栓治疗心肌梗死38试验来评估治疗结局改善”的试验中，1466例急性冠脉综合征患者被分配接受普拉格雷治疗。在健康受试者中，对于任何检测的CYP 2C 19、CYP 2C 9、CYP 2B 6、CYP 3A 5和CYP 1A 2基因，在至少一个功能降低等位基因的携带者与非携带者中未观察到普拉格雷的药代动力学或药效学反应显著减弱。与这些研究结果相一致，在与普拉格雷治疗的急性冠脉综合征的受试者，没有显着的关联被发现之间的任何测试cardiac基因型和心血管死亡，心肌梗死，或stroke. Conclusions常见的功能性cardiac基因变异不影响活性药物代谢产物水平，抑制血小板聚集，或临床心血管事件率与普拉格雷治疗的人。这些药物遗传学结果与氯吡格雷的观察结果相反，这可能部分解释了对2种药物的不同药理学和临床反应。（循环。2009; 119：2553-2560）。
Background-Both clopidogrel and prasugrel require biotransformation to active metabolites by cytochrome P450 (CYP) enzymes. Among persons treated with clopidogrel, carriers of reduced-function CYP2C19 alleles have significantly lower levels of active metabolite, diminished platelet inhibition, and higher rates of adverse cardiovascular events. The effect of CYP polymorphisms on the clinical outcomes in patients treated with prasugrel remains unknown.Methods and Results-The associations between functional variants in CYP genes, plasma concentrations of active drug metabolite, and platelet inhibition in response to prasugrel were tested in 238 healthy subjects. We then examined the association of these genetic variants with cardiovascular outcomes in a cohort of 1466 patients with acute coronary syndromes allocated to treatment with prasugrel in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel-Thrombolysis in Myocardial Infarction 38 trial. Among the healthy subjects, no significant attenuation of the pharmacokinetic or the pharmacodynamic response to prasugrel was observed in carriers versus noncarriers of at least 1 reduced-function allele for any of the CYP genes tested (CYP2C19, CYP2C9, CYP2B6, CYP3A5, and CYP1A2). Consistent with these findings, in subjects with acute coronary syndromes treated with prasugrel, no significant associations were found between any of the tested CYP genotypes and risk of cardiovascular death, myocardial infarction, or stroke.Conclusions-Common functional CYP genetic variants do not affect active drug metabolite levels, inhibition of platelet aggregation, or clinical cardiovascular event rates in persons treated with prasugrel. These pharmacogenetic findings are in contrast to observations with clopidogrel, which may explain, in part, the different pharmacological and clinical responses to the 2 medications. (Circulation. 2009; 119: 2553-2560.)