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首页> 外文期刊>The Journal of Clinical Pharmacology: Official Journal of the American College of Clinical Pharmacology >The influence of genetic polymorphism of Cyp2c19 isoenzyme on the pharmacokinetics of clopidogrel and its metabolites in patients with cardiovascular diseases
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The influence of genetic polymorphism of Cyp2c19 isoenzyme on the pharmacokinetics of clopidogrel and its metabolites in patients with cardiovascular diseases

机译:Cyp2c19同工酶基因多态性对心血管疾病患者氯吡格雷及其代谢产物药代动力学的影响

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摘要

An extensive investigation on pharmacokinetics of clopidogrel and its metabolites as well as pharmacodynamics of the drug was performed in patients with cardiovascular disease carrying various alleles coding CYP2C19 isoenzyme. The influence of non-genetic factors on the clopidogrel response was also studied. Plasma concentrations of clopidogrel, its carboxylic metabolite, and diastereoisomers of a thiol metabolite (the inactive H3 and the active H4) following an administration of 75mg of the drug were determined in three groups of patients divided with respect to their CYP2C19 genotype: ultrametabolizers, extensive metabolizers, and intermediate metabolizers. The mean peak plasma concentration of H4 in intermediate metabolizers was 3.1- and 2.8-fold lower than that of ultrametabolizers (P=0.055) and extensive metabolizers (P=0.026), respectively. The mean H4 area under the curve (AUC0-24h) for intermediate metabolizers were significantly lower than that for ultrametabolizers (P=0.046). Intermediate metabolizers exhibited a significantly higher platelet aggregation than ultrametabolizers and extensive metabolizers (P=0.035). A multivariate analysis showed that the effect of CYP2C19*2 allele on an ADP-induced platelet aggregation was better pronounced in the presence of non-genetic risk factors (P=0.008). We concluded that the CYP2C19*2 genotype is the primary determinant of the antiplatelet response to clopidogrel therapy.
机译:在患有携带编码CYP2C19同工酶等位基因的心血管疾病患者中,对氯吡格雷及其代谢产物的药代动力学以及该药的药效学进行了广泛的研究。还研究了非遗传因素对氯吡格雷反应的影响。根据三类患者的CYP2C19基因型,确定了三类患者服用75mg药物后的氯吡格雷,其羧酸代谢产物和巯基代谢产物的非对映异构体(非活性H3和活性H4)的血浆浓度:代谢物和中间代谢物。中级代谢者中H4的平均血浆峰值浓度分别比超代谢者(P = 0.055)和广泛代谢者(P = 0.026)低3.1倍和2.8倍。中等代谢者曲线下的平均H4面积(AUC0-24h)明显低于超代谢者(P = 0.046)。中间代谢物比超代谢物和广泛代谢物表现出明显更高的血小板凝集性(P = 0.035)。多元分析表明,在存在非遗传危险因素的情况下,CYP2C19 * 2等位基因对ADP诱导的血小板聚集的影响更好(P = 0.008)。我们得出的结论是,CYP2C19 * 2基因型是氯吡格雷治疗抗血小板反应的主要决定因素。

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