Tarkiainen E K, Holmberg M T, Tornio A, Neuvonen M, Neuvonen P J, Backman J T, Niemi M
Department of Clinical Pharmacology, University of Helsinki and HUSLAB, Helsinki University Hospital, Helsinki, Finland.
Clin Pharmacol Ther. 2015 Jun;97(6):650-8. doi: 10.1002/cpt.101. Epub 2015 May 9.
Carboxylesterase 1 (CES1) hydrolyzes the prodrug clopidogrel to an inactive carboxylic acid metabolite. We studied the pharmacokinetics and pharmacodynamics of 600 mg oral clopidogrel in healthy white volunteers, including 10 carriers and 12 noncarriers of CES1 c.428G>A (p.Gly143Glu, rs71647871) single nucleotide variation (SNV). Clopidogrel carboxylic acid to clopidogrel area under the plasma concentration-time curve from 0 hours to infinity (AUC0-∞ ) ratio was 53% less in CES1 c.428G>A carriers than in noncarriers (P = 0.009), indicating impaired hydrolysis of clopidogrel. Consequently, the AUC0-∞ of clopidogrel and its active metabolite were 123% (P = 0.004) and 67% (P = 0.009) larger in the c.428G>A carriers than in noncarriers. Consistent with these findings, the average inhibition of P2Y12 -mediated platelet aggregation 0-12 hours after clopidogrel intake was 19 percentage points higher in the c.428G>A carriers than in noncarriers (P = 0.036). In conclusion, the CES1 c.428G>A SNV increases clopidogrel active metabolite concentrations and antiplatelet effects by reducing clopidogrel hydrolysis to inactive metabolites.
羧酸酯酶1（CES1）可将前体药物氯吡格雷水解为无活性的羧酸代谢物。我们研究了600mg口服氯吡格雷在健康白人志愿者中的药代动力学和药效学，其中包括10名携带CES1基因c.428G>A（p.Gly143Glu，rs71647871）单核苷酸变异（SNV）的个体和12名非携带者。与非携带者相比，CES1基因c.428G>A携带者中氯吡格雷羧酸与氯吡格雷从0小时到无穷大的血浆浓度-时间曲线下面积（AUC0-∞）之比低53%（P = 0.009），表明氯吡格雷的水解受损。因此，c.428G>A携带者中氯吡格雷及其活性代谢物的AUC0-∞分别比非携带者高123%（P = 0.004）和67%（P = 0.009）。与这些发现一致，氯吡格雷摄入后0至12小时，c.428G>A携带者中P2Y12介导的血小板聚集的平均抑制率比非携带者高19个百分点（P = 0.036）。总之，CES1基因c.428G>A SNV通过减少氯吡格雷水解为无活性代谢物，增加了氯吡格雷活性代谢物的浓度和抗血小板作用。
