Paraoxonase-1 is a major determinant of clopidogrel efficacy
Paraoxonase-1 is a major determinant of clopidogrel efficacy
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DOI：
10.1038/nm.2281
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发表时间：
2011-01-01
期刊：
影响因子：
82.9
通讯作者：
Taubert, Dirk
中科院分区：
文献类型：
--
作者：
Bouman, Heleen J.;Schoemig, Edgar;Taubert, Dirk
抗血小板药物氯吡格雷的临床疗效受到其可变生物转化为活性代谢物的阻碍1，2。对氯吡格雷治疗的临床反应的变异性被归因于遗传因素，但氯吡格雷生物激活的具体基因和机制仍不清楚。使用体外代谢组学分析技术，我们确定对氧磷酶-1（PON 1）为氯吡格雷生物活化的关键酶，其常见的Q192 R多态性决定活性代谢物形成的速率。我们在接受支架植入术和氯吡格雷治疗的冠心病患者中检测PON 1 Q192 R基因型的临床相关性。PON 1 QQ 192纯合子个体的支架内血栓形成风险显著高于RR 192纯合子个体，PON 1血浆活性较低，活性代谢物血浆浓度较低，血小板抑制较低。因此，我们确定PON 1是氯吡格雷生物活化和临床活性的关键因素。这些发现具有治疗意义，可用于前瞻性评估氯吡格雷的临床疗效。
Clinical efficacy of the antiplatelet drug clopidogrel is hampered by its variable biotransformation into the active metabolite1,2. The variability in the clinical response to clopidogrel treatment has been attributed to genetic factors, but the specific genes and mechanisms underlying clopidogrel bioactivation remain unclear. Using in vitro metabolomic profiling techniques, we identified paraoxonase-1 (PON1) as the crucial enzyme for clopidogrel bioactivation, with its common Q192R polymorphism determining the rate of active metabolite formation. We tested the clinical relevance of the PON1 Q192R genotype in a population of individuals with coronary artery disease who underwent stent implantation and received clopidogrel therapy. PON1 QQ192 homozygous individuals showed a considerably higher risk than RR192 homozygous individuals of stent thrombosis, lower PON1 plasma activity, lower plasma concentrations of active metabolite and lower platelet inhibition. Thus, we identified PON1 as a key factor for the bioactivation and clinical activity of clopidogrel. These findings have therapeutic implications and may be exploited to prospectively assess the clinical efficacy of clopidogrel.