Department of Cardiology, St. Antonius Hospital Nieuwegein, Nieuwegein, The Netherlands.
Nat Med. 2011 Jan;17(1):110-6. doi: 10.1038/nm.2281. Epub 2010 Dec 19.
Clinical efficacy of the antiplatelet drug clopidogrel is hampered by its variable biotransformation into the active metabolite. 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.
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影响。氯吡格雷治疗临床反应的变异性归因于遗传因素，但氯吡格雷生物活化的具体基因和机制仍不清楚。我们使用体外代谢组学分析技术，确定对氧磷酶 1（PON1）为氯吡格雷生物活化的关键酶，其常见的 Q192R 多态性决定了活性代谢物形成的速度。我们在接受支架植入和氯吡格雷治疗的冠心病患者人群中测试了 PON1 Q192R 基因型的临床相关性。PON1 QQ192 纯合子个体发生支架血栓的风险明显高于 RR192 纯合子个体，PON1 血浆活性较低，活性代谢物的血浆浓度较低，血小板抑制作用较低。因此，我们确定 PON1 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，并可能被用于前瞻性评估氯吡格雷的临床疗效。
