Université Pierre et Marie Curie-Paris 6, INSERM UMR S 956, Pharmacology Department, Pitié-Salpêtrière University Hospital, Paris, France.
Circ Cardiovasc Interv. 2011 Oct 1;4(5):422-8. doi: 10.1161/CIRCINTERVENTIONS.111.963025. Epub 2011 Oct 4.
Reduced concentrations of clopidogrel active metabolite have been associated with diminished platelet inhibition and higher rates of adverse cardiovascular events. Paraoxonase-1 (PON1) has recently been proposed as a key enzyme for clopidogrel metabolic activation. We tested the effects of PON1 polymorphisms on clopidogrel pharmacokinetics and pharmacodynamics and the occurrence of cardiovascular outcomes in young post-myocardial infarction (MI) patients treated with clopidogrel.
We genotyped PON1 (Q192R and L55M) and CYP2C19 variants in 106 patients enrolled in the PK/PD CLOVIS-2 trial. Patients were randomly exposed to a 300-mg or 900-mg clopidogrel loading dose in a crossover study design. Clopidogrel active metabolite isomer H4 (clopi-H4) and platelet function testing were measured serially after loading dose. There was no significant association between PON1 Q192R or L55M and clopi-H4 formation or antiplatelet response to clopidogrel after either loading dose. Using multivariable linear regression analyses, the CYP2C19*2 allele was the only predictor of clopi-H4 generation and platelet response irrespective of the platelet function assay. CYP2C19 loss-of-function but not PON1 variants were significantly associated with increased risk of major cardiovascular events (death, MI, and urgent coronary revascularization) occurring during long-term clopidogrel exposure in 371 young post-MI patients (age <45 years) enrolled in the AFIJI cohort (CYP2C19 loss-of-function allele carrier versus noncarrier: hazard ratio, 2.26; 95% confidence interval, 1.15-4.41, P=0.02; PON1 QQ192 versus QR/RR192: hazard ratio, 1.03; 95% confidence interval, 0.50-2.11, P=0.93; PON1 LL55 versus LM/MM55: hazard ratio, 1.52; 95% confidence interval, 0.75-3.08, P=0.24).
Our study does not confirm that PON1 Q192R or L55M can influence clopidogrel pharmacokinetics or pharmacodynamics in post-MI patients.
氯吡格雷活性代谢物浓度降低与血小板抑制减弱和心血管不良事件发生率升高有关。对氧磷酶 1（PON1）最近被提出是氯吡格雷代谢激活的关键酶。我们检测了 PON1 多态性对氯吡格雷药代动力学和药效学的影响，以及在接受氯吡格雷治疗的年轻心肌梗死后患者中发生心血管结局的情况。
我们在 PK/PD CLOVIS-2 试验中入组的 106 例患者中对 PON1（Q192R 和 L55M）和 CYP2C19 变异进行了基因分型。患者以交叉设计接受 300mg 或 900mg 氯吡格雷负荷剂量。负荷剂量后连续测量氯吡格雷活性代谢物异构体 H4（clopi-H4）和血小板功能试验。PON1 Q192R 或 L55M 与两种负荷剂量后的 clopi-H4 形成或氯吡格雷的抗血小板反应均无显著相关性。使用多变量线性回归分析，CYP2C19*2 等位基因是 clopi-H4 生成和血小板反应的唯一预测因子，与血小板功能测定无关。在 AFIJI 队列中入组的 371 例年轻心肌梗死后患者（年龄<45 岁）接受长期氯吡格雷暴露期间，CYP2C19 失活功能但不是 PON1 变异与主要心血管事件（死亡、心肌梗死和紧急冠状动脉血运重建）风险增加显著相关（CYP2C19 失活功能等位基因携带者与非携带者：风险比，2.26；95%置信区间，1.15-4.41，P=0.02；PON1 QQ192 与 QR/RR192：风险比，1.03；95%置信区间，0.50-2.11，P=0.93；PON1 LL55 与 LM/MM55：风险比，1.52；95%置信区间，0.75-3.08，P=0.24）。
我们的研究并未证实 PON1 Q192R 或 L55M 可影响心肌梗死后患者的氯吡格雷药代动力学或药效学。
