Cardiovascular Center, St. Josef - Hospital, Gudrunstrasse 56, D-44791 Bochum, Germany.
Thromb Haemost. 2013 Jul;110(1):131-40. doi: 10.1160/TH13-01-0021. Epub 2013 Apr 25.
The cytochrome P450 (CYP) isoenzymes are essential for the metabolic activation of the prodrug prasugrel. Little is known about the impact of polymorphism of these isoenzymes on the prevalence of prasugrel low responsiveness (PLR) in patients with coronary artery disease. We investigated the frequency of PLR and the question whether PLR is associated with decreased/non-function polymorphisms of the CYP isoenzymes (2C92, 2C93, 2C192, 2C193, and 2B66). Our study included 355 patients who underwent percutaneous coronary stenting. The patients were initially treated with either prasugrel (n=90; 60/10 mg: loading/daily maintenance dose) or 600/75 mg clopidogrel hydrogensulfate (n=265) in combination with 500/100 mg acetylsalicylic acid (ASA). Platelet function was tested by impedance aggregometry 48 hours after taking the loading dose. Prasugrel achieved on the average significantly higher levels of platelet inhibition as compared to clopidogrel (mean 27.3 U vs 41.2 U). The frequencies of low response for prasugrel, clopidogrel and ASA were 9.8%, 35.1% and 14.9%, respectively. We identified only body mass index to be associated with PLR. PLR was not caused by a loss of ADP P2Y12-receptor function. Half of the patients with PLR were carriers of the reduced-function allele CYP2B66, and 41.7% had the genetic variant CYP2C92. The allele CYP2C93 was detected in three patients with PLR (25%) and two patients with PLR (16.7%) carried the gene variant CYP2C192. In conclusion, the rate of low responders was significantly lower among patients treated with prasugrel than with clopidogrel. PLR are more often carriers of CYP2C92 (50% in PLR) than when compared to the prevalence described in literature. Also, there is a trend to an increased frequency of CYP2B6*6 in PLR. In conclusion, CYP2B6 and CYP2C9 polymorphisms seem to be associated with prasugrel low-response.
细胞色素 P450（CYP）同工酶对于前药普拉格雷的代谢激活至关重要。关于这些同工酶的多态性对冠心病患者中普拉格雷低反应（PLR）的流行程度的影响知之甚少。我们研究了 PLR 的频率，以及 PLR 是否与 CYP 同工酶（2C92、2C93、2C192、2C193 和 2B66）的减少/无功能多态性相关。我们的研究纳入了 355 名接受经皮冠状动脉介入治疗的患者。这些患者最初分别接受普拉格雷（n=90；负荷剂量/每日维持剂量 60/10 mg）或氯吡格雷氢硫酸盐 600/75 mg（n=265）联合 500/100 mg 乙酰水杨酸（ASA）治疗。在服用负荷剂量后 48 小时，通过阻抗聚集法测试血小板功能。与氯吡格雷相比，普拉格雷平均达到更高水平的血小板抑制（平均 27.3 U 对 41.2 U）。普拉格雷、氯吡格雷和 ASA 的低反应频率分别为 9.8%、35.1%和 14.9%。我们只发现体重指数与 PLR 相关。PLR 不是由 ADP P2Y12 受体功能丧失引起的。一半的 PLR 患者是 CYP2B66 低功能等位基因的携带者，41.7%的患者携带 CYP2C92 基因变异体。PLR 患者中有 3 名（25%）携带 CYP2C93 等位基因，2 名 PLR 患者（16.7%）携带 CYP2C192 基因变异体。总之，与氯吡格雷相比，接受普拉格雷治疗的患者中低反应者的比例显著降低。PLR 携带者中 CYP2C92（PLR 中为 50%）的比例高于文献中描述的流行率。此外，PLR 中 CYP2B6*6 的频率也有增加的趋势。总之，CYP2B6 和 CYP2C9 多态性似乎与普拉格雷低反应相关。
