Department of Clinical Pharmacology, Hospital Universitario de La Princesa, Instituto Teófilo Hernando, Universidad Autónoma de Madrid, Instituto de Investigación Sanitaria La Princesa, Madrid, Spain.
Department of Clinical Pharmacology, Hospital Universitario de La Princesa, Instituto Teófilo Hernando, Universidad Autónoma de Madrid, Instituto de Investigación Sanitaria La Princesa, Madrid, Spain; UICEC Hospital Universitario de La Princesa, Spanish Clinical Research Network, Instituto de Investigación Sanitaria La Princesa, Madrid, Spain.
Clin Ther. 2019 Jun;41(6):1199-1212.e2. doi: 10.1016/j.clinthera.2019.04.037. Epub 2019 May 23.
Clopidogrel is a thienopyridine prodrug that inhibits platelet aggregation. It is prescribed to prevent atherothrombotic and thromboembolic events in patients receiving a stent implant in carotid, vertebral, or cranial arteries. The influence of cytochrome P-450 (CYP) 2C19 on the response to clopidogrel has been widely studied; however, the effect of other genes involved in clopidogrel absorption and metabolism has not been established in this cohort of patients.
This observational retrospective study assessed the antiplatelet response and the prevalence of hemorrhagic or ischemic events after percutaneous neurointervention in clopidogrel-treated patients, related to 35 polymorphisms in the genes encoding the clopidogrel-metabolizing enzymes (CYP2C19, CYP1A2, CYP2B6, CYP2C9, CYP2C9, CYP3A4, CYP3A5, carboxylesterase-1 [CES1], and paraoxonase-1 [PON1]), P-glycoprotein transporter (ABCB1), and platelet receptor P2Y. Polymorphisms were analyzed by quantitative real-time polymerase chain reaction and matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry. Antiplatelet response was documented with the VerifyNow system (Accriva, San Diego, California).
We confirmed that CYP2C19 is the most important enzyme involved in clopidogrel response. The carriage of the CYP2C192 allele was strongly associated with hyporesponse to clopidogrel, while the CYP2C1917 allele was a protective factor for the development of ischemic events (odds ratio = 0.149; P = 0.002) but a risk factor for bleeding (odds ratio = 3.60; P = 0.038). Patients carrying ABCB1 mutated alleles showed lower aggregation values, suggesting that clopidogrel absorption is influenced by P-glycoprotein. In fact, the percentage of responders was significantly higher in the group carrying the mutated haplotype compared to the wild type (80.8% vs 43.3%; P = 0.009). Patients with the CES1 G143E C/T genotype showed a considerably lower, aggregation value versus wild-type patients, although the difference was not significant likely due to the small sample size (59.0 [21.2] vs 165.2 [86.0] PRU; P = 0.084), which suggests an increased active metabolite formation. No relationship was found between polymorphisms in other CYP genes, PON1, or P2RY12 and response to clopidogrel in patients subjected to neurointervention procedures.
Therapeutic guidelines recommend that CYP2C19 intermediate and poor metabolizers with acute coronary syndromes undergoing percutaneous coronary intervention receive an alternative antiplatelet therapy; however, genotype-guided therapy is not a standard recommendation for neurovascular conditions. This is the first study to carry out a joint analysis of CYP2C19 and other genes involved in clopidogrel treatment in patients receiving percutaneous neurointervention. Our findings support routine genotyping in clopidogrel-treated patients. Moreover, we encourage considering an alternative antiplatelet therapy in CYP2C19 intermediate, poor and ultrarapid metabolizers. Additionally, ABCB1 polymorphisms could be considered for a better pharmacogenetic approach.
氯吡格雷是一种噻吩并吡啶前体药物，可抑制血小板聚集。它被开处方用于预防颈动脉、椎动脉或颅动脉支架植入患者的动脉粥样硬化血栓形成和血栓栓塞事件。细胞色素 P-450（CYP）2C19 对氯吡格雷反应的影响已得到广泛研究；然而，在这组患者中，尚未确定参与氯吡格雷吸收和代谢的其他基因的影响。
本观察性回顾性研究评估了接受氯吡格雷治疗的患者在经皮神经介入治疗后抗血小板反应和出血或缺血事件的发生率，与编码氯吡格雷代谢酶（CYP2C19、CYP1A2、CYP2B6、CYP2C9、CYP2C9、CYP3A4、CYP3A5、羧酸酯酶-1 [CES1] 和对氧磷酶-1 [PON1]）、P-糖蛋白转运体（ABCB1）和血小板受体 P2Y 的基因中 35 个多态性有关。通过定量实时聚合酶链反应和基质辅助激光解吸/电离-飞行时间质谱分析多态性。用 VerifyNow 系统（Accriva，圣地亚哥，加利福尼亚州）记录抗血小板反应。
我们证实 CYP2C19 是参与氯吡格雷反应的最重要的酶。CYP2C192 等位基因的携带与氯吡格雷低反应强烈相关，而 CYP2C1917 等位基因是缺血事件发展的保护因素（比值比=0.149；P=0.002），但也是出血的危险因素（比值比=3.60；P=0.038）。携带 ABCB1 突变等位基因的患者聚集值较低，表明氯吡格雷的吸收受到 P-糖蛋白的影响。事实上，与野生型相比，携带突变单倍型的患者的反应者比例明显更高（80.8%比 43.3%；P=0.009）。与野生型患者相比，携带 CES1 G143E C/T 基因型的患者的聚集值明显较低，尽管由于样本量较小，差异无统计学意义（59.0 [21.2] 比 165.2 [86.0] PRU；P=0.084），这表明活性代谢物形成增加。在接受神经介入治疗的患者中，未发现 CYP 基因、PON1 或 P2RY12 中的其他多态性与氯吡格雷的反应之间存在关系。
治疗指南建议急性冠脉综合征接受经皮冠状动脉介入治疗的 CYP2C19 中间和弱代谢者接受替代抗血小板治疗；然而，基因型指导的治疗并不是神经血管疾病的标准推荐。这是第一项在接受经皮神经介入治疗的患者中联合分析 CYP2C19 和其他参与氯吡格雷治疗的基因的研究。我们的研究结果支持对接受氯吡格雷治疗的患者进行常规基因分型。此外，我们鼓励在 CYP2C19 中间代谢、弱代谢和超快代谢者中考虑替代抗血小板治疗。此外，还可以考虑 ABCB1 多态性以进行更好的药物遗传学方法。
