Gladding Patrick, Webster Mark, Zeng Irene, Farrell Helen, Stewart Jim, Ruygrok Peter, Ormiston John, El-Jack Seif, Armstrong Guy, Kay Patrick, Scott Douglas, Gunes Arzu, Dahl Marja-Liisa
Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, New Zealand.
JACC Cardiovasc Interv. 2008 Dec;1(6):620-7. doi: 10.1016/j.jcin.2008.09.008.
This study assessed the effect of pharmacogenetics on the antiplatelet effect of clopidogrel.
Variability in clopidogrel response might be influenced by polymorphisms in genes coding for drug metabolism enzymes (cytochrome P450 [CYP] family), transport proteins (P-glycoprotein) and/or target proteins for the drug (adenosine diphosphate-receptor P2Y12).
Sixty patients undergoing elective percutaneous coronary intervention in the randomized PRINC (Plavix Response in Coronary Intervention) trial had platelet function measured using the VerifyNow P2Y12 analyzer after a 600-mg or split 1,200-mg loading dose and after a 75- or 150-mg daily maintenance dosage. Polymerase chain reaction-based genotyping evaluated polymorphisms in the CYP2C19, CYP2C9, CYP3A4, CYP3A5, ABCB1, P2Y12, and CES genes.
CYP2C1911 carriers had greater platelet inhibition 2 h after a 600-mg dose (median: 23%, range: 0% to 66%), compared with platelet inhibition in CYP2C192 or 4 carriers (10%, 0% to 56%, p = 0.029) and CYP2C1917 carriers (9%, 0% to 98%, p = 0.026). CYP2C192 or *4 carriers had greater platelet inhibition with the higher loading dose than with the lower dose at 4 h (37%, 8% to 87% vs. 14%, 0% to 22%, p = 0.002) and responded better with the higher maintenance dose regimen (51%, 15% to 86% vs. 14%, 0% to 67%, p = 0.042).
Carriers of the CYP2C19*2 and *4 alleles showed reduced platelet inhibition after a clopidogrel 600-mg loading dose but responded to higher loading and maintenance dose regimens. Genotyping for the relevant gene polymorphisms may help to individualize and optimize clopidogrel treatment. (Australia New Zealand Clinical Trials Registry; ACTRN12606000129583).
本研究评估药物遗传学对氯吡格雷抗血小板作用的影响。
氯吡格雷反应的变异性可能受编码药物代谢酶（细胞色素P450 [CYP]家族）、转运蛋白（P-糖蛋白）和/或药物靶蛋白（二磷酸腺苷受体P2Y12）的基因多态性影响。
在随机PRINC（冠状动脉介入治疗中波立维的反应）试验中，60例接受择期经皮冠状动脉介入治疗的患者在给予600 mg或分次给予1200 mg负荷剂量以及75 mg或150 mg每日维持剂量后，使用VerifyNow P2Y12分析仪测量血小板功能。基于聚合酶链反应的基因分型评估了CYP2C19、CYP2C9、CYP3A4、CYP3A5、ABCB1、P2Y12和CES基因的多态性。
与CYP2C192或4携带者（10%，0%至56%，p = 0.029）和CYP2C1917携带者（9%，0%至98%，p = 0.026）相比，CYP2C1911携带者在给予600 mg剂量后2小时血小板抑制作用更强（中位数：23%，范围：0%至66%）。CYP2C192或*4携带者在4小时时较高负荷剂量组的血小板抑制作用高于较低剂量组（37%，8%至87%对14%，0%至22%，p = 0.002），且较高维持剂量方案的反应更好（51%，15%至86%对14%，0%至67%，p = 0.042）。
CYP2C192和4等位基因携带者在给予氯吡格雷600 mg负荷剂量后血小板抑制作用降低，但对较高的负荷和维持剂量方案有反应。对相关基因多态性进行基因分型可能有助于氯吡格雷治疗的个体化和优化。（澳大利亚新西兰临床试验注册中心；ACTRN12606000129583）
