Pharmacology & Therapeutics, Faculty of Medicine, American University of Beirut, Riad El Solh, Beirut 1107 2020, Lebanon.
J Clin Pharmacol. 2011 Oct;51(10):1418-28. doi: 10.1177/0091270010382910. Epub 2010 Dec 8.
The authors assessed the impact of CYP2C92, CYP2C93, and/or VKORC1-1639G>A/1173C>T single-nucleotide polymorphisms on oral anticoagulants in a Lebanese population. This study recruited 231 Lebanese participants on long-term warfarin or acenocoumarol maintenance therapy with an international normalized ratio (INR) monitored at the American University of Beirut Medical Center. CYP2C9 and VKORC1 variant alleles were screened by real-time PCR. Plasma R- and S-warfarin and R- and S-acenocoumarol levels were assayed using high-performance liquid chromatography. The variant allele frequencies of CYP2C92, CYP2C93, and VKORC1 -1639G>A/1173C>T were 15.4%, 7.8%, and 52.4%, respectively. Fifty-five participants were excluded from analysis because of nontherapeutic INR values at recruitment, leaving 43 participants taking warfarin and 133 taking acenocoumarol. There was a significant decrease in the weekly maintenance dose of both drugs with CYP2C9 and VKORC1 variants when compared with wild-type patients. CYP2C92 had the least impact on the response to both drugs. The concentrations of R- and S-warfarin in plasma were significantly correlated with CYP2C9 genotypes. For acenocoumarol, time to reach target INR was more prolonged in patients carrying any CYP2C9 variant allele but failed to reach statistical significance because of low numbers of patients. There was no association between allelic variants and bleeding events. This is the first pharmacogenetic study of oral anticoagulants in Arabs. The authors showed that both CYP2C9 and VKORC1 polymorphisms are common in Lebanon and influence warfarin and acenocoumarol dose requirements, with the CYP2C92 polymorphism having less effect on acenocoumarol, the most commonly used oral anticoagulant in Lebanon.
作者评估了 CYP2C92、CYP2C93 和/或 VKORC1-1639G>A/1173C>T 单核苷酸多态性对黎巴嫩人群口服抗凝剂的影响。本研究招募了 231 名在贝鲁特美国大学医学中心接受国际标准化比值（INR）监测的长期华法林或醋硝香豆素维持治疗的黎巴嫩参与者。通过实时 PCR 筛选 CYP2C9 和 VKORC1 变异等位基因。使用高效液相色谱法测定血浆 R-和 S-华法林以及 R-和 S-醋硝香豆素水平。CYP2C92、CYP2C93 和 VKORC1-1639G>A/1173C>T 的变异等位基因频率分别为 15.4%、7.8%和 52.4%。由于招募时 INR 值非治疗性，有 55 名参与者被排除在分析之外，最终有 43 名参与者服用华法林，133 名参与者服用醋硝香豆素。与野生型患者相比，携带 CYP2C9 和 VKORC1 变异的两种药物的每周维持剂量均显著降低。CYP2C92 对两种药物的反应影响最小。R-和 S-华法林在血浆中的浓度与 CYP2C9 基因型显著相关。对于醋硝香豆素，携带任何 CYP2C9 变异等位基因的患者达到目标 INR 的时间延长，但由于患者数量较少，未达到统计学意义。等位基因变异与出血事件之间没有关联。这是阿拉伯人中第一个关于口服抗凝剂的遗传药理学研究。作者表明，CYP2C9 和 VKORC1 多态性在黎巴嫩很常见，影响华法林和醋硝香豆素的剂量需求，其中 CYP2C92 多态性对华法林的影响较小，而华法林是黎巴嫩最常用的口服抗凝剂。
