BACKGROUND Warfarin is primarily metabolized by cytochrome P450 2C9 (CYP2C9) enzyme, which is encoded by the CYP2C9 gene. CYP2C9*2 and CYP2C9*3 variants significantly influence warfarin metabolism and subsequently the required dose of warfarin. OBJECTIVES The current retrospective study was aimed to determine the influence of CYP2C9 variants on warfarin metabolic ratio (MR, warfarin/7-hydroxy warfarin) and warfarin maintenance therapy in 210 patients (mean age 44.6±11.6 (SD) years; male to female ratio 81:129). METHODS High-performance liquid chromatography (HPLC) with UV detector was used to measure plasma concentrations of warfarin and 7-hydroxy warfarin. Plasma samples were collected 12 h after the previous dose of warfarin was administered. CYP2C9 variants (rs1799853 and rs1057910) were identified using real-time polymerase chain reaction allele-discrimination method. RESULTS The mean daily maintenance dose of warfarin was 4.6±1.8 (SD) mg. The mean plasma warfarin and 7-hydroxy warfarin concentrations were 3.7±1.6 (SD) μg/mL and 1.1±0.54 (SD) μg/mL, respectively. Patients carrying other CYP2C9 variants required 39% lower warfarin maintenance dose 3.3±1.2(SD)mg than CYP2C9*1*1 carrier 4.9±1.8(SD)mg, (p<0.0001). MRs differed significantly between CYP2C9 variant carriers (8.1±5.1) and normal genotype carriers (4.8±3.9) (p<0.0001). Probit analysis identified an MR value of 7.6 as the anti-mode (sensitivity of 84% and specificity of 55%) to differentiate poor and intermediate metabolizers (carriers of any CYP2C9*2 or CYP2C9*3 variants) from normal metabolizers (CYP2C9*1*1 genotype). CONCLUSION The present study results provide, insights on the effect of CYP2C9 genetic polymorphisms on inter-individual variability in warfarin metabolism and emphasizes utility of phenotyping in a setting of genotype-guided dosing of warfarin in South Indian population.

中文翻译：

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CYP2C9 多态性对南印度患者华法林和 7-羟基华法林血浆浓度的影响。

背景技术华法林主要由CYP2C9基因编码的细胞色素P450 2C9 (CYP2C9)酶代谢。CYP2C9*2 和 CYP2C9*3 变体显着影响华法林代谢，进而影响华法林所需剂量。目的 目前的回顾性研究旨在确定 CYP2C9 变体对 210 名患者（平均年龄 44.6±11.6 (SD) 岁；男女比例）的华法林代谢比（MR，华法林/7-羟基华法林）和华法林维持治疗的影响。 81:129)。方法采用带紫外检测器的高效液相色谱法（HPLC）测定血浆中华法林和7-羟基华法林的浓度。在前一剂华法林给药后 12 小时采集血浆样本。CYP2C9 变体（rs1799853 和 rs1057910）使用实时聚合酶链反应等位基因鉴别方法进行鉴定。结果华法林的平均每日维持剂量为4.6±1.8 (SD) mg。平均血浆华法林和 7-羟基华法林浓度分别为 3.7±1.6 (SD) μg/mL 和 1.1±0.54 (SD) μg/mL。携带其他 CYP2C9 变体的患者需要的华法林维持剂量 3.3±1.2(SD)mg 比 CYP2C9*1*1 载体 4.9±1.8(SD)mg 低 39% (p<0.0001)。CYP2C9 变异携带者 (8.1±5.1) 和正常基因型携带者 (4.8±3.9) 之间的 MR 存在显着差异 (p<0.0001)。概率分析确定 MR 值为 7。6 作为抗模式（84% 的敏感性和 55% 的特异性）来区分不良和中等代谢者（任何 CYP2C9*2 或 CYP2C9*3 变体的携带者）与正常代谢者（CYP2C9*1*1 基因型）。结论 本研究结果提供了关于 CYP2C9 基因多态性对华法林代谢的个体间变异性影响的见解，并强调了表型在南印度人群中以基因型指导的华法林给药设置的效用。