Department of Pharmacology, Jawaharlal Institute of Postgraduate Medical Education & Research (JIPMER), Pondicherry, India.
CANSEARCH Research Platform in Pediatric Oncology and Hematology, Department of Pediatrics, Gynecology and Obstetrics, University of Geneva, Geneva, Switzerland.
Curr Drug Metab. 2021;22(12):989-995. doi: 10.2174/1389200222666211119104412.
Warfarin is primarily metabolized by cytochrome P450 2C9 (CYP2C9) enzyme, which is encoded by the CYP2C9 gene. CYP2C92 and CYP2C93 variants significantly influence warfarin metabolism and subsequently the required dose of warfarin.
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).
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.
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 CYP2C911 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 CYP2C92 or CYP2C93 variants) from normal metabolizers (CYP2C911 genotype).
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.
华法林主要通过细胞色素 P450 2C9（CYP2C9）酶代谢，该酶由 CYP2C9 基因编码。CYP2C92 和 CYP2C93 变体显著影响华法林的代谢，进而影响华法林的所需剂量。
本回顾性研究旨在确定 CYP2C9 变体对华法林代谢比（MR，华法林/7-羟基华法林）和 210 例患者（平均年龄 44.6±11.6（SD）岁；男女比例 81:129）华法林维持治疗的影响。
采用高效液相色谱法（HPLC）结合紫外检测器测定华法林和 7-羟基华法林的血浆浓度。在给予华法林前一次剂量 12 小时后采集血浆样本。采用实时聚合酶链反应等位基因鉴别法检测 CYP2C9 变体（rs1799853 和 rs1057910）。
华法林的平均日维持剂量为 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 39%的低维持剂量 3.3±1.2（SD）mg，而 CYP2C911 携带者需要 4.9±1.8（SD）mg，（p<0.0001）。CYP2C9 变体携带者的 MR 差异显著（8.1±5.1）和正常基因型携带者（4.8±3.9）（p<0.0001）。概率分析确定 MR 值为 7.6 作为抗模式（敏感性为 84%，特异性为 55%），以区分代谢不良和中间代谢者（携带任何 CYP2C92 或 CYP2C93 变体）与正常代谢者（CYP2C911 基因型）。
本研究结果提供了 CYP2C9 遗传多态性对个体间华法林代谢变异性的影响的见解，并强调了表型在印度南部人群华法林基因型指导剂量中的作用。
