Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Japan.
Drug Metab Pharmacokinet. 2011 Jun;26(3):295-9. doi: 10.2133/dmpk.DMPK-10-NT-082. Epub 2011 Jan 25.
The primary aim of the present study was to evaluate the effect of the genotype of vitamin K epoxide reductase complex 1 (VKORC1) on warfarin dose requirements in Japanese pediatric patients. Forty-eight pediatric patients (0.42-19.25 years old) in whom stable anticoagulation was achieved by warfarin were enrolled in this study, and the polymorphic alleles of VKORC1 and CYP2C9 were determined for each subject. The relative impact of covariates on the anticoagulant effect of warfarin was evaluated by multiple regression analysis. It was found that VKORC1 genotype and age were major factors affecting the relationship between the weight-normalized warfarin dose and the therapeutic prothrombin time-international normalized ratio (PT-INR). Because only one patient had the CYP2C9*3 allele, we could not evaluate the effect of CYP2C9 polymorphisms on the anticoagulant effect of warfarin. In contrast, the anticoagulant effect of warfarin in patients with the VKORC1 1173CT or 1173CC genotype was 52.3% of that in patients with the 1173TT genotype. In addition, the anticoagulant effect of warfarin was shown to increase by 10.5% per year in Japanese pediatric patients. In conclusion, genotyping of VKORC1 will be useful in establishing individual anticoagulant therapy with warfarin, and it should be noted that a higher weight-normalized dose of warfarin is required in younger pediatric patients.
本研究的主要目的是评估维生素 K 环氧化物还原酶复合物 1（VKORC1）基因型对日本儿科患者华法林剂量需求的影响。本研究纳入了 48 例儿科患者（0.42-19.25 岁），他们通过华法林稳定抗凝，确定了每个患者的 VKORC1 和 CYP2C9 多态性等位基因。通过多元回归分析评估了协变量对华法林抗凝作用的相对影响。结果发现，VKORC1 基因型和年龄是影响体重标准化华法林剂量与治疗性凝血酶原时间-国际标准化比值（PT-INR）关系的主要因素。由于只有一名患者携带 CYP2C9*3 等位基因，我们无法评估 CYP2C9 多态性对华法林抗凝作用的影响。相比之下，VKORC1 1173CT 或 1173CC 基因型患者的华法林抗凝效果是 1173TT 基因型患者的 52.3%。此外，日本儿科患者的华法林抗凝效果每年增加 10.5%。总之，VKORC1 基因分型将有助于建立华法林个体化抗凝治疗，需要注意的是，年龄较小的儿科患者需要更高的体重标准化华法林剂量。
