Department of Clinical Pharmacology & Genetics, School of Pharmaceutical Sciences, University of Shizuoka, and Department of Pharmacy, Shizuoka Children's Hospital, Shizuoka, Japan.
Drug Metab Pharmacokinet. 2013;28(2):132-7. doi: 10.2133/dmpk.dmpk-12-rg-078. Epub 2012 Aug 14.
The aim of this study was to reveal the contribution of CYP4F2, CYP2C9, and VKORC1 genetic polymorphisms on the pharmacokinetics and pharmacodynamics of warfarin in Japanese pediatric patients. Genetic analyses of CYP4F2 (rs2108622), CYP2C9 (*2 and *3), and VKORC1 (-1639G>A) were performed, and plasma unbound warfarin, vitamin K1 (VK1), and menaquinone-4 (MK-4) concentrations were determined in 37 Japanese pediatric patients. The patients with CYP4F2 variant alleles C/T and T/T scored significantly lower values for the warfarin sensitivity index (INR/Cpss) and had significantly higher plasma concentrations of MK-4 than patients with the CYP4F2 allele C/C. Moreover, the plasma MK-4 concentration was negatively correlated with the warfarin sensitivity index. In contrast, the VKORC1 genetic polymorphism did not influence the warfarin sensitivity index. In patients with the CYP2C9 *3 allele, the unbound oral clearance values (normalized to body surface area) for S-warfarin were found to be significantly lower than in patients with the wild-type allele. In conclusion, CYP4F2 genetic polymorphism and plasma MK-4 concentration influence the pharmacodynamics of warfarin, suggesting a mechanism though which CYP4F2 genotype affects warfarin dose.
本研究旨在揭示 CYP4F2、CYP2C9 和 VKORC1 基因多态性对日本儿科患者华法林药代动力学和药效学的影响。对 CYP4F2(rs2108622)、CYP2C9(*2 和 3)和 VKORC1(-1639G>A)进行了基因分析，并测定了 37 例日本儿科患者的游离华法林、维生素 K1(VK1)和甲萘醌-4(MK-4)的血浆浓度。与 CYP4F2 等位基因 C/C 的患者相比，C/T 和 T/T 变异等位基因的患者华法林敏感性指数(INR/Cpss)评分显著较低，MK-4 的血浆浓度显著较高。此外，血浆 MK-4 浓度与华法林敏感性指数呈负相关。相比之下，VKORC1 基因多态性并不影响华法林的敏感性指数。在 CYP2C93 等位基因的患者中，S-华法林的未结合口服清除率(按体表面积标准化)明显低于野生型等位基因的患者。总之，CYP4F2 基因多态性和血浆 MK-4 浓度影响华法林的药效学，表明 CYP4F2 基因型通过影响华法林剂量来影响药效学的机制。
