RESUMO
INTRODUCTION: Warfarin is characterized by a large inter-individual variability in dosage requirement. This study aimed to analyze the contribution of the CYP4F2 genetic polymorphism and plasma vitamin K concentration on the warfarin pharmacodynamics in patients and to clarify the plasma vitamin K concentration affecting warfarin sensitivity index in rats. MATERIALS AND METHODS: Genetic analyses of selected genes were performed and plasma concentrations of warfarin, vitamin K1 (VK1) and menaquinone-4 (MK-4) were measured in 217 Japanese patients. We also assessed the association of plasma VK1 and MK-4 concentrations with the warfarin sensitivity index (INR/Cp) in rats. RESULTS: Patients with the CYP4F2 (rs2108622) TT genotype had significantly higher plasma VK1 and MK-4 concentrations than those with CC and CT genotypes. The multiple linear regression model including VKORC1, CYP4F2, and CYP2C9 genetic variants, age, and weight could explain 42% of the variability in warfarin dosage. The contribution of CYP4F2 polymorphism was estimated to be 2.2%. In contrast, plasma VK1 and MK-4 concentrations were not significantly associated with warfarin dosage in patients. Nevertheless, we were able to demonstrate that the warfarin sensitivity index was attenuated and negatively correlated with plasma VK1 concentration by the oral administration of VK1 in rats, as it resulted in a higher VK1 concentration than that in patients. CONCLUSIONS: The plasma VK1 and MK-4 concentrations are significantly influenced by CYP4F2 genetic polymorphism but not associated with warfarin therapy at the observed concentration in Japanese patients. The CYP4F2 polymorphism is poorly associated with inter-individual variability of warfarin dosage requirement.
Assuntos
Anticoagulantes/farmacocinética , Sistema Enzimático do Citocromo P-450/genética , Polimorfismo de Nucleotídeo Único , Vitamina K 1/sangue , Vitamina K 2/análogos & derivados , Varfarina/farmacocinética , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Animais , Anticoagulantes/administração & dosagem , Anticoagulantes/uso terapêutico , Povo Asiático/genética , Biotransformação/genética , Citocromo P-450 CYP2C9/genética , Sistema Enzimático do Citocromo P-450/metabolismo , Sistema Enzimático do Citocromo P-450/fisiologia , Família 4 do Citocromo P450 , Resistência a Medicamentos/genética , Feminino , Variação Genética/genética , Genótipo , Humanos , Coeficiente Internacional Normatizado , Masculino , Pessoa de Meia-Idade , Ratos , Ratos Sprague-Dawley , Trombofilia/tratamento farmacológico , Trombofilia/enzimologia , Vitamina K 1/antagonistas & inibidores , Vitamina K 2/antagonistas & inibidores , Vitamina K 2/sangue , Vitamina K Epóxido Redutases/genética , Varfarina/administração & dosagem , Varfarina/uso terapêutico , Adulto JovemRESUMO
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.