Influence of CYP4F2 polymorphisms and plasma vitamin K levels on warfarin sensitivity in Japanese pediatric patients.
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.
Department of Clinical Pharmacology & Genetics, School of Pharmaceutical Sciences, University of Shizuoka, and Department of Pharmacy, Shizuoka Children's Hospital, Shizuoka, Japan.
Keita
K
Hirai
Hideki
H
Hayashi
Yasuo
Y
Ono
Kohei
K
Izumiya
Masaki
M
Tanaka
Takayo
T
Suzuki
Tatsuichiro
T
Sakamoto
Kunihiko
K
Itoh
D000293:Adolescent; D000483:Alleles; D000925:Anticoagulants / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D044466:Asian People / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D065729:Cytochrome P-450 CYP2C9; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D000072470:Cytochrome P450 Family 4; D004351:Drug Resistance / Q000235:genetics; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D008661:Metabolism, Inborn Errors / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000235:genetics; D010837:Vitamin K 1 / Q000097:blood*; D024482:Vitamin K 2 / Q000097:blood; D064417:Vitamin K Epoxide Reductases / Q000235:genetics; D014859:Warfarin / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*
D000925:Anticoagulants; D024482:Vitamin K 2; D014859:Warfarin; D010837:Vitamin K 1; D003577:Cytochrome P-450 Enzyme System; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D000072470:Cytochrome P450 Family 4; C117480:CYP4F2 protein, human; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases