Plasma vitamin K concentrations depend on CYP4F2 polymorphism and influence on anticoagulation in Japanese patients with warfarin therapy.
BACKGROUND
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.


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.
Department of Clinical Pharmacology & Genetics, School of Pharmaceutical Sciences, University of Shizuoka, 52-1, Yada, Suruga-ku, Shizuoka 422-8526, Japan.
Keita
K
Hirai
Department of Clinical Pharmacology & Genetics, School of Pharmaceutical Sciences, University of Shizuoka, 52-1, Yada, Suruga-ku, Shizuoka 422-8526, Japan.
Yuto
Y
Yamada
Department of Clinical Pharmacology & Genetics, School of Pharmaceutical Sciences, University of Shizuoka, 52-1, Yada, Suruga-ku, Shizuoka 422-8526, Japan; Laboratory of Pharmacy Practice and Social Science, Gifu Pharmaceutical University, 1-25-4 Daigakunishi, Gifu 501-1196, Japan.
Hideki
H
Hayashi
Department of Clinical Pharmacology & Genetics, School of Pharmaceutical Sciences, University of Shizuoka, 52-1, Yada, Suruga-ku, Shizuoka 422-8526, Japan.
Masaki
M
Tanaka
Department of Clinical Pharmacology & Genetics, School of Pharmaceutical Sciences, University of Shizuoka, 52-1, Yada, Suruga-ku, Shizuoka 422-8526, Japan.
Kohei
K
Izumiya
Department of Clinical Pharmacology & Genetics, School of Pharmaceutical Sciences, University of Shizuoka, 52-1, Yada, Suruga-ku, Shizuoka 422-8526, Japan.
Masayuki
M
Suzuki
Department of Clinical Pharmacology & Genetics, School of Pharmaceutical Sciences, University of Shizuoka, 52-1, Yada, Suruga-ku, Shizuoka 422-8526, Japan.
Misa
M
Yoshizawa
Department of Cardiology, Shizuoka General Hospital, 4-27-1, Kita-ando, Aoi-ku, Shizuoka 420-8527, Japan.
Hideaki
H
Moriwaki
Department of Cardiovascular Surgery, Shizuoka General Hospital, 4-27-1, Kita-ando, Aoi-ku, Shizuoka 420-8527, Japan.
Takehide
T
Akimoto
Department of Clinical Pharmacology & Genetics, School of Pharmaceutical Sciences, University of Shizuoka, 52-1, Yada, Suruga-ku, Shizuoka 422-8526, Japan.
Daiki
D
Tsuji
Department of Clinical Pharmacology & Genetics, School of Pharmaceutical Sciences, University of Shizuoka, 52-1, Yada, Suruga-ku, Shizuoka 422-8526, Japan.
Kazuyuki
K
Inoue
Department of Clinical Pharmacology & Genetics, School of Pharmaceutical Sciences, University of Shizuoka, 52-1, Yada, Suruga-ku, Shizuoka 422-8526, Japan. Electronic address: itohk@u-shizuoka-ken.ac.jp.
Kunihiko
K
Itoh
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000818:Animals; D000925:Anticoagulants / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D044466:Asian People / Q000235:genetics; D001711:Biotransformation / Q000235:genetics; D065729:Cytochrome P-450 CYP2C9 / Q000235:genetics; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D000072470:Cytochrome P450 Family 4; D004351:Drug Resistance / Q000235:genetics; D005260:Female; D014644:Genetic Variation / Q000235:genetics; D005838:Genotype; D006801:Humans; D019934:International Normalized Ratio; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D051381:Rats; D017207:Rats, Sprague-Dawley; D019851:Thrombophilia / Q000188:drug therapy / Q000201:enzymology; D010837:Vitamin K 1 / Q000037:antagonists & inhibitors / Q000097:blood*; D024482:Vitamin K 2 / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000097:blood; D064417:Vitamin K Epoxide Reductases / Q000235:genetics; D014859:Warfarin / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D055815:Young Adult
D000925:Anticoagulants; D024482:Vitamin K 2; C030814:menatetrenone; D014859:Warfarin; D010837:Vitamin K 1; D003577:Cytochrome P-450 Enzyme System; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; C465348:Cyp4f1 protein, rat; D000072470:Cytochrome P450 Family 4; C117480:CYP4F2 protein, human; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases
CYP2C9; CYP4F2; Menaquinone-4; VKORC1; Vitamin K1; Warfarin