title: Effect of CYP2C9, CYP4F2 and VKORC1 genetic polymorphisms on pharmacokinetics and pharmacodynamics of mean daily maintenance dose of warfarin in Chinese patients.
abstract: In this study, we studied the effects of different genetic variants of CYP2C9, VKORC1 and CYP4F2, and clinical factors on the concentration levels of S-warfarin (WF), R-WF and S, R-7-OH-WF, as well as the mean daily maintenance dose of warfarin in 211 patients on warfarin therapy for at least 3 months. The genotypes of single nucleotide polymorphism (SNP), CYP2C9, VKORC1 1173C>T and CYP4F2 were identified by PCR. Plasma concentrations of S-WF and R-WF and S-7-OH-WF, R-7-OH-WF were determined by high-performance liquid chromatography tandem mass spectrometry on chiral columns. The warfarin dosage requirement correlated negatively with age and was in direct proportion to body weight. VKORC1 1173CC carrier had significantly lower dosage requirements than that with the heterozygous VKORC1 1173CT genotype. The concentration of both 7-OH-S-WF and 7-OH-R-WF, and the warfarin dose showed a significant difference. There were significant differences in the concentrations of S-WF and 7-OH-S-WF among the CYP2C9 variants. The concentration of warfarin, 7-OH-WF and warfarin maintenance dose were not affected by the CYP4F2 V433M variant. In conclusion, VKORC1 1173C>T genotype correlates strongly with a lower daily warfarin dose and the concentration of S-7-OH, R-7-OH warfarin in Han Shanghainese patients. In addition, the results not only demonstrated the effect on pharmacodynamics of warfarin, but also enhanced the enzymatic activity of CYP450 to influence the pharmacokinetic of warfarin.
authors.affiliation: Department of Hematology, Shanghai Tongren Hospital, Shanghai, China.
authors.forename: Wenfang
authors.initials: W
authors.lastname: Zhuang
authors.forename: Wei
authors.initials: W
authors.lastname: Wen
authors.forename: Binbin
authors.initials: B
authors.lastname: Xuan
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Chen
authors.forename: Yanan
authors.initials: Y
authors.lastname: Cao
authors.forename: Zhixin
authors.initials: Z
authors.lastname: Sun
authors.forename: Jun
authors.initials: J
authors.lastname: Ma
mesh_terms: D000368:Aged; D000925:Anticoagulants / Q000008:administration & dosage* / Q000493:pharmacokinetics; D044466:Asian People / Q000235:genetics; D065729:Cytochrome P-450 CYP2C9 / Q000235:genetics* / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D000072470:Cytochrome P450 Family 4; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D064417:Vitamin K Epoxide Reductases / Q000235:genetics*; D014859:Warfarin / Q000008:administration & dosage* / Q000493:pharmacokinetics
chemical_list: D000925:Anticoagulants; D014859:Warfarin; D003577:Cytochrome P-450 Enzyme System; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D000072470:Cytochrome P450 Family 4; C117480:CYP4F2 protein, human; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases