Association Between Genetic Polymorphisms and Steady-State Plasma Concentration of Warfarin Optical Isomers

Background We evaluated the effects of CYP2C19*2, CYP2C9*3, VKORC1 A1639G, CYP4F2, and MDR1 C3435T gene polymorphisms on the plasma concentrations of R- and S-warfarin enantiomers at the same dose.

Methods The plasma concentrations of R- and S-warfarin were determined by ultra performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) in 136 patients. The PCR-RFLP genotyping results were verified by pyrosequencing. The Hardy–Weinberg equilibrium of genotype frequencies was assessed using the Chi-square analysis. Relationships between genotype and plasma concentrations of the enantiomers were analyzed by Kruskal–Wallis test.

Results There was no significant difference in the dosage between groups (P > 0.05). The CYP2C19*2, CYP2C9*3, CYP4F2, MDR1 C3435T, and VKORC1 A1639G mutation frequencies were 37.5%, 6.25%, 19.12%, 31.25%, and 3.31%, respectively. The plasma concentrations were non-normally distributed. The S-warfarin plasma concentration was significantly higher in CYP2C9*3 carriers than in non-carriers (P = 0.018) and in patients carrying the T allele of CYP4F2 than those carrying the C allele (P = 0.03). The VKORC1 A1639G polymorphism did not affect the steady-state plasma concentrations of R- and S-warfarin. The enantiomer ratio in homozygous patients (GG) was significantly lower than that in heterozygous patients (GA) and those lacking the mutation (AA) (P = 0.039). Enantiomer plasma levels were not significantly different between MDR1 C3435T and CYP2C19*2 (P > 0.052).

Conclusions The CYP2C9*3 and CYP4F2 mutations are associated with increased plasma concentrations of S-warfarin. The VKORC1 A1639G polymorphism might affect the plasma ratio of R- and S-warfarin. Maintenance dose reduction during warfarin administration can be considered for patients with the CYP2C9*3 and CYP4F2 mutations.