Pustaka Ilmiah Universitas Padjadjaran

Abstrak

Responsiveness to low-dose warfarin associated with genetic variants of VKORC1, CYP2C9, CYP2C19, and CYP4F2 in an Indonesian population

Purpose The aim of this study was to assess the pharmacoki¬netics and pharmacodynamics of warfarin associated with ge¬netic polymorphisms in VKORC1, CYP2C9, CYP2C19, and CYP4F2 in Indonesian patients treated with low-dose warfarin, Methods Genotyping of VKORC1, CYP2C9, CYP2C19, and CYP4F2 was carried out in 103 patients treated with a daily dose of 1-2 mg warfarin, 89 of whom were treated with a fixed daily dose of warfarin (1 mg). The plasma concentrations of S- and R-warfarin and S- and R-7-hydroxy¬warfarin were used as pharmacokinetic indices, while pro-thrombin time expressed as the international normalized ratio (PT-INR) was used as a pharmacodynamic index. Results In patients treated with a fixed daily dose of warfarin (1 mg), a higher PT-INR was associated with YKORCI-1639 AA [median 1 35; interquartile range (IQR)1.21-1.50] than with the GA (1.18; IQR1.12-1.32; p<0.01) and GG (1.02; IQR=1.02-1.06; p<0.01) polymorphisms, and with CYP2C9*1/*3 (1.63; IQR 1.45-1.85) compared to *1/*1 (1.23; IQR 1.13-1.43;p<0.05). The S-warfarin concentration was significantly higher in patients with CYP2C9*1/*3 than in those with *1/*1 (p<0.05). With low-dose warfarin adminis¬tration, there was no significant difference in the concentra¬tions of warfarin metabolites among any of the genotype variants. The genotype variations of CYP2C19 and CYP4F2 were not significantly associated with the PT-NR. Conclusion For low-dose warfarin treatment, the VKORC1- 1639 G>A and CYP2C9 genotype variations affected the pharmacokinetics and phannacodynamics of warfarin, while we could not find significant effects of CYP4F2 or CYP2C19 genotype variations on warfarin (metabolite) concentrations or PT-INR.