Responsiveness to low-dose warfarin associated with genetic variants of VKORC1, CYP2C9, CYP2C19, and CYP4F2 in an Indonesian population
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The aim of this study was to assess the pharmacokinetics and pharmacodynamics of warfarin associated with genetic polymorphisms in VKORC1, CYP2C9, CYP2C19, and CYP4F2 in Indonesian patients treated with low-dose warfarin.
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-hydroxywarfarin were used as pharmacokinetic indices, while prothrombin time expressed as the international normalized ratio (PT-INR) was used as a pharmacodynamic index.
In patients treated with a fixed daily dose of warfarin (1 mg), a higher PT-INR was associated with VKORC1-1639 AA [median 1.35; interquartile range (IQR) 1.21–1.50] than with the GA (1.18; IQR 1.12–1.32; 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 administration, there was no significant difference in the concentrations of warfarin metabolites among any of the genotype variants. The genotype variations of CYP2C19 and CYP4F2 were not significantly associated with the PT-INR.
For low-dose warfarin treatment, the VKORC1-1639 G > A and CYP2C9 genotype variations affected the pharmacokinetics and pharmacodynamics of warfarin, while we could not find significant effects of CYP4F2 or CYP2C19 genotype variations on warfarin (metabolite) concentrations or PT-INR.
KeywordsWarfarin Pharmacogenetics VKORC1 CYP2C9 CYP4F2
The authors thank all physicians and nursing staffs of the cardiovascular services units in Al-Islam Hospital, Salamun Hospital, and Hasan Sadikin Hospital, Bandung, Indonesia, for their participation in this study. We thank Norisca Aliza Putriana and Sari Handayani for their assistance in collecting patient data and providing technical support. We also thank Aiko Matsumoto for her secretarial assistance.
Conflict of interests
- 19.Gao L, He L, Luo J, Xu B, Yang J, Zhang YX et al (2011) Extremely low warfarin dose in patients with genotypes of CYP2C9*3/*3 and VKORC1-1639A/A. Chin Med J (Engl) 124(17):2767–2770Google Scholar
- 21.Aomori T, Yamamoto K, Oguchi-Katayama A, Kawai Y, Ishidao T, Mitani Y et al (2009) Rapid single-nucleotide polymorphism detection of cytochrome P450 (CYP2C9) and vitamin K epoxide reductase (VKORC1) genes for the warfarin dose adjustment by the SMart-amplification process version 2. Clin Chem 55(4):804–812PubMedCrossRefGoogle Scholar
- 22.Furuta T, Shirai N, Takashima M, Xiao F, Hanai H, Sugimura H et al (2001) Effect of genotypic differences in CYP2C19 on cure rates for Helicobacter pylori infection by triple therapy with a proton pump inhibitor, amoxicillin, and clarithromycin. Clin Pharmacol Ther 69(3):158–168PubMedCrossRefGoogle Scholar
- 29.Kwon A, Jo SH, Im HJ, Jo YA, Park JY, Kang HJ, et al. (2011) Pharmacogenetic distribution of warfarin and its clinical significance in Korean patients during initial anticoagulation therapy. J Thromb Thrombolysis 32(4):467–473Google Scholar
- 35.Singh O, Sandanaraj E, Subramanian K, Lee LH, Chowbay B (2011) The influence of CYP4F2 rs2108622 (V433M) on warfarin dose requirement in Asian patients. Drug Metab Pharmacokinet 26(2):130–136Google Scholar
- 36.Nakamura K, Obayashi K, Araki T, Aomori T, Fujita Y, Okada Y, et al. (2012) CYP4F2 gene polymorphism as a contributor to warfarin maintenance dose in Japanese subjects. J Clin Pharm Ther 37(4):481–485Google Scholar
- 39.Gan GG, Phipps ME, Lee MM, Lu LS, Subramaniam RY, Bee PC, et al. (2011) Contribution of VKORC1 and CYP2C9 polymorphisms in the interethnic variability of warfarin dose in Malaysian populations. Ann Hematol 90(6):635–641Google Scholar