title: Responsiveness to low-dose warfarin associated with genetic variants of VKORC1, CYP2C9, CYP2C19, and CYP4F2 in an Indonesian population.
abstract: OBJECTIVE
  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.
  
  
  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-hydroxywarfarin were used as pharmacokinetic indices, while prothrombin 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 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Clinical Pharmacology, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi 371-8511, Japan. taofikr@unpad.ac.id
authors.forename: T
authors.initials: T
authors.lastname: Rusdiana
authors.forename: T
authors.initials: T
authors.lastname: Araki
authors.forename: T
authors.initials: T
authors.lastname: Nakamura
authors.forename: A
authors.initials: A
authors.lastname: Subarnas
authors.forename: K
authors.initials: K
authors.lastname: Yamamoto
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism; D044466:Asian People / Q000235:genetics*; D001711:Biotransformation; D001777:Blood Coagulation / Q000187:drug effects*; D016009:Chi-Square Distribution; D065731:Cytochrome P-450 CYP2C19; D065729:Cytochrome P-450 CYP2C9; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism; D000072470:Cytochrome P450 Family 4; D016903:Drug Monitoring / Q000379:methods; D005260:Female; D005787:Gene Frequency; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D007214:Indonesia / Q000453:epidemiology; D019934:International Normalized Ratio; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics* / Q000378:metabolism; D015999:Multivariate Analysis; D010597:Pharmacogenetics; D010641:Phenotype; D011517:Prothrombin Time; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D000925:Anticoagulants; C101436:8-hydroxywarfarin; D014859:Warfarin; D003577:Cytochrome P-450 Enzyme System; C087837:7-hydroxywarfarin; D006899:Mixed Function Oxygenases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D000072470:Cytochrome P450 Family 4; C117480:CYP4F2 protein, human; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases