title: Different contributions of polymorphisms in VKORC1 and CYP2C9 to intra- and inter-population differences in maintenance dose of warfarin in Japanese, Caucasians and African-Americans.
abstract: OBJECTIVE
  To investigate pharmacokinetic and pharmacodynamic factors associated with population differences in warfarin doses needed to achieve anticoagulation, in particular the possible involvement of genetic variability in vitamin K epoxide reductase (VKOR) and CYP2C9.
  
  
  METHODS
  Warfarin maintenance dose, unbound plasma S-warfarin concentration [Cu(S)] and INR were determined in 157 Caucasians, 172 Japanese, and 36 African-Americans stably anticoagulated patients. In a subset (n = 166), fully carboxylated plasma normal prothrombin levels (NPT) were also measured. Genotyping for seven CYP2C9 (CYP2C9*1 through 6 and *11) and seven VKORC1 variants were performed in 115 Caucasians and 64 Japanese patients and 66 healthy African-Americans. Multivariate analysis was performed to identify covariates associated with warfarin requirement.
  
  
  RESULTS
  The relationship between NPT and Cu(S) indicated Japanese are more susceptible to inhibition of NPT production by S-warfarin than the other two populations. VKORC1 1173 C > T had a greater frequency in Japanese (89.1%) than Caucasians (42.2%) and African-Americans (8.6%). CYP2C9 variants with reduced metabolizing ability were less frequent in Japanese compared to the other two populations. The median warfarin dose was significantly higher in Caucasians than Japanese patients (5.5 versus 3.5 mg/day), however, when matched for CYP2C9*1 homozygosity, no difference in dose was observed between VKORC1 genotype-matched groups. Furthermore, VKORC1 1173C > T and CYP2C9 (*2/*3/*11) genotypes, age and weight were identified as independent covariates contributing to interpatient variability in warfarin dosage.
  
  
  CONCLUSIONS
  Both VKORC1 and CYP2C9 polymorphisms contribute to inter-population difference in warfarin doses among the three populations, but their contribution to intra-population variability may differ within each population.
authors.affiliation: Department of Pharmacotherapy, Meiji Pharmaceutical University, Kiyose, Tokyo, Japan. harumit@my-pharm.ac.jp
authors.forename: Harumi
authors.initials: H
authors.lastname: Takahashi
authors.forename: Grant R
authors.initials: GR
authors.lastname: Wilkinson
authors.forename: Edith A
authors.initials: EA
authors.lastname: Nutescu
authors.forename: Takashi
authors.initials: T
authors.lastname: Morita
authors.forename: Marylyn D
authors.initials: MD
authors.lastname: Ritchie
authors.forename: Maria G
authors.initials: MG
authors.lastname: Scordo
authors.forename: Vittorio
authors.initials: V
authors.lastname: Pengo
authors.forename: Martina
authors.initials: M
authors.lastname: Barban
authors.forename: Roberto
authors.initials: R
authors.lastname: Padrini
authors.forename: Ichiro
authors.initials: I
authors.lastname: Ieiri
authors.forename: Kenji
authors.initials: K
authors.lastname: Otsubo
authors.forename: Toshitaka
authors.initials: T
authors.lastname: Kashima
authors.forename: Sosuke
authors.initials: S
authors.lastname: Kimura
authors.forename: Shinichi
authors.initials: S
authors.lastname: Kijima
authors.forename: Hirotoshi
authors.initials: H
authors.lastname: Echizen
mesh_terms: D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D044466:Asian People; D044383:Black People; D065729:Cytochrome P-450 CYP2C9; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D007223:Infant; D007564:Japan; D008297:Male; D006899:Mixed Function Oxygenases / Q000235:genetics*; D010597:Pharmacogenetics / Q000379:methods*; D014481:United States; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000494:pharmacology*; D044465:White People; D001741:Black or African American
chemical_list: D014859:Warfarin; D006899:Mixed Function Oxygenases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases