title: CYP2C19*17 affects R-warfarin plasma clearance and warfarin INR/dose ratio in patients on stable warfarin maintenance therapy.
abstract: OBJECTIVE
  We aimed to assess the influence of CYP2C19*17 on R-warfarin clearance as well as the effect of CYP2C19, CYP2C8, CYP2C9, and VKORC1 polymorphisms together with non-genetic factors on warfarin international normalized ratio (INR)/daily dose.
  
  
  METHODS
  One hundred fifty Caucasian Italian outpatients with data on steady-state plasma concentrations of S- and R-warfarin were genotyped for CYP2C19 (*2, *3, *4, *17), CYP2C9 (*2, *3), CYP2C8*3, and VKORC1*2. The statistical analysis was performed on the effect of genotypes/haplotypes, age, sex, and body weight on the clearance of warfarin enantiomers and dose-normalized INR.
  
  
  RESULTS
  R-warfarin clearance was 32% higher in carriers of CYP2C19*17 than in carriers of CYP2C19*2 (mean 2.5 mL/min, 95% confidence interval (CI) 2.3-2.8 vs. 1.9 mL/min, 95% CI 1.7-2.2; P post hoc = 0.01). Patients with CYP2C19*1/*1 genotype had an intermediate clearance (mean 2.1 mL/min, 95% CI 1.8-2.4). The genotypes of VKORC1, CYP2C9, and CYP2C19, together with non-genetic factors (age, sex, and body weight) explained 52% of the variability in warfarin INR/daily dose, of which CYP2C19 genotypes accounted for 7%.
  
  
  CONCLUSIONS
  This is the first study to include the gain-of-function CYP2C19*17 allele when assessing the impact of CYP2C19 polymorphisms on the clearance of warfarin enantiomers. CYP2C19 genotypes influenced the clearance of R-warfarin and contributed significantly to the variability in INR/daily dose, indirectly indicating a clinical relevance of R-warfarin.
authors: Department of Laboratory Medicine, Division of Clinical Pharmacology, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
authors: Ming
authors: M
authors: Chang
authors: Mao Mao
authors: MM
authors: Söderberg
authors: Maria Gabriella
authors: MG
authors: Scordo
authors: Gunnel
authors: G
authors: Tybring
authors: Marja-Liisa
authors: ML
authors: Dahl
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D065731:Cytochrome P-450 CYP2C19 / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005838:Genotype; D006801:Humans; D019934:International Normalized Ratio / Q000379:methods; D008297:Male; D008657:Metabolic Clearance Rate / Q000235:genetics*; D008875:Middle Aged; D010949:Plasma / Q000378:metabolism*; D011110:Polymorphism, Genetic / Q000235:genetics*; D014859:Warfarin / Q000097:blood* / Q000378:metabolism*; D044465:White People / Q000235:genetics; D055815:Young Adult
chemical_list: D014859:Warfarin; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19
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