title: Warfarin dose adjustments based on CYP2C9 genetic polymorphisms.
abstract: BACKGROUND
  The dose response relationship of warfarin is unpredictable. Polymorphism of the Cytochrome P4502C9 enzyme leads to warfarin hypersensitivity presumably due to decreased metabolism of the S-enantiomer. The purpose of this study was to further characterize the relationship between CYP2C9 genotype and phenotype and to develop a basis for guidelines to interpret CYP2C9 genotype for warfarin dosing.
  
  
  RESULTS
  Patients stabilized on warfarin therapy were recruited from an anticoagulation clinic. Patients were genotyped for CYP2C9*2, CYP2C9*3 and CYP2C9*5 alleles by standard methods of polymerase chain reaction amplification and restriction endonuclease digestion. Phenotype was determined by; dose (mg/kg/d) required to maintain anticoagulation, (INR 2.0-3.0), oral plasma S-warfarin clearance, and the plasma S:R-warfarin ratio. In this cohort, no subjects were found to have the CYP2C9*5 allele. The plasma S-warfarin concentration did not differ with age, dose or CYP2C9 genotype. Both CYP2C9*2 and *3 alleles were associated with lower maintenance dosages, lower total and R-warfarin plasma concentrations, decreased oral clearance of S-warfarin, increased plasma S:R-warfarin ratio and extended S-warfarin elimination half-life. Advancing age was found to decrease Warfarin maintenance dose in subjects with the common active CYP2C9*1/*1 genotype but did not influence dose requirement of subjects with one or more variant CYP2C9 alleles.
  
  
  CONCLUSIONS
  Subjects who have been titrated to a consistent target INR demonstrate comparable plasma S-warfarin concentrations independent of CYP2C9 genotype. The warfarin dose required to maintain a consistent target INR between subjects differs as a function of S-warfarin clearance which is decreased by both CYP2C9*2 and or CYP2C9*3 variant alleles. The variables of CYP2C9 genotype and age can be applied to restrict the dosage range considered for individual patients.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Louisville School of Medicine, Louisville, KY 40292, USA. mwlind01@gwise.louisville.edu
authors.forename: Mark W
authors.initials: MW
authors.lastname: Linder
authors.forename: Stephen
authors.initials: S
authors.lastname: Looney
authors.forename: Jesse E
authors.initials: JE
authors.lastname: Adams
authors.forename: Nancy
authors.initials: N
authors.lastname: Johnson
authors.forename: Deborah
authors.initials: D
authors.lastname: Antonino-Green
authors.forename: Nichole
authors.initials: N
authors.lastname: Lacefield
authors.forename: Bonny L
authors.initials: BL
authors.lastname: Bukaveckas
authors.forename: Roland
authors.initials: R
authors.lastname: Valdes
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000704:Analysis of Variance; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D016009:Chi-Square Distribution; D065729:Cytochrome P-450 CYP2C9; D005260:Female; D014644:Genetic Variation / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000235:genetics*; D014859:Warfarin / Q000008:administration & dosage*
chemical_list: D014859:Warfarin; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases