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Warfarin dose adjustments based on CYP2C9 genetic polymorphisms.

Mark W Linder·Stephen Looney·Jesse E Adams·Nancy Johnson·Deborah Antonino-Green·Nichole Lacefield·Bonny L Bukaveckas·Roland Valdes
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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. METHODS AND 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.

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AdultAge FactorsAgedAged, 80 and overAnalysis of VarianceAryl Hydrocarbon HydroxylasesChi-Square DistributionCytochrome P-450 CYP2C9FemaleGenetic VariationHumansMaleMiddle AgedPolymorphism, GeneticWarfarinComparative StudyJournal ArticleResearch Support, Non-U.S. Gov't

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Mark W Linder, Stephen Looney, Jesse E Adams, Nancy Johnson, Deborah Antonino-Green, Nichole Lacefield, Bonny L Bukaveckas, Roland Valdes. 2002. Warfarin dose adjustments based on CYP2C9 genetic polymorphisms.. https://doi.org/10.1023/a%3A1025052827305

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