TY - JOUR
T1 - Warfarin dose adjustments based on CYP2C9 genetic polymorphisms
AU - Linder, Mark W.
AU - Looney, Stephen
AU - Adams, Jesse E.
AU - Johnson, Nancy
AU - Antonino-Green, Deborah
AU - Lacefield, Nichole
AU - Bukaveckas, Bonny L.
AU - Valdes, Roland
N1 - Funding Information:
This work was supported by grants from the University of Louisville School of Medicine (MWL) and the Jewish Hospital Research Foundation of Louisville (MWL).
PY - 2002/12
Y1 - 2002/12
N2 - 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.
AB - 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.
KW - CYP2C9
KW - Pharmacogenetics
KW - Warfarin
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U2 - 10.1023/A:1025052827305
DO - 10.1023/A:1025052827305
M3 - Article
C2 - 12913403
AN - SCOPUS:0042915883
SN - 0929-5305
VL - 14
SP - 227
EP - 232
JO - Journal of Thrombosis and Thrombolysis
JF - Journal of Thrombosis and Thrombolysis
IS - 3
ER -