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MICHAEL P. GULSETH, PHARM.D., BCPS, is Program Director, Anticoagulation Services, Sanford–University of South Dakota Medical Center, Sioux Falls. GLORIA R. GRICE, PHARM.D., BCPS, is Assistant Professor of Pharmacy Practice and Assistant Director of Experiential Programs, St. Louis College of Pharmacy, and Manager, Barnes-Jewish Hospital Anticoagulation Service, Washington University, St. Louis, MO. WILLIAM E. DAGER, PHARMD., is Pharmacist Specialist, University of California Davis Medical Center, Davis, and Clinical Professor of Pharmacy, School of Pharmacy, University of California San Francisco, San Francisco.

Address correspondence to Dr. Gulseth at Sanford–University of South Dakota Medical Center, 1305 West 18th Street, P.O. Box 5039, Sioux Falls, SD 57117 (gulsethm{at}sanfordhealth.org).

Purpose. The literature on the pharmacogenomics of warfarin and the use of genetic testing to optimize initial and maintenance warfarin dosing is reviewed. Summary. Warfarin tablets contain a racemic mixture of R- and S-isomers. The S-isomer is responsible for about 70% of warfarin’s anticoagulant effect. Cytochrome P-450 isoenzyme 2C9 (CYP2C9) metabolizes S-warfarin into two inactive metabolites. Genetic variations to the gene encoding CYP2C9 (CYP2C9 ) are known to affect warfarin clearance. Single nucleotide polymorphisms (SNPs) have been identified that clearly influence warfarin metabolism and sensitivity, including SNP variants of CYP2C9 and SNPs in vitamin K epoxide reductase complex subunit 1 (VKORC1), which influence an individual’s sensitivity to a given dose. Retrospective studies have evaluated potential factors influencing warfarin metabolism, maintenance dosing, and variability. Several dosing models used to predict warfarin dosing (initial or refinement) have been retrospectively evaluated in diverse patient populations. There are several arguments to support incorporating its use in current clinical practice; however, many expert clinicians in anticoagulation have expressed concern that the push for genotyping patients for CYP2C9 and VKORC1 is premature and not based on good, prospective evidence. Large, randomized controlled trials, in multiple patient populations, comparing clinical dosing to genetic-guided dosing are needed to fully determine the benefits of pharmacogenetic warfarin dosing. Conclusion. The increased understanding of pharmacogenomics may improve patient safety during initial dosing of warfarin. At this time, it is unknown if genotype-based dosing will become the standard of care for patients receiving the drug. Index terms: Anticoagulants; Dosage; Genetics; Metabolism; Methodology; Pharmacogenetics; Tests, laboratory; Warfarin

 

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