Abstract
Warfarin is an anticoagulant drug with narrow therapeutic index and high interindividual variability in dose requirement. S-warfarin is metabolized mainly by polymorphic cytochrome P450 (CYP) 2C9. We systematically quantified the influence of CYP2C9 genotype, demographic factors and concomitant drug treatment on warfarin metabolism and maintenance dose. The mean warfarin doses were lower in carriers of one (2.71 mg/day, 59 patients) and two polymorphic alleles (1.64 mg/day, 11 patients) than in carriers of two wild-type alleles (4.88 mg/day, 118 patients). Multiple regression analysis demonstrated that CYP2C9 genotype, age, concomitant treatment with warfarin metabolism inducers and lean body weight contributed significantly to interindividual variability in warfarin dose requirement (adjusted R2=0.37). The same factors, except for age, significantly influenced S-warfarin clearance (adjusted R2=0.42). These results can serve as a starting point for designing prospective studies in patients in the initiation phase of genotype-based warfarin therapy.
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Acknowledgements
We wish to thank Tina Globokar, MD from the University Medical Centre in Ljubljana, and Mitja Lainscak, MD from the General Hospital Murska Sobota for recruiting the patients and providing the clinical data. We also thank Gaj Vidmar, MSc, from the Institute of Biomedical Informatics, Faculty of Medicine in Ljubljana, for his assistance with the statistical analysis of the data. Control DNA samples for CYP2C9 genotyping were kindly provided by Umit Yasar and Marja Liisa Dahl, both formerly from the Karolinska Institutet, Huddinge University Hospital. This work was financially supported by the Ministry of Education, Science and Sport of Slovenia (Grants Nos. PO-0503-0381, P1-0170 and P1-0189-0787)
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Herman, D., Locatelli, I., Grabnar, I. et al. Influence of CYP2C9 polymorphisms, demographic factors and concomitant drug therapy on warfarin metabolism and maintenance dose. Pharmacogenomics J 5, 193–202 (2005). https://doi.org/10.1038/sj.tpj.6500308
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DOI: https://doi.org/10.1038/sj.tpj.6500308
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