1. ¹Institute of Biochemistry, Faculty of Medicine, Ljubljana, Slovenia
2. ²Faculty of Pharmacy, Ljubljana, Slovenia
3. ³Department for Vascular Diseases, University Medical Centre, Ljubljana, Slovenia

Correspondence: Dr V Dolzan, Institute of Biochemistry, Faculty of Medicine, Vrazov trg 2, Ljubljana SI-1000, Slovenia. Tel: +386 1 543 76 69; Fax: +386 1 543 76 41; E-mail: vita.dolzan@mf.uni-lj.si

⁴Both these authors contributed equally to this study.

Received 12 August 2004; Revised 31 January 2005; Accepted 24 February 2005; Published online 12 April 2005.

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.