1. ¹Department of Medical Sciences, Clinical Pharmacology, University Hospital, Uppsala, Sweden
2. ²Department of Genetics and Pathology, Medical Genetics, Rudbeck Laboratory, Uppsala, Sweden
3. ³Medical Products Agency, Uppsala, Sweden

Correspondence: M Wadelius, Department of Medical Sciences, Clinical Pharmacology, University Hospital, SE-751 85 Uppsala, Sweden. Tel: +46 18 611 49 45; Fax: + 46 18 51 92 37; E-mail: Mia.Wadelius@medsci.uu.se

⁴Temporary address: The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK. Tel: +44 1223 49 47 09.

Received 9 July 2003; Revised 3 October 2003; Accepted 14 October 2003; Published online 16 December 2003.

Abstract

The required dose of the oral anticoagulant warfarin varies greatly, and overdosing often leads to bleeding. Warfarin is metabolised by cytochrome P450 enzymes CYP2C9, CYP1A2 and CYP3A. The target cell level of warfarin may be dependent on the efflux pump P-glycoprotein, encoded by the adenosine triphosphate-binding cassette gene ABCB1 (multidrug resistance gene 1). Genetic variability in CYP2C9, CYP3A5 and ABCB1 was analysed in 201 stable warfarin-treated patients using solid-phase minisequencing, pyrosequencing and SNaPshot. CYP2C9 variants, age, weight, concurrent drug treatment and indication for treatment significantly influenced warfarin dosing in these patients, explaining 29% of the variation in dose. CYP3A5 did not affect warfarin dosing. An ABCB1 haplotype containing the exon 26 3435T variant was over-represented among low-dose patients. Thirty-six patients with serious bleeding complications had higher prothrombin time international normalised ratios than 189 warfarin-treated patients without serious bleeding, but there were no significant differences in CYP2C9, CYP3A5 or ABCB1 genotypes and allelic variants.