1. ¹Faculty of Pharmacy, Université de Montréal, Montreal, Quebec, Canada
2. ²Montreal Heart Institute, Montreal, Quebec, Canada
3. ³Institut Universitaire de Cardiologie, Hôpital Laval, Quebec, Quebec, Canada
4. ⁴Haut-Richelieu Hospital, St-Jean sur Richelieu, Quebec, Canada
5. ⁵Xanthus Pharmaceuticals, Cambridge, Massachusetts, USA
6. ⁶Faculty of Medicine, Genome Quebec & Montreal Heart Institute, Pharmacogenomics Centre, Université de Montréal, Montreal, Quebec, Canada
7. ⁷Cité de la Santé de Laval, Laval, Quebec, Canada

Correspondence: J Turgeon, (jacques.turgeon.chum@ssss.gouv.qc.ca)

Received 2 February 2007; Accepted 7 September 2007; Published online 14 November 2007.

Abstract

The relative contribution of phenotypic measures and CYP2C9-vitamin K epoxide reductase complex subunit 1 (VKORC1) polymorphisms to warfarin dose requirements at day 14 was determined in 132 hospitalized, heavily medicated patients. Phenotypic measures were (1) the urinary losartan metabolic ratio before the first dose of warfarin, (2) the S:R-warfarin ratio at day 1, and (3) a dose-adjusted international normalized ratio (INR) at day 4. CYP2C9 and VKORC1 genotypes were determined by gene chip analysis. In multivariate analyses, the dose-adjusted INR at day 4 explained 31% of variability observed in warfarin doses at day 14, whereas genotypic measures (CYP2C9-VKORC1) contributed 6.5% . When S:R-warfarin ratio was used, genotypes contributed more significantly (23.5% ). Finally, urinary losartan metabolic ratio was of low predictive value. The best models obtained explained 51% of intersubject variability in warfarin dose requirements. Thus, combination of a phenotypic measure to CYP2C9-VKORC1 genotypes represents a useful strategy to predict warfarin doses in patients receiving multiple drugs (114 drugs/day).