1. ¹Department of Clinical Pharmacology, University Medical Centre, Georg-August-University, Göttingen, Germany
2. ²Cologne Center for Genomics (CCG) and Institute for Genetics, University of Cologne, Cologne, Germany
3. ³Department of Pharmacology of Natural Products & Clinical Pharmacology, University of Ulm, Ulm, Germany

Correspondence: Dr SV Vormfelde, Department of Clinical Pharmacology, University Medical Centre, Robert-Koch-Strae 40, 37075 Göttingen, Germany. E-mail: svormfe@gwdg.de

Received 17 March 2006; Revised 19 June 2006; Accepted 27 June 2006; Published online 12 September 2006.

Abstract

In 97 unselected volunteers and two additional homozygous carriers of CYP2C9^*3, we investigated the oral clearance of torsemide in relation to 37 polymorphisms at the CYP2C gene locus. Torsemide total oral clearance was linearly associated with the number of CYP2C9^*3 alleles (geometric mean: 59, 40 and 20 ml/min in carriers of no, one and two alleles) and so were the methyl- and ring-hydroxylation but not the carboxylation clearance. Haplotypes including the CYP2C9^*3 allele were similarly associated with the clearances but no other variant and no haplotype not including the CYP2C9^*3 variant. The extended haplotype length (EHL) of the CYP2C9 haplotypes was positively associated with higher activity of the gene product. Torsemide total oral clearance was predictable with r²=82.1% using plasma concentrations at 0.5, 1, 2 and 24 h. In conclusion, torsemide's biotransformation strongly depended on the CYP2C9^*3 variant but no other. Higher clearance CYP2C9 haplotypes appear to be evolutionarily selected.