Genetic variation at the CYP2C locus and its association with torsemide biotransformation

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 r(2) = 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.