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

Item Type:Article
Title:Genetic variation at the CYP2C locus and its association with torsemide biotransformation
Creators Name:Vormfelde, S.V., Schirmer, M., Toliat, M.R., Meineke, I., Kirchheiner, J., Nuernberg, P. and Brockmoeller, J.
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 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.
Keywords:CYP2C9, Evolutionary selection, Haplotype, Hepatic clearance, Polymorphism, Torsemide
Source:Pharmacogenomics Journal
Publisher:Nature Publishing Group
Page Range:200-211
Date:1 June 2007
Official Publication:https://doi.org/10.1038/sj.tpj.6500410
PubMed:View item in PubMed

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