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- Title
Genetic variation at the CYP2C locus and its association with torsemide biotransformation.
- Authors
Vormfelde, S. V.; Schirmer, M.; Toliat, M. R.; Meineke, I.; Kirchheiner, J.; Nürnberg, P.; Brockmöller, 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 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.The Pharmacogenomics Journal (2007) 7, 200–211. doi:10.1038/sj.tpj.6500410; published online 12 September 2006
- Subjects
GENETIC polymorphisms; HYDROXYLATION; PHARMACOGENOMICS; CHEMICAL reactions; POPULATION genetics
- Publication
Pharmacogenomics Journal, 2007, Vol 7, Issue 3, p200
- ISSN
1470-269X
- Publication type
Article
- DOI
10.1038/sj.tpj.6500410