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. and Schirmer, M. and Toliat, M.R. and Meineke, I. and Kirchheiner, J. and 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
ISSN:	1470-269X
Publisher:	Nature Publishing Group
Volume:	7
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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