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

The Pharmacogenomics Journal volume 7, pages 200–211 (2007)Cite this article

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.

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Acknowledgements

The study was in part supported by the national genome research network Grants 01 GS 0107 and 01 GR 0416. The skilful contributions of Franziska Tuchen, Michaela Torn and Jan Westermann to the clinical study part and that of Sabine Engelhardt to the drug concentration analyses are gratefully acknowledged.

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Authors and Affiliations

  1. Department of Clinical Pharmacology, University Medical Centre, Georg-August-University, Göttingen, Germany

    S V Vormfelde, M Schirmer, I Meineke & J Brockmöller

  2. Cologne Center for Genomics (CCG) and Institute for Genetics, University of Cologne, Cologne, Germany

    M R Toliat & P Nürnberg

  3. Department of Pharmacology of Natural Products & Clinical Pharmacology, University of Ulm, Ulm, Germany

    J Kirchheiner

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  1. S V Vormfelde
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Correspondence to S V Vormfelde.

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Vormfelde, S., Schirmer, M., Toliat, M. et al. Genetic variation at the CYP2C locus and its association with torsemide biotransformation. Pharmacogenomics J 7, 200–211 (2007). https://doi.org/10.1038/sj.tpj.6500410

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