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Influence of CYP2D6 and CYP2C19 genotypes on venlafaxine metabolic ratios and stereoselective metabolism in forensic autopsy cases

The Pharmacogenomics Journal volume 15, pages 165–171 (2015)Cite this article

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Abstract

We investigated whether polymorphisms in the CYP2D6 and CYP2C19 genes influence the metabolic ratios and enantiomeric S/R ratios of venlafaxine (VEN) and its metabolites O-desmethylvenlafaxine (ODV), N-desmethylvenlafaxine (NDV) and N,O-didesmethylvenlafaxine (DDV) in blood from forensic autopsy cases. In all, 94 postmortem cases found positive for VEN during toxicological screening were included. The CYP2D6 genotype was shown to significantly influence the ODV/VEN (P=0.003), DDV/NDV (P=0.010) and DDV/ODV (P=0.034) ratios. The DDV/ODV (P=0.013) and DDV/VEN (P=0.021) ratios were significantly influenced by the CYP2C19 genotype. The S/R ratios of VEN were significantly influenced by both CYP2D6 and CYP2C19 genotypes. CYP2D6 poor metabolizers (PMs) had lower S/R VEN ratios and CYP2C19 PMs had high S/R ratios of VEN in comparison. Our results show that the CYP2D6 genotype influences the O-demethylation whereas CYP2C19 influences the N-demethylation of VEN and its metabolites. In addition, we show a stereoselective metabolism where CYP2D6 favours the R-enantiomer whereas CYP2C19 favours the S-enantiomer.

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Acknowledgements

This work was supported by grants from the Swedish Research Council, the Lions Research Foundation and the National Board of Forensic Medicine in Sweden.

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Authors and Affiliations

  1. Division of Drug Research, Department of Medical and Health Sciences, Clinical Pharmacology, Linköping University, Linköping, Sweden

    L Karlsson, H Green & F C Kugelberg

  2. Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden

    A-L Zackrisson, M Josefsson, H Green & F C Kugelberg

  3. Department of Physics, Chemistry and Biology, Linköping University, Linköping, Sweden

    M Josefsson

  4. Division of Clinical Pharmacology, Department of Medical and Health Sciences, Faculty of Health, Sciences, Linköping University, County Council of Östergötland, Linköping, Sweden

    B Carlsson

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  1. L Karlsson
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Correspondence to L Karlsson.

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Karlsson, L., Zackrisson, AL., Josefsson, M. et al. Influence of CYP2D6 and CYP2C19 genotypes on venlafaxine metabolic ratios and stereoselective metabolism in forensic autopsy cases. Pharmacogenomics J 15, 165–171 (2015). https://doi.org/10.1038/tpj.2014.50

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