title: Influence of CYP2D6 and CYP2C19 genotypes on venlafaxine metabolic ratios and stereoselective metabolism in forensic autopsy cases.
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.
authors.affiliation: Division of Drug Research, Clinical Pharmacology, Department of Medical and Health Sciences, Linköping University, Linköping, Sweden.
authors.forename: L
authors.initials: L
authors.lastname: Karlsson
authors.affiliation: Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
authors.forename: A-L
authors.initials: AL
authors.lastname: Zackrisson
authors.affiliation: 1] Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden [2] Department of Physics, Chemistry and Biology, Linköping University, Linköping, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Josefsson
authors.affiliation: Division of Clinical Pharmacology, Department of Medical and Health Sciences, Faculty of Health, Sciences, Linköping University, County Council of Östergötland, Linköping, Sweden.
authors.forename: B
authors.initials: B
authors.lastname: Carlsson
authors.affiliation: 1] Division of Drug Research, Clinical Pharmacology, Department of Medical and Health Sciences, Linköping University, Linköping, Sweden [2] Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
authors.forename: H
authors.initials: H
authors.lastname: Green
authors.affiliation: 1] Division of Drug Research, Clinical Pharmacology, Department of Medical and Health Sciences, Linköping University, Linköping, Sweden [2] Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
authors.forename: F C
authors.initials: FC
authors.lastname: Kugelberg
mesh_terms: D001344:Autopsy / Q000379:methods; D065731:Cytochrome P-450 CYP2C19 / Q000235:genetics*; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D005260:Female; D044707:Forensic Sciences; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000235:genetics*; D000069470:Venlafaxine Hydrochloride / Q000378:metabolism*
chemical_list: D000069470:Venlafaxine Hydrochloride; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6