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2012 (English)In: Forensic Science International, ISSN 0379-0738, E-ISSN 1872-6283, Vol. 214, no 1-3, p. 124-134Article in journal (Refereed) Published
Abstract [en]
Venlafaxine (VEN) is an antidepressant drug mainly metabolized by the cytochrome P450 (CYP) enzyme CYP2D6 to the active metabolite O-desmethylvenlafaxine (ODV). VEN is also metabolized to N-desmetylvenlafaxine (NDV) via CYP3A4. ODV and NDV are further metabolized to N,O-didesmethylvenlafaxine (DDV). VEN is a racemic mixture of the S- and R-enantiomers and these have in vitro displayed different degrees of serotonin and noradrenaline reuptake inhibition. The aim of the study was to investigate if an enantioselective analysis of VEN and its metabolites, in combination with genotyping for CYP2D6, could assist in the interpretation of forensic toxicological results in cases with different causes of deaths. Concentrations of the enantiomers of VEN and metabolites were determined in femoral blood obtained from 56 autopsy cases with different causes of death. The drug analysis was done by liquid chromatography tandem mass spectrometry (LC/MS/MS) and the CYP2D6 genotyping by PCR and pyrosequencing. The mean (median) enantiomeric S/R ratios of VEN, ODV, NDV and DDV were 0.99 (0.91), 2.17 (0.93), 0.92 (0.86) and 1.08 (1.03), respectively. However, a substantial variation in the relationship between the S- and R-enantiomers of VEN and metabolites was evident (S/R ratios ranging from 0.23 to 17.6). In six cases, a low S/R VEN ratio (mean 0.5) was associated with a high S/R ODV ratio (mean 11.9). Genotyping showed that these individuals carried two inactive CYP2D6 genes indicating a poor metabolizer phenotype. From these data we conclude that enantioselective analysis of VEN and ODV can predict if a person is a poor metabolizer genotype/phenotype for CYP2D6. Knowledge of the relationship between the S- and R-enantiomers of this antidepressant drug and its active metabolite is also important since the enantiomers display different pharmacodynamic profiles.
Place, publisher, year, edition, pages
Elsevier, 2012
Keywords
CYP2D6; Enantiomers; Forensic toxicology; Postmortem toxicology; Venlafaxine
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-72238 (URN)10.1016/j.forsciint.2011.07.034 (DOI)000298634900032 ()21840145 (PubMedID)
Note
Funding agencies|Forensic Science Center of Linkoping University||National Board of Forensic Medicine in Sweden||Swedish Research Council| 2009-4740 |
2011-11-232011-11-232017-12-08Bibliographically approved