Division of Drug Research, Clinical Pharmacology, Department of Medical and Health Sciences, Linköping University, Linköping, Sweden.
Forensic Sci Int. 2012 Jan 10;214(1-3):124-34. doi: 10.1016/j.forsciint.2011.07.034. Epub 2011 Aug 12.
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.
文拉法辛（VEN）是一种主要通过细胞色素 P450（CYP）酶 CYP2D6 代谢为活性代谢物 O-去甲文拉法辛（ODV）的抗抑郁药。VEN 也通过 CYP3A4 代谢为 N-去甲文拉法辛（NDV）。ODV 和 NDV 进一步代谢为 N,O-二去甲文拉法辛（DDV）。VEN 是 S-和 R-对映异构体的外消旋混合物，体外显示出不同程度的 5-羟色胺和去甲肾上腺素再摄取抑制作用。本研究旨在探讨如果对 VEN 及其代谢物进行对映选择性分析，并结合 CYP2D6 基因分型，是否有助于解释不同死因的法医毒理学结果。从 56 例不同死因的尸检病例中采集股动脉血，测定对映体 VEN 和代谢物的浓度。药物分析采用液相色谱串联质谱（LC/MS/MS），CYP2D6 基因分型采用 PCR 和焦磷酸测序。VEN、ODV、NDV 和 DDV 的对映体 S/R 比值的平均值（中位数）分别为 0.99（0.91）、2.17（0.93）、0.92（0.86）和 1.08（1.03）。然而，VEN 和代谢物的 S-和 R-对映体之间的关系存在显著差异（S/R 比值范围为 0.23 至 17.6）。在 6 例中，低 S/R VEN 比值（平均值 0.5）与高 S/R ODV 比值（平均值 11.9）相关。基因分型显示这些个体携带两个无活性的 CYP2D6 基因，表明其代谢表型差。根据这些数据，我们得出结论，VEN 和 ODV 的对映选择性分析可以预测个体是否为 CYP2D6 的代谢表型差。了解这种抗抑郁药及其活性代谢物的 S-和 R-对映体之间的关系也很重要，因为对映体显示出不同的药效学特征。
