Tramadol (TR) metabolism is mainly dependent on the enzymatic activity of CYP2D6, which is controlled by genetic polymorphisms. Individuals are classified as poor (PMs), intermediate (IMs), extensive (EMs) or ultrarapid metabolizers (UMs) according to their genotype or phenotype. The determination of the metabolic phenotype for CYP2D6 can be of utmost importance in forensic and clinical contexts that involve TR intake. The present study aimed to describe CYP2D6 genetic variants in cases of TR-related deaths and to assess which metabolic ratio(s) (MRs) would allow to determine CYP2D6 phenotype without having to perform genetic analyses. Forty-eight postmortem blood samples were selected from TR-related death cases previously analyzed in a forensic context in North of France between 2013 and 2019. Initial available data included blood concentrations of TR and its two main metabolites (M1 & M2) determined using a LC-MS/MS method. TR metabolism was expressed as various MRs comprising TR/M1, TR/M2 and M2/M1. After DNA extraction, sequencing was used for genetic variant detections that affect CYP2D6 activity/expression. In the present study, the allelic variants with the higher frequency were CYP2D6*1 (68%), followed by *4 (21%). The most frequent phenotype is EMs (59.6%), followed by IMs (23.4%), PMs (12.8%) and UMs (6.4%). There was no significant correlation between each calculated MR and the genotypically predicted phenotypes, except for M2/M1 which appears related to the PM phenotype. The observed distribution of CYP2D6 genetic variants in this TR-related death population was similar to that found in the general Caucasian population. The present study displayed that the blood M2/M1 ratio could be the best-correlated TR MR to the PM phenotype, and could thus be used in forensic contexts where genetic analyses are not possible or poorly informative. For the other phenotypes, especially the UM phenotype, genetic analysis appears to be the only reliable method to predict the CYP2D6 phenotype.

中文翻译：

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曲马多相关死亡：与代谢比率相关的遗传分析

曲马多 (TR) 代谢主要依赖于 CYP2D6 的酶活性，受基因多态性控制。根据他们的基因型或表型，个体被分为差 (PM)、中等 (IM)、广泛 (EM) 或超快代谢 (UM)。在涉及 TR 摄入的法医和临床环境中，确定 CYP2D6 的代谢表型可能是最重要的。本研究旨在描述 TR 相关死亡病例中的 CYP2D6 遗传变异，并评估哪些代谢比 (MR) 将允许确定 CYP2D6 表型而无需进行遗传分析。从 2013 年至 2019 年期间在法国北部的法医环境中分析的 TR 相关死亡病例中选择了 48 份死后血液样本。初始可用数据包括使用 LC-MS/MS 方法测定的 TR 及其两种主要代谢物（M1 和 M2）的血液浓度。TR 代谢表示为各种 MR，包括 TR/M1、TR/M2 和 M2/M1。DNA 提取后，测序用于影响 CYP2D6 活性/表达的遗传变异检测。在本研究中，频率较高的等位基因变异是 CYP2D6*1 (68%)，其次是 *4 (21%)。最常见的表型是 EM（59.6%），其次是 IM（23.4%）、PM（12.8%）和 UM（6.4%）。除了看起来与 PM 表型相关的 M2/M1 之外，每个计算的 MR 与基因型预测的表型之间没有显着相关性。在这个与 TR 相关的死亡人群中观察到的 CYP2D6 遗传变异分布与在一般高加索人群中发现的分布相似。本研究表明，血液 M2/M1 比率可能是与 PM 表型最相关的 TR MR，因此可用于无法进行遗传分析或信息量不足的法医环境。对于其他表型，尤其是 UM 表型，遗传分析似乎是预测 CYP2D6 表型的唯一可靠方法。