Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Artillerigatan 12, 58758 Linkoping, Sweden; Division of Drug Research, Department of Biomedical and Clinical Sciences, Faculty of Health and Science, Linkoping University, 58183 Linkoping, Sweden.
Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Artillerigatan 12, 58758 Linkoping, Sweden.
Forensic Sci Int Genet. 2021 Jul;53:102510. doi: 10.1016/j.fsigen.2021.102510. Epub 2021 Mar 26.
Genetic disposition can cause variation in oxycodone pharmacokinetic characteristics and decrease or increase the expected clinical response. In forensic medicine, determination of cause of death or assessing time between drug intake and death can be facilitated by knowledge of parent and metabolite concentrations. In this study, the aim was to investigate if CYP2D6 genotyping can facilitate interpretation by investigating the frequency of the four CYP2D6 phenotypes, poor metabolizer, intermediate metabolizer, extensive metabolizer, and ultra-rapid metabolizer in postmortem cases, and to study if the CYP2D6 activity was associated with a certain cause of death, concentration, or metabolic ratio. Cases positive for oxycodone in femoral blood (n = 174) were genotyped by pyrosequencing for CYP2D6*3, *4, and 6 and concentrations of oxycodone, noroxycodone, oxymorphone, and noroxymorphone were determined by LC-MS/MS (LLOQ 0.005 µg/g). Digital droplet PCR was used to determine the copy number variation for CYP2D65. Cases were categorized by cause of death. It was found that poor and intermediate CYP2D6 metabolizers had significantly higher oxycodone and noroxycodone concentrations compared to extensive and ultra-rapid metabolizers. CYP2D6 phenotype were equally distributed between cause of death groups, showing that no phenotype was overrepresented in any of the cause of death groups. We also found that the concentration ratio between oxymorphone and oxycodone depended on the CYP2D6 activity when death was unrelated to intoxication. In general, a low metabolite to parent ratio indicate an acute intake. By using receiver operating characteristic (ROC) analysis, we conclude that an oxymorphone/oxycodone ratio lower than 0.075 has a high sensitivity for separating intoxications with oxycodone from other intoxications and non-intoxications. However, the phenotype needs to be known to reach a high specificity. Therefore, the ratio should not be used as a biomarker on its own to distinguish between different causes of death but needs to be complemented by genotyping.
遗传易感性可导致羟考酮药代动力学特征的变化，并降低或增加预期的临床反应。在法医学中，通过了解母体药物和代谢物的浓度，可以促进对死亡原因的判断或评估药物摄入与死亡之间的时间间隔。在这项研究中，我们旨在通过研究死后病例中四种 CYP2D6 表型（弱代谢型、中间代谢型、广泛代谢型和超快代谢型）的频率，来探讨 CYP2D6 基因分型是否有助于解释，并研究 CYP2D6 活性是否与某种死亡原因、浓度或代谢比值相关。采用焦磷酸测序法对股动脉血中检出羟考酮阳性的 174 例病例进行 CYP2D63、4 和6 基因分型，采用 LC-MS/MS 法（LLOQ 为 0.005μg/g）测定羟考酮、去羟考酮、羟吗啡酮和去羟吗啡酮的浓度。采用数字液滴 PCR 法测定 CYP2D65 的拷贝数变异。根据死亡原因对病例进行分类。结果发现，与广泛代谢型和超快代谢型相比，弱代谢型和中间代谢型的羟考酮和去羟考酮浓度显著更高。CYP2D6 表型在死因组之间分布均匀，表明在任何死因组中都没有表型过度代表。我们还发现，当死亡与中毒无关时，羟吗啡酮与羟考酮的浓度比值取决于 CYP2D6 活性。一般来说，低代谢物与母体比值表明急性摄入。通过接受者操作特征（ROC）分析，我们得出结论，当羟吗啡酮/羟考酮比值低于 0.075 时，对于区分羟考酮中毒与其他中毒和非中毒具有较高的敏感性。然而，需要知道表型才能达到较高的特异性。因此，该比值不能单独用作区分不同死因的生物标志物，而需要与基因分型相结合。
