DataSheet1_Metabolic stability and metabolite profiling of emerging synthetic cathinones.PDF

Synthetic cathinones constitute the second largest groups of new psychoactive substances (NPS), which are especially popular among adolescents and young adults. Due to their potential toxicity, the recreational use of these NPS constitute a serious worldwide public health problem. However, their fast appearance in the market renders the continuous updating of NPS information highly challenging for forensic authorities. The unavailability of pharmacokinetic data for emerging NPS is critical for forensic and clinical verifications. With the ultimate goal of having a proactive approach towards the NPS issue, high resolution mass spectrometry was used in the current work to assess preliminary pharmacokinetic data for 8 selected cathinones: 4 reported substances (4-CIC, 3-CMC, 4-CMC and 4-MEAP) and 4 previously unreported ones (3-CIC, 4-MDMB, 4-MNEB and 4-MDMP) for which the emergence on the NSP market is expected to be eminent, were also included in this study. Based on the calculation of pharmacokinetic parameters, half-life and intrinsic clearance, 4-CMC and 4-MDMB are low and high clearance compounds, respectively, and all the remaining cathinones included in this study are intermediate clearance compounds. This fact anticipates the key role of metabolites as suitable biomarkers to extend detection windows beyond those provided by the parent cathinones. Reduction of the keto group and hydroxylation on the alkyl chains were the common metabolic pathways identified for all cathinones. However, the relative importance of these metabolic transformations is dependent on the cathinone substituents. The glucuronic acid conjugation to metabolites stemming for keto group reduction constituted the sole Phase II transformation identified. To our knowledge, this study constitutes the first metabolite profiling of the already reported synthetic cathinones 4-CIC, 3-CMC and 4-CMC. Noteworthy is the fact that 3-CMC accounts for almost a quarter of the quantity of powders seized during 2020. The analytical methods developed, and the metabolites characterized, are now available to be included in routine screening methods to attest the consumption of the 8 cathinones studied.

合成卡西酮是新精神活性物质（new psychoactive substances, NPS）中的第二大类，在青少年与青年群体中尤为流行。鉴于其潜在毒性，这类新精神活性物质的娱乐性滥用已构成全球性严重公共卫生问题。然而，这类物质在市场上快速涌现，使得法医机构持续更新新精神活性物质相关信息的工作面临极大挑战。新兴新精神活性物质的药代动力学数据（pharmacokinetic data）缺失，对法医鉴定与临床验证工作而言是关键性的制约因素。本研究以主动应对新精神活性物质问题为最终目标，采用高分辨质谱法（high resolution mass spectrometry）对8种筛选出的卡西酮类物质的初步药代动力学数据进行评估：其中包括4种已报道的物质（4-CIC、3-CMC、4-CMC及4-MEAP），以及4种此前未被报道、预计即将在新精神活性物质市场出现的物质（3-CIC、4-MDMB、4-MNEB及4-MDMP），上述8种物质均纳入本研究。通过药代动力学参数、半衰期（half-life）及固有清除率（intrinsic clearance）的计算结果可知，4-CMC与4-MDMB分别属于低清除率与高清除率化合物，本研究纳入的其余卡西酮类物质均属于中等清除率化合物。这一结果预示着，代谢物可作为理想的生物标志物（biomarker），将检测窗口拓展至母本卡西酮类物质所能覆盖的范围之外。研究发现，酮基还原与烷基链羟基化是所有卡西酮类物质共有的代谢途径。但上述两类代谢转化的相对重要性取决于卡西酮类物质的取代基种类。酮基还原生成的代谢物与葡萄糖醛酸结合，是本研究中发现的唯一II相代谢（Phase II metabolism）转化途径。据我们所知，本研究是首次针对已报道的合成卡西酮类物质4-CIC、3-CMC及4-CMC开展代谢物谱分析（metabolite profiling）的研究。值得注意的是，2020年缉获的粉末中，3-CMC占比接近四分之一。本研究开发的分析方法与已表征的代谢物，现已可纳入常规筛查流程，用于确认受试者是否摄入本次研究涉及的8种卡西酮类物质。