Consumption of synthetic cathinones, the second largest class of new psychoactive substances (NPS) reported worldwide, represents a serious public health risk. One of the biggest challenges created by the rapid spread of NPS on the illegal drug market is the discovery of selective biomarkers for their detection in biological matrices, which is only possible through the study of their metabolic profile. The synthetic cathinones 4′-methyl-N,N-dimethylcathinone (4-MDMC), 4′-methyl-N,N-diethylcathinone (4-MDEC), 4′-chloro-α-pyrrolidinovalerophenone (4Cl-PVP), and 4′-chloroethylcathinone (4-CEC) are NPS recently seized in Europe, and, with the exception of 4-CEC, no metabolism study was reported for these cathinones. With the ultimate goal of overcoming this gap, these cathinones were incubated in vitro in human and rat liver microsomes in the presence of Phase I and II (glucuronidation) co-factors, using α-pyrrolidinovalerophenone (α-PVP) as positive control. The metabolite identification was performed by liquid chromatography coupled to tandem high resolution mass spectrometry (LC-HRMS/MS). This allowed the identification of multiple Phase I and glucuronide metabolites of the selected cathinones. Additionally, a new glucuronide conjugate, derived from the recreational drug α-PVP, was herein identified for the first time. Importantly, we have demonstrated that 4-MDMC and 4-MDEC can act as prodrugs of the controlled substances 4-MMC and 4-MEC, respectively. The metabolites herein identified are expected to play an important role not only by acting as potential selective biomarkers of the intake of the synthetic cathinones selected for this study but also to understand their potential adverse effects and link these causative agents to toxicities, thereby helping in the treatment of non-fatal intoxications.

全世界报告的第二大类新型精神活性物质（NPS）消费合成的卡西酮具有严重的公共健康风险。NPS在非法药物市场上迅速传播所带来的最大挑战之一是发现选择性生物标记物以在生物基质中对其进行检测，这只有通过研究其代谢特征才能实现。合成卡西酮4'-甲基-ñ，ñ-二甲基卡西酮（4-MDMC），4'-甲基-ñ，ñ-二乙基卡西酮（4-MDEC），4′-氯-α-吡咯烷基戊二酮（4Cl-PVP）和4'-氯乙基卡西酮（4-CEC）是最近在欧洲缉获的NPS，并且 4-CEC，没有关于这些卡西酮的代谢研究的报道。为了克服这一差距，我们对这些卡西酮进行了培育体外在人和大鼠肝微粒体中存在I和II期（葡萄糖醛酸化）辅助因子的情况下，使用α-吡咯烷基戊基二苯甲酮（α-PVP）作为阳性对照。代谢物鉴定是通过液相色谱与串联高分辨率质谱法（LC-HRMS / MS）进行的。这样就可以鉴定出所选Cathinones的多个I期和葡萄糖醛酸代谢产物。另外，本文首次鉴定了衍生自消遣性药物α-PVP的新葡糖醛酸苷缀合物。重要的是，我们已经证明4-MDMC 和 4-MDEC 可以作为管制药物的前药 4毫米 和 4-MEC， 分别。预期本文中鉴定出的代谢物不仅会充当本研究中所选合成雄酮的摄入量的潜在选择性生物标志物，而且还应了解其潜在的不良作用并将这些病原体与毒性联系起来，从而发挥重要作用，从而有助于非致命性中毒的治疗。