Cai Yu-Gang, Wang Yan-Jun, Wu Yong-Fu, Feng Jia-Yi, Mo Yan, Wang Qing-Hong, Dai Yong
Luzhou Public Security Bureau Criminal Science and Technology Research Institute, Luzhou, Sichuan, 646000, China.
Sichuan Provincial Public Security Department Criminal Investigation Bureau, Chengdu, Sichuan, 610015, China.
Forensic Sci Int Synerg. 2025 Jul 14;11:100623. doi: 10.1016/j.fsisyn.2025.100623. eCollection 2025 Dec.
This study investigated the metabolic profiles of two isomeric psychoactive agents, methyl-ketamine [2-(ortho-tolyl)-2-(methylamino)cyclohexanone] and 2-oxo-PCE [2-(phenyl)-2-(ethylamino)cyclohexanone], in rats. Following oral administration, blood, liver, and urine samples were collected at timed intervals and analyzed via ultrahigh performance liquid chromatography quadrupole time-of-flight mass spectrometry (UHPLC-QTOF-MS). Metabolomic comparisons revealed distinct metabolic pathways driven by structural differences. Methyl-ketamine primarily underwent cyclohexanone hydroxylation, dehydration, N-demethylation, cyclohexanone carbonyl hydrogenation, and glucuronidation, with N-dealkylation as the dominant process. In contrast, 2-oxo-PCE metabolism involved carbonyl hydrogenation of cyclohexanone, N-diethylation, deamination, hydroxylation, dehydration, and glucuronidation. Structural variations-specifically the steric hindrance imposed by the methyl group on o-tolyl in methyl-ketamine-were identified as key factors influencing metabolic divergence. This hindered the carbonyl hydrogenation of cyclohexanone observed in 2-oxo-PCE, while promoting hydroxylation/dehydration reactions in methyl-ketamine. Post-N-dealkylation, methyl-ketamine retained cyclohexyl hydroxylation/dehydration, whereas 2-oxo-PCE exhibited deamination and cyclohexanone carbonyl hydrogenation/dehydration. Notably, urinary metabolite profiles in humans were mirrored those in rats, and relevance was shown. It was elucidated how structural isomerism dictating metabolic outcomes and offering insights into the mechanistic basis of new psychoactive substances. The study underscored steric effects as critical determinants of metabolic pathways and provided a foundation for predicting pharmacokinetic behavior in related compounds.
本研究调查了两种同分异构的精神活性药物——甲基氯胺酮[2-(邻甲苯基)-2-(甲氨基)环己酮]和2-氧代-PCE[2-(苯基)-2-(乙氨基)环己酮]在大鼠体内的代谢谱。口服给药后，在不同时间间隔采集血液、肝脏和尿液样本，并通过超高效液相色谱四极杆飞行时间质谱(UHPLC-QTOF-MS)进行分析。代谢组学比较揭示了由结构差异驱动的不同代谢途径。甲基氯胺酮主要经历环己酮羟基化、脱水、N-去甲基化、环己酮羰基氢化和葡萄糖醛酸化，其中N-脱烷基化是主要过程。相比之下，2-氧代-PCE代谢涉及环己酮羰基氢化、N-二乙基化、脱氨基、羟基化、脱水和葡萄糖醛酸化。结构变异——特别是甲基氯胺酮中甲基对邻甲苯基产生的空间位阻——被确定为影响代谢差异的关键因素。这阻碍了2-氧代-PCE中观察到的环己酮羰基氢化，同时促进了甲基氯胺酮中的羟基化/脱水反应。N-脱烷基化后，甲基氯胺酮保留环己基羟基化/脱水，而2-氧代-PCE表现出脱氨基和环己酮羰基氢化/脱水。值得注意的是，人类尿液代谢物谱与大鼠相似，并显示出相关性。阐明了结构异构如何决定代谢结果，并为新型精神活性物质的作用机制提供了见解。该研究强调空间效应是代谢途径的关键决定因素，并为预测相关化合物的药代动力学行为提供了基础。
