Zhejiang Police College, Key Laboratory of Drug Prevention and Control Technology of Zhejiang Province, Hangzhou 310053, PR China; College of Environment, Zhejiang University of Technology, Hangzhou 310014, PR China.
Binjiang Institute of Zhejiang University, Hangzhou 310053, PR China.
J Pharm Biomed Anal. 2024 Apr 15;241:115987. doi: 10.1016/j.jpba.2024.115987. Epub 2024 Jan 20.
To explore the metabolites of 5-Methoxy-N-isopropyl-N-methyltryptamine (5-MeO-MiPT) and unveil its toxicological effects, we examined its metabolic profiles using zebrafish and human liver microsome models. Employing ultra-high-performance liquid chromatography Q Exactive hybrid quadrupole-Orbitrap high-resolution mass spectrometry (UPLC-QE-HRMS), we analyzed samples from intoxicated zebrafish and human liver microsomes. In the zebrafish model, we identified a total of six metabolites. Primary phase I metabolic pathways involved N-Demethylation and Indole-hydroxylation reactions, while phase II metabolism included Glucoside conjugation directly, Glucoside conjugation after Indole-hydroxylation, and Sulfonation following Indole-hydroxylation. In the human liver microsome model, nine metabolites were generated. Major phase I metabolic pathways encompassed N-Demethylation, 5-O-Demethylation, and N-Depropylation, N-Oxidation, Indole-hydroxylation, N-Demethylation combined with Indole-hydroxylation, and 5-O-Methylation-carboxylation. Phase II metabolism involved Glucoside conjugation after Indole-hydroxylation, as well as Glucoside conjugation after 5-O-Demethylation. Proposed phase I metabolites, such as 5-MeO-MiPT-N-Demethylation (5-MeO-NiPT) and 5-MeO-MiPT-Indole-hydroxylation, alongside the phase II metabolite OH&Glucoside conjugation-5-MeO-MiPT, were identified as effective markers for screening 5-MeO-MiPT intake. This study systematically delineates the phase I and II metabolites of 5-MeO-MiPT, confirming their pathways through in vivo and in vitro extrapolation. Additionally, inclusion of the parent drug itself and OH&Glucoside conjugation-5-MeO-MiPT could serve as valuable confirmation tools.
为了探究 5-甲氧基-N-异丙基-N-甲基色胺（5-MeO-MiPT）的代谢产物并揭示其毒理学效应，我们利用斑马鱼和人肝微粒体模型研究了其代谢谱。采用超高效液相色谱 Q Exactive 杂交四极杆轨道阱高分辨率质谱（UPLC-QE-HRMS），我们分析了染毒斑马鱼和人肝微粒体样品。在斑马鱼模型中，我们共鉴定出 6 种代谢产物。主要的一期代谢途径涉及 N-去甲基化和吲哚羟化反应，而二期代谢包括直接葡萄糖苷化、吲哚羟化后葡萄糖苷化以及吲哚羟化后磺化。在人肝微粒体模型中，生成了 9 种代谢产物。主要的一期代谢途径包括 N-去甲基化、5-O-去甲基化、N-去丙基化、N-氧化、吲哚羟化、N-去甲基化与吲哚羟化结合以及 5-O-甲基化-羧酸化。二期代谢涉及吲哚羟化后葡萄糖苷化以及 5-O-去甲基化后葡萄糖苷化。推测的一期代谢产物，如 5-MeO-MiPT-N-去甲基化（5-MeO-NiPT）和 5-MeO-MiPT-吲哚羟化，以及二期代谢产物 OH&Glucoside 结合-5-MeO-MiPT，被鉴定为筛选 5-MeO-MiPT 摄入的有效标志物。本研究系统描绘了 5-MeO-MiPT 的一期和二期代谢产物，通过体内和体外外推确认了它们的代谢途径。此外，包含母体药物本身和 OH&Glucoside 结合-5-MeO-MiPT 可以作为有价值的确认工具。
