Caspar Achim T, Helfer Andreas G, Michely Julian A, Auwärter Volker, Brandt Simon D, Meyer Markus R, Maurer Hans H
Department of Experimental and Clinical Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, Saarland University, 66421, Homburg, Saar, Germany.
Anal Bioanal Chem. 2015 Sep;407(22):6697-719. doi: 10.1007/s00216-015-8828-6. Epub 2015 Jun 25.
25I-NBOMe, a new psychoactive substance, is a potent 5-HT2A receptor agonist with strong hallucinogenic potential. Recently, it was involved in several fatal and non-fatal intoxication cases. The aim of the present work was to study its phase I and II metabolism and its detectability in urine screening approaches. After application of 25I-NBOMe to male Wistar rats, urine was collected over 24 h. The phase I and II metabolites were identified by LC-HR-MS/MS in urine after suitable workup. For the detectability studies, standard urine screening approaches (SUSA) by GC-MS, LC-MS(n), and LC-HR-MS/MS were applied to rat and also to authentic human urine samples submitted for toxicological analysis. Finally, an initial CYP activity screening was performed to identify CYP isoenzymes involved in the major metabolic steps. 25I-NBOMe was mainly metabolized by O-demethylation, O,O-bis-demethylation, hydroxylation, and combinations of these reactions as well as by glucuronidation and sulfation of the main phase I metabolites. All in all, 68 metabolites could be identified. Intake of 25I-NBOMe was detectable mainly via its metabolites by both LC-MS approaches, but not by the GC-MS SUSA. Initial CYP activity screening revealed the involvement of CYP1A2 and CYP3A4 in hydroxylation and CYP2C9 and CYP2C19 in O-demethylation. The presented study demonstrated that 25I-NBOMe was extensively metabolized and could be detected only by the LC-MS screening approaches. Since CYP2C9 and CYP3A4 are involved in initial metabolic steps, drug-drug interactions might occur in certain constellations.
25I-NBOMe是一种新型精神活性物质，是一种强效的5-HT2A受体激动剂，具有很强的致幻潜力。最近，它涉及多起致命和非致命中毒案例。本研究的目的是研究其I期和II期代谢情况以及在尿液筛查方法中的可检测性。将25I-NBOMe应用于雄性Wistar大鼠后，收集24小时内的尿液。经过适当处理后，通过液相色谱-高分辨质谱/质谱（LC-HR-MS/MS）鉴定尿液中的I期和II期代谢物。为了进行可检测性研究，将气相色谱-质谱（GC-MS）、液相色谱-质谱（n）和液相色谱-高分辨质谱/质谱的标准尿液筛查方法（SUSA）应用于大鼠以及提交进行毒理学分析的真实人类尿液样本。最后，进行了初步的细胞色素P450（CYP）活性筛查，以鉴定参与主要代谢步骤的CYP同工酶。25I-NBOMe主要通过O-去甲基化、O,O-双去甲基化、羟基化以及这些反应的组合进行代谢，还通过主要I期代谢物的葡萄糖醛酸化和硫酸化进行代谢。总共可以鉴定出68种代谢物。通过两种液相色谱方法，主要通过其代谢物可检测到25I-NBOMe的摄入，但气相色谱-质谱SUSA无法检测到。初步的CYP活性筛查显示，CYP1A2和CYP3A4参与羟基化，CYP2C9和CYP2C19参与O-去甲基化。本研究表明，25I-NBOMe被广泛代谢，只能通过液相色谱筛查方法检测到。由于CYP2C9和CYP3A4参与初始代谢步骤，在某些情况下可能会发生药物相互作用。
