Metabolic profiling of a new synthetic cannabinoid receptor agonist, ADMB-FUBIATA, with human liver microsomes, human primary hepatocytes and human recombinant CYP450 enzymes using LC-quadrupole-orbitrap MS

化学 轨道轨道 微粒体 大麻素 兴奋剂 大麻素受体 羧酸酯酶 药理学 药物代谢 代谢途径 代谢物 生物化学 受体 色谱法 质谱法 医学
作者
Hou Xiaoli,Ying Zhang,Duoqi Xu,Shiyang Qin,Chenyu Xue,Jifen Wang,Xinyang Zhou,Junjie Shangguan,Zhuoyan Li,Jiatong Liu,Zhenjun Jia,Jianghai Lu
出处
期刊:Journal of Pharmaceutical and Biomedical Analysis [Elsevier]
卷期号:249: 116342-116342
标识
DOI:10.1016/j.jpba.2024.116342
摘要

A novel synthetic cannabinoid receptor agonist (SCRA), ADMB-FUBIATA, featuring an acetamide-linked structure, has emerged on the illicit drug market. To provide dependable verification of its consumption and identify reliable biomarkers, we investigated an in vitro metabolism study of ADMB-FUBIATA incubated with human primary hepatocytes (HPHs) for the first time and correlated our findings with those from human liver microsomes (HLMs). In this work, ADMB-FUBIATA (10 μM) was incubated with HLM and HPH for 1 and 5 h, respectively, and then subjected to LC-quadrupole-orbitrap MS. A total of 25 metabolites across 8 metabolic pathways were identified after incubation with HLM and HPH, respectively. Monohydroxylation and N-dealkylation were the major metabolic pathways, and formation to ketone was first identified. In addition, the metabolism of ADMB-FUBIATA were found to be mediated by multiple CYP450 enzymes, predominantly CYP2C19, 2D6, and 3A4. This research also initially characterized the fragmentation patterns of the metabolites of ADMB-FUBIATA, elaborating on their structural relationship with ADMB-FUBIATA analogs. To effectively monitor ADMB-FUBIATA abuse, metabolites M4 and M1 were proposed as reliable biomarkers by cross-validating the HLM and HPH incubation results.
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