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

• Published in: Journal of pharmaceutical and biomedical analysis 2024-10, Vol.249, p.116342, Article 116342
• Main Authors: Hou, Xiaolong, Zhang, Ying, Xu, Duoqi, Qin, Shiyang, Xue, Chenyu, Wang, Jifen, Zhou, Xinyang, Shangguan, Jianyang, Li, Zhuoyan, Liu, Jiatong, Jia, Zhenjun, Lu, Jianghai
• Format: Article
• Language: English
• Subjects: ADMB-FUBIATA; Human liver microsomes; Human primary hepatocytes; Human recombinant CYP450s; in vitro metabolism; Synthetic cannabinoid receptor agonist
• ISSN: 0731-7085; 1873-264X; 1873-264X
• DOI: 10.1016/j.jpba.2024.116342

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. [Display omitted] •The in vitro metabolism of ADMB-FUBIATA after incubation with human primary hepatocytes (HPH) was investigated for the first time.•25 metabolites were identified after incubation with HLM and HPH, respectively, in which formation to ketone was identified for the first time.•The metabolism of ADMB-FUBIATA involved multiple CYP450 enzymes, predominantly CYP2C19, 2D6 and 3A4.