UPLC-HR-MS/MS-based determination study on the metabolism of four synthetic cannabinoids, ADB-FUBICA, AB-FUBICA, AB-BICA and ADB-BICA, by human liver microsomes.

Since 2012, several cannabimimetic indazole and indole derivatives with valine amino acid amide residue have emerged in the illicit drug market, and have gradually replaced the old generations of synthetic cannabinoids (SCs) with naphthyl or adamantine groups. Among them, ADB-FUBICA [N-(1-amino-3,3-dimethyl-1-oxobutan-2-yl)-1-(4-fluorobenzyl)-1H-indole-3-carboxamide], AB-FUBICA [N-(1-amino-3-methyl-1-oxobutan-2-yl)-1-(4-fluorobenzyl)-1H-indole-3-carboxamide], AB-BICA [N-(1-amino-3-methyl-1-oxobutan-2-yl)-1-benzyl-1H-indole-3-carboxamide] and ADB-BICA [N-(1-amino-3,3-dimethyl-1-oxobutan-2-yl)-1-benzyl-1H-indole-3-carboxamide] were detected in China recently, but unfortunately no information about their in vitro human metabolism is available. Therefore, biomonitoring studies to screen their consumption lack any information about the potential biomarkers (e.g. metabolites) to target. To bridge this gap, we investigated their phase I metabolism by incubating with human liver microsomes, and the metabolites were identified by ultra-performance liquid chromatography-high resolution-tandem mass spectrometry. Metabolites generated by N-dealkylation and hydroxylation on the 1-amino-alkyl moiety were found to be predominant for all these four substances, and others which underwent hydroxylation, amide hydrolysis and dehydrogenation were also observed in our investigation. Based on our research, we recommend that the N-dealkylation and hydroxylation metabolites are suitable and appropriate analytical markers for monitoring their intake.