In vitro metabolism of synthetic cannabinoid AM1220 by human liver microsomes and Cunninghamella elegans using liquid chromatography coupled with high resolution mass spectrometry

• Published in: Forensic toxicology Vol. 36; no. 2; pp. 435 - 446
• Main Authors: Watanabe, Shimpei, Kuzhiumparambil, Unnikrishnan, Fu, Shanlin
• Format: Journal Article
• Language: English
• Published: Tokyo Springer Japan 01.07.2018
• Subjects: Forensic Medicine; Forensic Science; Medical Law; Medicinal Chemistry; Medicine; Medicine & Public Health; Original; Original Article; Pharmacology/Toxicology; High resolution mass spectrometry; Human liver microsomes; Synthetic cannabinoid; In vitro metabolism; AM1220; Cunninghamella elegans
• ISSN: 1860-8965; 1860-8973
• DOI: 10.1007/s11419-018-0424-y

Purpose Identifying intake of synthetic cannabinoids generally requires the metabolism data of the drugs so that appropriate metabolite markers can be targeted in urine testing. However, the continuous appearance of new cannabinoids during the last decade has made it difficult to keep up with all the compounds including {1-[(1-methylpiperidin-2-yl)methyl]-1 H -indol-3-yl}(naphthalen-1-yl)methanone (AM1220). In this study, metabolism of AM1220 was investigated with human liver microsomes and the fungus Cunninghamella elegans . Methods Metabolic stability of AM1220 was analysed by liquid chromatography–tandem mass spectrometry in multiple reaction monitoring mode after 1 µM incubation in human liver microsomes for 30 min. Tentative structure elucidation of metabolites was performed on both human liver microsome and fungal incubation samples using liquid chromatography–high-resolution mass spectrometry. Results Half-life of AM1220 was estimated to be 3.7 min, indicating a high clearance drug. Nine metabolites were detected after incubating human liver microsomes while seven were found after incubating Cunninghamella elegans , leading to 11 metabolites in total (five metabolites were common to both systems). Demethylation, dihydrodiol formation, combination of the two, hydroxylation and dihydroxylation were the observed biotransformations. Conclusions Three most abundant metabolites in both human liver microsomes and Cunninghamella elegans were desmethyl, dihydrodiol and hydroxy metabolites, despite different isomers of dihydrodiol and hydroxy metabolites in each model. These abundant metabolites can potentially be useful markers in urinalysis for AM1220 intake.