title: CYP3A4 Mediates Oxidative Metabolism of the Synthetic Cannabinoid AKB-48.
abstract: Synthetic cannabinoid designer drugs have emerged as drugs of abuse during the last decade, and acute intoxication cases are documented in the scientific literature. Synthetic cannabinoids are extensively metabolized, but our knowledge of the involved enzymes is limited. Here, we investigated the metabolism of N-(1-adamantyl)-1-pentyl-1H-indazole-3-carboxamide (AKB-48), a compound identified in herbal blends from 2012 and onwards. We screened for metabolite formation using a panel of nine recombinant cytochrome P450 (CYP) enzymes (CYP1A2, 2B6, 2C8, 2C9, 2C18, 2C19, 2D6, 2E1, and 3A4) and compared the formed metabolites to human liver microsomal (HLM) incubations with specific inhibitors against CYP2D6, 2C19, and 3A4, respectively. The data reported here demonstrate CYP3A4 to be the major CYP enzyme responsible for the oxidative metabolism of AKB-48, preferentially performing the oxidation on the adamantyl moiety. Genetic polymorphisms are likely not important with regard to toxicity given the major involvement of CYP3A4. Adverse drug-drug interactions (DDIs) could potentially occur in cases with co-intake of strong CYP3A4 inhibitors, e.g., HIV antivirals and azole antifungal agents.
authors.affiliation: Section of Forensic Chemistry, Department of Forensic Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Frederik V's Vej 11, 3rd floor, 2100, Copenhagen, Denmark, niels.holm@sund.ku.dk.
authors.forename: Niels Bjerre
authors.initials: NB
authors.lastname: Holm
authors.forename: Line Marie
authors.initials: LM
authors.lastname: Nielsen
authors.forename: Kristian
authors.initials: K
authors.lastname: Linnet
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives* / Q000378:metabolism; D002186:Cannabinoids / Q000378:metabolism*; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D006801:Humans; D007191:Indazoles / Q000378:metabolism*; D008862:Microsomes, Liver / Q000378:metabolism*; D010084:Oxidation-Reduction
chemical_list: D002186:Cannabinoids; D065607:Cytochrome P-450 Enzyme Inhibitors; D007191:Indazoles; C000606545:N-(1-adamantyl)-1-pentylindazole-3-carboxamide; D003577:Cytochrome P-450 Enzyme System; D051544:Cytochrome P-450 CYP3A; D000218:Adamantane