title: First characterization of AKB-48 metabolism, a novel synthetic cannabinoid, using human hepatocytes and high-resolution mass spectrometry.
abstract: Since the federal authorities scheduled the first synthetic cannabinoids, JWH-018 and JWH-073, new synthetic cannabinoids were robustly marketed. N-(1-Adamantyl)-1-pentylindazole-3-carboxamide (AKB-48), also known as APINACA, was recently observed in Japanese herbal smoking blends. The National Forensic Laboratory Information System registered 443 reports of AKB-48 cases in the USA from March 2010 to January 2013. In May 2013, the Drug Enforcement Administration listed AKB-48 as a Schedule I drug. Recently, AKB-48 was shown to have twice the CB1 receptor binding affinity than CB2. These pharmacological effects and the difficulty in detecting the parent compound in urine highlight the importance of metabolite identification for developing analytical methods for clinical and forensic investigations. Using human hepatocytes and TripleTOF mass spectrometry, we identified 17 novel phase I and II AKB-48 metabolites, products of monohydroxylation, dihydroxylation, or trihydroxylation on the aliphatic adamantane ring or N-pentyl side chain. Glucuronide conjugation of some mono- and dihydroxylated metabolites also occurred. Oxidation and dihydroxylation on the adamantane ring and N-pentyl side chain formed a ketone. More metabolites were identified after 3 h of incubation than at 1 h. For the first time, we present a AKB-48 metabolic scheme obtained from human hepatocytes and high-resolution mass spectrometry. These data are needed to develop analytical methods to identify AKB-48 consumption in clinical and forensic testing.
authors.affiliation: Chemistry and Drug Metabolism, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, 251 Bayview Boulevard, Suite 200, Room 05A-721, Baltimore, Maryland, 21224, USA.
authors.forename: Adarsh S
authors.initials: AS
authors.lastname: Gandhi
authors.forename: Mingshe
authors.initials: M
authors.lastname: Zhu
authors.forename: Shaokun
authors.initials: S
authors.lastname: Pang
authors.forename: Ariane
authors.initials: A
authors.lastname: Wohlfarth
authors.forename: Karl B
authors.initials: KB
authors.lastname: Scheidweiler
authors.forename: Hua-Fen
authors.initials: HF
authors.lastname: Liu
authors.forename: Marilyn A
authors.initials: MA
authors.lastname: Huestis
mesh_terms: D002186:Cannabinoids / Q000032:analysis* / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D013058:Mass Spectrometry / Q000379:methods*
chemical_list: D002186:Cannabinoids
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