Metabolic and pharmacokinetic characterization of a new synthetic cannabinoid APINAC in rats

• Published in: Forensic toxicology Vol. 36; no. 1; pp. 88 - 101
• Main Authors: Hwang, Jungjoong, Hwang, Jiho, Ganganna, Bogonda, Song, Insuk, Heo, Moon Young, Ahn, Sung-Hoon, Lee, Jongkook
• Format: Journal Article
• Language: English
• Published: Tokyo Springer Japan 2018
• Subjects: Forensic Medicine; Forensic Science; Medical Law; Medicinal Chemistry; Medicine; Medicine & Public Health; Original Article; Pharmacology/Toxicology; LC–IT-TOF-MS/MS; Rat model; APINAC; Synthetic cannabinoid; Metabolism; Pharmacokinetics
• ISSN: 1860-8965; 1860-8973
• DOI: 10.1007/s11419-017-0387-4

Purpose Adamantan-1-yl 1-pentyl-1 H -indazole-3-carboxylate (APINAC), a new synthetic cannabinoid, was recently isolated from a dietary supplement and identified in our laboratories. The metabolism and pharmacokinetics of APINAC were studied in vitro and in vivo with a rat model. Methods APINAC (2.0 μM) was incubated with rat liver microsomes (RLMs) for up to 90 min to determine its phase I metabolic profile. APINAC was also administered to rats at a dose of 5 mg/kg intravenously (i.v.) or 10 mg/kg per os (p.o.). Blood samples were collected at specific time points, and urine samples were also collected for 1 day following APINAC administration. The analyses were conducted by both high- and low-resolution liquid chromatography–tandem mass spectrometry. Results Although APINAC was rapidly metabolized by RLMs ( t 1/2 , 15.2 ± 0.4 min), in vivo pharmacokinetic experiments in rats revealed moderate to long half-lives [11.3 h (i.v.) and 3.8 h (p.o.)]. A total of 22 APINAC metabolites could be detected in the RLMs and rat urine. APINAC was predominantly metabolized via ester hydrolysis to carboxylic acids M1 (with hydroxylation) and M18 (without hydroxylation), representative markers for APINAC intake. Hydroxylation of APINAC, with or without subsequent oxidation and glucuronidation, was observed in the case of the other metabolites. Conclusions The diagnosis of illegal APINAC intake can be realized through the detection of several characteristic APINAC metabolites in human urine and/or APINAC itself in blood.