In vitro and in vivo metabolisms of 1-pentyl-3-(4-methyl-1-naphthoyl)indole (JWH-122)

Autor: Peter Van Eenoo, Simone Esposito, Leen Lootens, Koen Deventer, Lore Geldof, Nik De Brabanter, Philip Meuleman, Geert Leroux-Roels
Rok vydání: 2013
Předmět:
Zdroj: Forensic Toxicology. 31:212-222
ISSN: 1860-8973
1860-8965
DOI: 10.1007/s11419-013-0179-4
Popis: 1-Pentyl-3-(4-methyl-1-naphthoyl)indole (JWH-122) is an agonist of the cannabinoid receptors CB1 and CB2. In this study, the phase I and phase II metabolisms of JWH-122 were investigated using two models. In vitro studies using incubations of JWH-122 with human liver microsomes were performed to obtain metabolites of the drug at the initial step; 11 classes of metabolites were found and analyzed by liquid chromatography–mass spectrometry (LC–MS) and liquid chromatography–tandem mass spectrometry (LC–MS–MS). Hydroxylation(s) on the naphthalene moiety and/or the indole moiety of the molecule took place as such or in combination with dehydrogenation or cleavage of the N-pentyl side chain. Furthermore, dihydrodiol metabolites were formed probably via epoxide formation on the naphthalene moiety, irrespective of the combination with hydroxylation(s). A metabolite carrying a carboxyl group on the N-pentyl side chain was also detected. As the second step of the study, in vivo experiments using chimeric mice were performed; the mice were orally administered JWH-122, and their urine samples were collected, subjected to enzymatic hydrolysis, and analyzed by LC–MS and LC–MS–MS. The urine samples without hydrolysis were also analyzed for their molecular formulae in the conjugated forms by LC–high resolution MS. The in vivo model using chimeric mice confirmed most metabolite classes and clarified the phase II metabolism of JWH-122. It was concluded that all metabolites formed in vivo were excreted conjugated as glucuronide or sulfate, with conjugation rates above 50 %.
Databáze: OpenAIRE
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