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

1-Pentyl-3-(4-methyl-1-naphthoyl)indole (JWH-122) is an agonist of the cannabinoid receptors CB 1 and CB 2. 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 also dihydrodiol metabolites are formed probably via epoxide formation on the naphthalene moiety, irrespective of the combination with hydroxylation(s). A metabolite carrying a carboxylgroup 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 to be subjected to enzymatic hydrolysis, followed by the LC-MS and LC-MS-MS analyses. 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 could confirm most metabolite classes and clarify the phase II metabolism of JWH-122. From these results, it can be concluded that all metabolites formed in vivo are excreted conjugated as glucuronide or sulfate, with conjugation rates above 50%