In Vitro Metabolism and Hepatic Intrinsic Clearance of the Synthetic Cannabinoid Receptor Agonist JWH-122 and Its Four ω-Halogenated Analogues.

The number of new psychoactive substances (NPS) emerging on the illicit drug market has increased over the last decade. Halogenation of existing illicit drugs is a particular trend, with the purpose of both circumventing the law and altering the toxicodynamic and toxicokinetic profiles of the compounds. This study investigates the in vitro impact of JWH-122 ω-halogenation (fluoro, chloro, bromo and iodo) on the metabolism, apparent intrinsic hepatic clearance and analytical targets for detecting drug consumption. Metabolite profiling was conducted with pooled human liver microsomes, suspended rat hepatocytes and pooled human hepatocytes. The in vitro half-life was also determined in pooled human hepatocytes. All samples were analysed by liquid chromatography/high-resolution mass spectrometry. All compounds, except for JWH-122, showed high formation rates of phase I metabolites, predominantly ω-COOH and methylnaphthyl hydroxylation metabolites. Phase II metabolites were ω-O-glucuronides, methylnaphthyl O-glucuronides and ω-glutathione conjugates. The relative ion intensity of the glutathione conjugates increased with the ω-halogen size, with I-JWH-122 having the highest intensity. Stability studies gave a low half-life and a high intrinsic hepatic clearance for JWH-122 (1305 mL/min/kg) and MAM-2201 (1408 mL/min/kg). Cl-, Br- and I-JWH-122 showed increasing half-life with increasing ω-halogen size, with intrinsic clearance values of 235-502 mL/min/kg. The recommended analytical targets for consumption of JWH-122 or ω-halogenated JWH-122 analogues are the ω-COOH metabolites for unspecific profiling and the methylnaphthyl hydroxylated metabolites to distinguish the compounds. Furthermore, ω-halogenation with larger halogens appears to increase the intrinsic hepatic stability, thereby prolonging exposure and possibly the duration of action.