Targeted and non‐targeted metabolite identification of MAM‐2201 in human, mouse, and rat hepatocytes

Abstract

MAM-2201 is a fluorinated naphthoylindole synthetic cannabinoid with potent psychoactive properties that has been detected as an active ingredient in herbal incense blends. To gain a greater understanding of MAM-2201 metabolism and to compare its metabolic fate in humans with those in animals, the metabolism of MAM-2201 in human, mouse, and rat hepatocytes was investigated using liquid chromatography-high-resolution mass spectrometry combined with targeted and non-targeted metabolite profiling approaches. Nineteen phase I metabolites (M1-M19) reported previously in human liver microsomes and 13 novel metabolites were identified in human, mouse, and rat hepatocytes: 1 phase I metabolite (M20) and 12 phase II metabolites including 6 glucuronides (G1-G6), 1 sulfate (S1), and 5 glutathione (GSH) conjugates (GS1-GS5) of MAM-2201 metabolites. G3 was human-specific, but M20, G1, G2, and 5 GSH conjugates were rat-specific, indicating species-related differences in MAM-2201 metabolism. The findings in the present study can be useful for the experimental design and assessment of metabolism-mediated toxic risk of MAM-2201.

Comprehensive investigation on synthetic cannabinoids: Metabolic behavior and potency testing, using 5F‐APP‐PICA and AMB‐FUBINACA as model compounds

“…Similarly to M4 and M5, the metabolite M7 was obtained after oxidative deamination from M6. Additional biotransformations described for these cannabinoids, such as N ‐alkyl hydroxylation/oxidation, were not found for 5F‐APP‐PICA …”

“…Although there are differences in the fragmentation of both compounds, a generic fragmentation pathway can be proposed based on most of the observed ions (Figure ) . The information about the fragmentation pathway of both synthetic cannabinoids can be used by forensic laboratories for the identification of these SCs, but also for elucidation of similar cannabinoids, as most present similar fragmentation …”

“…The information about the fragmentation pathway of both synthetic cannabinoids can be used by forensic laboratories for the identification of these SCs, but also for elucidation of similar cannabinoids, as most present similar fragmentation. 6,[44][45][46] Tables S1 and S2 show the fragmentation observed for all the 5F-APP-PICA and AMB-FUBINACA metabolites, respectively, in ESI + and ESI − , including the chromatographic retention time, and the elemental composition and mass error of the (de)protonated molecule and its fragments. Compounds that were present in incubation samples but not in blanks nor stability samples were considered as potential metabolites.…”

“…The N-dealkylation of the fluoropentyl moiety (M6) has also been reported for MAM-2201. 46 Similarly to M4 and M5, the metabolite M7 was obtained after oxidative deamination from M6.…”

“…Additional biotransformations described for these cannabinoids, such as N-alkyl hydroxylation/oxidation, were not found for 5F-APP-PICA. 46,48 5F-APP-PICA was rapidly metabolized during incubation. At 60 minutes, only 20% of the initial response was present, with less than 0.5% remaining at 180 minutes, as depicted in Figure 3.…”