Informace o publikaci
Effect of synthetic cannabinoids on P450 metabolic activity in rat liver microsomes
| Autoři | |
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| Rok publikování | 2025 |
| Druh | Konferenční abstrakty |
| Fakulta / Pracoviště MU | |
| Citace | |
| Popis | Introduction The endocannabinoid system (ECS) plays a fundamental role in regulating diverse physiological processes in the human body, including appetite, pain sensation, immune response, and mood 1,2. Given its broad functional scope, the ECS has become an important target in therapeutic development. A gap in knowledge emerges when trying to relate the ECS with changes in drug pharmacokinetics, however, increasing evidence suggests that cannabinoids such as ??-tetrahydrocannabinol (THC), cannabidiol (CBD), and cannabinol (CBN) can inhibit several human CYP isoforms 3–10. However, much less is known about the metabolic impact of synthetic cannabinoids, especially those designed to selectively activate cannabinoid receptors (e.g., CB1 agonists or antagonists). This study aims to fill that gap by systematically evaluating the inhibitory effects of selected synthetic cannabinoids—specifically AM251, AM281, ACEA and ACPA—on key CYP isoforms using rat liver microsomes (RLMs) as a preclinical model. We focused on CYP1A2, CYP2C6, CYP2D2, and CYP3A enzymes due to their pharmacological relevance in drug metabolism. By characterizing isoform-specific inhibition, we aim to better understand the potential for synthetic cannabinoid-induced drug interactions and inform safer therapeutic development. Objective: To evaluate the impact of synthetic cannabinoids (AM251/AM281/ACEA/ACPA) on CYP enzyme activity across different concentrations, focusing on isoform-specific inhibition parameters (IC50 and Ki). Methods: In vitro assays using pooled drug-naive rat liver microsomes (n> 6) and CYP-specific substrates were performed to determine IC50 and K? for CYP1A2, CYP2C6, CYP2D2, and CYP3A1/2. Samples were analysed by HPLC in triplicate. IC50 and K? values were determined using nonlinear regression analysis and significance was assessed using SigmaPlot; figures were prepared in BioRender and GraphPad Prism. Preliminary Results: Our data show various degree of isoform-specific CYP inhibition by synthetic cannabinoids. Particularly, AM251 inhibited CYP1A2 (IC50 = 18.78 µM, K? = 8.2 µM), CYP2C6 (IC50 = 3.73 µM, K? = 15.3 µM), and CYP2D2 (IC50 = 2.19 µM, K? = 5.5 µM) in a dose-dependent manner. AM281 inhibited CYP1A2 (IC50 = 6.77 µM, K? = 17 µM) and CYP2C6 (IC50 = 7.45 µM, K? = 4.1 µM), though its inhibition model was unclear. ACEA inhibited all tested CYPs: CYP1A2 (IC50 = 25.6 µM, K? = 15.2 µM), CYP2C6 (IC50 = 34.87 µM, K? = 49.3 µM), and CYP3A (IC50 = 73.35 µM; K? = 13 µM), with no evidence of mechanism-based inhibition. ACPA inhibited CYP1A2 (IC50 = 9.84 µM, K? = 4.1 µM) and CYP2C6 (IC50 = 18.05 µM). Conclusion: Synthetic cannabinoids exhibit isoform- and ligand-specific CYP inhibition in rat liver microsomes. AM251 and AM281 were the most potent, particularly on CYP1A2, CYP2C6, and CYP2D2. ACEA showed weaker, reversible inhibition across CYPs, while ACPA moderately inhibited CYP1A2 and CYP2C6. These results suggest potential for synthetic cannabinoid-induced drug interactions via selective CYP modulation, warranting further preclinical investigation. This work was supported by the Specific University Research (MUNI/A/1722/2024) provided by MŠMT. |
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