Informace o publikaci
In vitro cytochrome P450 inhibitory studies of CB1 antagonist AM251
| Autoři | |
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| Rok publikování | 2024 |
| Druh | Další prezentace na konferencích |
| Fakulta / Pracoviště MU | |
| Citace | |
| Popis | In vitro cytochrome P450 inhibitory studies of CB1 antagonist AM251 Petr John, Carlos Daniel Ferreira Fonseca, Ondřej Zendulka, Jan Juřica Department of Pharmacology, Masaryk University Introduction: Due to its function in regulating physiological processes, new therapeutics have lately focused on the endocannabinoid system (ECS). Clinically utilized phytocannabinoids are known to inhibit CYP activity, and we assume that CYP enzyme activity may be indirectly influenced by ECS modulation. Understanding ECS-CYP interactions is crucial to prevent drug-drug interactions and to ensure safe pharmacotherapy with medicines that target ECS. Methodology: We tested the effect of the CB1 AM251 antagonist on the cytochrome P450 enzymatic activity. In vitro inhibition studies of AM251 were conducted with the use of rat liver microsomal fraction (RLM) obtained from drug-naive healthy control animals. The NADPH-regenerating system was used, and selective probe substrates were diclofenac - CYP2C6, testosterone- CYP3A, CYP2C11, CYP2A, CYP2B, phenacetine- CYP1A2, dextromethorphan- CYP2D6. The CYP-specific reactions of AM251 –treated RLM (up to 225 µM) were compared to the reaction rates of control RLM. The results were evaluated with the use of Sigmaplot 14.5 software (Inpixon, UK), and in case of an inhibitory effect observed, the Ki and IC50 values were obtained. Results: Results from the in vitro inhibition experiment indicate the impact of AM251 on specific CYP enzymes. Values Ki and IC50 for CYP1A2 and CYP2C6 were obtained (Ki = CYP1A2- 4,33–?18,02, CYP2C6- 6,14–?25,18). The AM251 decreased enzyme relative velocity below 50 % for CYP1A2, CYP2C and CYP2D6. These results suggest that AM251 may affect these enzymes differently and influence different metabolic pathways. In contrast to the above-mentioned AM251, it did not interfere with CYP3A, CYP2A, or CYP2B-mediated biotransformations of the probe drugs. Some sort of inhibition was observed in CYP2D6 and weak inhibition was observed in CYP2C11 interaction studies. Conclusion: The CB1 antagonist exerted inhibition of some of the tested cytochrome P450 isoforms, especially of CYP1A2, CYP2C6 and CYP2D6. These findings provide valuable insights into the specific interactions between AM251 and CYP enzymes, highlighting potential variations in drug metabolism pathways. Further research is necessary to understand the mechanism of interaction between ECS and CYP enzymes. This might help to predict drug interactions and improve the safety of cannabinoid-based treatments in clinical practice. The study was supported by MUNI/A/1580/2023 and MUNI/LF-SUp/1365/2023 grant research projects. |