Effect of synthetic cannabinoids on P450 metabolic activity in
rat liver microsomes

a 2025

Effect of synthetic cannabinoids on P450 metabolic activity in rat liver microsomes

FERREIRA FONSECA, Carlos Daniel; Petr JOHN; Ondřej ZENDULKA a Jan JUŘICA

Základní údaje

Originální název

Effect of synthetic cannabinoids on P450 metabolic activity in rat liver microsomes

Autoři

FERREIRA FONSECA, Carlos Daniel ; Petr JOHN; Ondřej ZENDULKA a Jan JUŘICA

Vydání

38th ECNP Congress, 2025

Další údaje

Jazyk

angličtina

Typ výsledku

Konferenční abstrakt

Obor

30300 3.3 Health sciences

Utajení

není předmětem státního či obchodního tajemství

Označené pro přenos do RIV

Organizační jednotka

Lékařská fakulta

Klíčová slova anglicky

Pharmacology; Pharmacokinetics

Změněno: 17. 3. 2026 14:46, Mgr. Tereza Miškechová

Anotace

V originále

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 Δ⁹-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-naïve rat liver microsomes (n> 6) and CYP-specific substrates were performed to determine IC₅₀ and Kᵢ for CYP1A2, CYP2C6, CYP2D2, and CYP3A1/2. Samples were analysed by HPLC in triplicate. IC₅₀ and Kᵢ 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, Kᵢ = 8.2 µM), CYP2C6 (IC₅₀ = 3.73 µM, Kᵢ = 15.3 µM), and CYP2D2 (IC₅₀ = 2.19 µM, Kᵢ = 5.5 µM) in a dose-dependent manner. AM281 inhibited CYP1A2 (IC₅₀ = 6.77 µM, Kᵢ = 17 µM) and CYP2C6 (IC₅₀ = 7.45 µM, Kᵢ = 4.1 µM), though its inhibition model was unclear. ACEA inhibited all tested CYPs: CYP1A2 (IC₅₀ = 25.6 µM, Kᵢ = 15.2 µM), CYP2C6 (IC₅₀ = 34.87 µM, Kᵢ = 49.3 µM), and CYP3A (IC₅₀ = 73.35 µM; Kᵢ = 13 µM), with no evidence of mechanism-based inhibition. ACPA inhibited CYP1A2 (IC₅₀ = 9.84 µM, Kᵢ = 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.

Návaznosti

MUNI/A/1722/2024, interní kód MU

Název: Specifický farmakologický výzkum v oblasti farmakokinetiky, behaviorální neuropsychofarmakologie a personalizované farmakoterapie v onkologii

Investor: Masarykova univerzita, Specifický farmakologický výzkum v oblasti farmakokinetiky, behaviorální neuropsychofarmakologie a personalizované farmakoterapie v onkologii

Citovat

FERREIRA FONSECA, Carlos Daniel; Petr JOHN; Ondřej ZENDULKA a Jan JUŘICA. Effect of synthetic cannabinoids on P450 metabolic activity in rat liver microsomes. In 38th ECNP Congress. 2025.

@proceedings{2551279,
   author = {Ferreira Fonseca, Carlos Daniel and John, Petr and Zendulka, Ondřej and Juřica, Jan},
   booktitle = {38th ECNP Congress},
   keywords = {Pharmacology; Pharmacokinetics},
   language = {eng},
   title = {Effect of synthetic cannabinoids on P450 metabolic activity in rat liver microsomes},
   year = {2025}
}

TY  - CONF
ID  - 2551279
AU  - Ferreira Fonseca, Carlos Daniel - John, Petr - Zendulka, Ondřej - Juřica, Jan
PY  - 2025
TI  - Effect of synthetic cannabinoids on P450 metabolic activity in rat liver microsomes
KW  - Pharmacology
KW  - Pharmacokinetics
N2  - 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 Δ⁹-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-naïve rat liver microsomes (n> 6) and CYP-specific substrates were performed to determine IC₅₀ and Kᵢ for CYP1A2, CYP2C6, CYP2D2, and CYP3A1/2. Samples were analysed by HPLC in triplicate. IC₅₀ and Kᵢ 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, Kᵢ = 8.2 µM), CYP2C6 (IC₅₀ = 3.73 µM, Kᵢ = 15.3 µM), and CYP2D2 (IC₅₀ = 2.19 µM, Kᵢ = 5.5 µM) in a dose-dependent manner. AM281 inhibited CYP1A2 (IC₅₀ = 6.77 µM, Kᵢ = 17 µM) and CYP2C6 (IC₅₀ = 7.45 µM, Kᵢ = 4.1 µM), though its inhibition model was unclear. ACEA inhibited all tested CYPs: CYP1A2 (IC₅₀ = 25.6 µM, Kᵢ = 15.2 µM), CYP2C6 (IC₅₀ = 34.87 µM, Kᵢ = 49.3 µM), and CYP3A (IC₅₀ = 73.35 µM; Kᵢ = 13 µM), with no evidence of mechanism-based inhibition. ACPA inhibited CYP1A2 (IC₅₀ = 9.84 µM, Kᵢ = 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.
ER  -

FERREIRA FONSECA, Carlos Daniel; Petr JOHN; Ondřej ZENDULKA a Jan JUŘICA. Effect of synthetic cannabinoids on P450 metabolic activity in rat liver microsomes. In \textit{38th ECNP Congress}. 2025.

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