Publication details

Modulating effects of CB1 agonist methananadamide on the activity of CYP450 isoenzymes in rat



Year of publication 2008
Type Article in Proceedings
Conference The International Journal of Neuropsychopharmacology
MU Faculty or unit

Faculty of Medicine

Field Pharmacology and pharmaceutical chemistry
Keywords (R)-(+)-Methanandamide; cytochrome P 450; isolated perfused rat liver; sex difference
Description Effects of substances from Cannabis indica on human are well known. Experiments with these natural molecules and their analogues led to discovery of endogenous cannabinoid system. By now, there are many ligands of (CB) known. Anandamide is one of the natural agonist of CB1 and CB2 receptors. Methanandamide is metabolically more stable and selective ligand of CB1 receptors. Effects mediated by non-receptor mechanisms should be impeached instead of studying only the receptor activity of canabinoids. It is required to determine the potentional for interactions with other drugs with regard to their probable clinical use. Action of methanandamide on the activity of hepatic cytochrome P450 (CYP450) can be important factor influencing its therapeutical use. The work was carried out on male Wistar Albino rats (200g). Methanandamide was administered intraperitoneally daily in Tocrisolve solution for 7 days at the dose of 1mg/kg. Control group animals were treated with Tocrisolve. Model of isolated perfused rat liver was used for determination of CYP450 1A2, 2D2 and 2C6 izoenzyme activity. Levels of marker substances dextromethorphan (2D6), tolbutamide (2C6), phenacetine (1A2) and their specific metabolites dextrorphan, hydroxytolbutamide and paracetamol were used for determination of the CYP450 activity. The influence of methanandamide on single CYP450 isoenzymes is diverse. Methanandamide has no effect on the activity of 1A2 isoenzyme, while the activity of 2C6 was higher when compared with control animals. Metabolism of dextromethorphan via 2D2 was inhibited after methanandamide administration. Studies describing influence of various cannabinoids on CYP450 activity conclude their inhibitory effects. Our results suggest that effects of methanandamide on the activity of CYP450 are not unified and depend on particular isoenzymes. CYP450 is major drug metabolizing system and modification of its activity can play key role in co-administration of drugs. With regard to our results, it is important to study the activity of single isoenzymes to prevent possible drug-drug interaction based on CYP450 enzymatic mechanism.
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