Investigation of MDMA Inhibitory Effect on CytochromeP450 3A4 in Isolated Perfused Rat Liver Model Using Tramadol

Purpose: MDMA (methylenedioxymethamphetamine) is a synthetic compound, which is a structurally derivative of amphetamine. Also, it acts like an amphetamine, structurally, and functionally. MDMA uses mechanism-based inhibition, to inhibit isoenzyme CYP2D6. It can also inhibit other isoenzymes contributing to its metabolism, including CYP3A4 which is the most important member of the cytochrome P450 superfamily. Since more than 50% of drugs are metabolized by CYP3A4, its inhibition may cause harmful and even lethal drug interactions. Tramadol, as an opioid-like analgesic, is mainly metabolized into O-desmethyl tramadol (M1), by CYP2D6 and undergoes N-demethylation to M2, by CYP2B6 and CYP3A4. Due to the significant potential of abusing tramadol, either alone or in combination with MDMA, the rate of its toxicity and side effects may increase following possible MDMA relevant enzyme inhibition. Methods: Different doses of MDMA (1-10 mg/kg) were intraperitoneally administered to Wistar male rats of both control and treatment groups. Then, after one hour, their isolated livers were perfused by perfusion buffer containing tramadol (1 µg/mL). Afterward, perfusate samples were collected. They were analyzed by HPLC to determine the concentrations of tramadol and its metabolites. Results: MDMA administration in treatment groups reduced M1 production. On the other hand, by following the treatment with different MDMA doses, the M2 metabolic ratio increased by 46 to 101%. Conclusion: it seems that the regular doses of MDMA cannot inhibit the CYP3A4 activity.