MDMA-induced CYP2D6 inhibition: concentration-dependent variability using dextromethorphan as a probe

Objectives: Ecstasy is commonly abused due to entactogenic effects. Although our previous studies on isolated perfused rat model confirmed inhibition of CYP2D6 by MDMA, the time for enzyme recovery was different when mirtazapine and tramadol were used as substrates. Therefore, present study intended to investigate CYP2D6 inhibition by MDMA using dextromethorphan as a well-known probe. Two different concentrations of dextromethorphan were used at therapeutic and saturated level to clarify observations.

Methods: Thirty-two rats were divided into two groups (dextromethorphan concentration: 2 µM or 300 µM). Each group was divided into four subgroups. Except for control, three treatment subgroups received a single dose of MDMA (1 mg/kg) 1 h, 1 week, and 1 month before liver perfusion, respectively.

Results: Mean metabolic ratio using therapeutic dextromethorphan concentration showed a statistically significant decrease only in the 1-hour group compared to control. The results of the mean metabolic ratio using the saturated concentration showed a reduction in all treatment groups (p-value<0.05).

Conclusions: It can be concluded that the isoenzyme behavior can be completely different using therapeutic vs. saturated probe concentrations. The best explanation for the duality observed in metabolic behavior seems to be the dependence of the metabolite on enzymatic pathway.