Assessment of CYP2D6 re-activation after inhibitory effect of MDMA using tramadol as a probe

Abstract

Abstract Background In recent years, the use of tramadol as a probe drug for human cytochrome p450 2D6 (CYP2D6) has been investigated. The objective of this study was to assess the recovery of rat CYP2D1 enzymatic activity after mechanism-based inhibition induced by a single dose of ecstasy (MDMA, 3,4-methylenedioxymethamphetamine) and evaluation of the tramadol ability as a probe drug. CYP2D1 is orthologous in rats to human CYP2D6 and was employed in the current study. Methods A total of 16 male rats were selected and divided into control and treatment groups. The control group did not receive MDMA, while rats in the treatment group received a single dose of MDMA (1 mg/kg) and were subsequently divided into groups that were tested at 1 h, 10 days or 30 days post-administration. The rats were subjected to liver perfusion with Krebs-Heinslet buffer containing tramadol for 60 min and the tramadol and M1 levels were determined by HPLC-fluorescence. Results The enzymatic activity of CYP2D1 for the 1-h group decreased significantly when compared with the control group (p<0.05). Moreover, enzymatic activity increased non-significantly in the 10- and 30-day groups in comparison with the control group. The concentration and AUC0−60 of tramadol increased in the 1-h and 10-day groups when compared with the control group but decreased in the 30-day group; however, none of these changes was statistically significant (p>0.05). The M1 metabolic ratio in the 1-h group decreased significantly when compared with the control group (p<0.05). The M1 metabolic ratio of the 10-day group increased and of the 30-day group decreased, but neither of these changes were significant. Conclusions Regardless of the genotype, the enzymatic activity of rat CYP2D1 recovered by 10 days post-administration of MDMA. It appears that tramadol, irrespective of its stereoselectivity, is not able to appraise rat hepatic CYP2D1 activity. It can be extrapolated that tramadol is a not suitable probe drug for human hepatic CYP2D1 because CYP2D1 in rats is orthologous to human CYP2D6. Further animal and human studies are required to confirm this hypothesis.