A single dose of methadone inhibits cytochrome P-4503A activity in healthy volunteers as assessed by the urinary cortisol ratio

To examine the effect of a single oral dose of methadone on cytochrome P450 (CYP) 3A activity using the urinary 6 beta -hydroxycortisol to cortisol ratio (UCR) as a marker of CYP3A activity. Methods A single oral dose (0.2 mg kg(-1)) of rac-methadone was administered to eight healthy female volunteers. Frequent blood samples and all urine over seven time periods was collected For 96 h following dosing. The UCR and the concentration of the major CYP3A metabolite of methadone, EDDP, were measured in urine. Methadone enantiomer concentrations were determined in plasma and urine. All quantifications were performed by validated high performance liquid chromatography assays. Results In all Volunteers a significant decline of the UCR from immediately predose values was observed at the 4-8 and 8-12 h collection periods (P < 0.05, 95% CI for the differences. 0.4.16 and 0.6.16, respectively) with a return to immediately predose values after 2-3 days, suggesting methadone was an inhibitor of CYP3A. The UCR was found to be significantly correlated with the amount of EDDP excreted in the urine and with the area under the plasma concentration vs time profile for total (R + S) methadone supporting in vitro data that CYP3A is primarily responsible for EDDP formation and has a significant influence on methadone disposition. Conclusions Methadone appears to be a CYP3A inhibitor in vivo following a single oral dose and measurements of the urinary cortisol ratio appear to be a useful index to follow this inhibition.