A single dose of methadone inhibits cytochrome P-4503A activity in healthyvolunteers 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 ra tio (UCR) as a marker of CYP3A activity. Methods A single oral dose (0.2 mg kg(-1)) of rac-methadone was administere d to eight healthy female volunteers. Frequent blood samples and all urine over seven time periods was collected For 96 h following dosing. The UCR an d the concentration of the major CYP3A metabolite of methadone, EDDP, were measured in urine. Methadone enantiomer concentrations were determined in p lasma and urine. All quantifications were performed by validated high perfo rmance 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 r eturn to immediately predose values after 2-3 days, suggesting methadone wa s an inhibitor of CYP3A. The UCR was found to be significantly correlated w ith the amount of EDDP excreted in the urine and with the area under the pl asma concentration vs time profile for total (R + S) methadone supporting i n 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 s ingle oral dose and measurements of the urinary cortisol ratio appear to be a useful index to follow this inhibition.