Pharmacokinetics of moclobemide after single and multiple oral dosing with 150 milligrams 3 times daily for 15 days

Abstract

This study was undertaken to determine the absolute bioavailability and steady-state concentrations of moclobemide after doses of 150 mg. In 14 healthy human volunteers, no differences in t_max, t_1/2β, Cl/F, C_max and AUC were found between a single oral dose of 100 mg and one of 150 mg. The mean absolute oral availability was 0.66 and 0.69 respectively. Plasma concentration profiles of moclobemide on repeated dosing with 150 mg 3 times daily for 15 days were essentially superimposable, although the mean concentration was higher than after the single 150 mg dose. This concentration increased over the first week and then remained relatively constant. Mean accumulation factors for moclobemide during the first week were 1.85 for C_max and 3.0 for AUC. These values were higher than predicted from single-dose characteristics. There was a marked reduction in the variability of AUC and clearance (CI/F) values at steady-state compared with the first dose. Minimum plasma concentrations of the 2 metabolites, Ro 12-5637 and Ro 12-8095, were relatively stable throughout dosing. The exact mechanism of the decrease in systemic and oral clearance of moclobemide with time during multiple oral dosing is not known at present. Either moclobemide inhibits its own clearance or moclobemide metabolism is inhibited by one or more of its metabolites. The findings indicate that, if dosage needs to be adjusted during treatment with moclobemide, the changes should be made carefully and at intervals of not less than 1 week.