MONOAMINE OXIDASE-A - PHARMACODYNAMICS IN HUMANS OF MOCLOBEMIDE, A REVERSIBLE AND SELECTIVE INHIBITOR

1 Single oral doses of 300, 450 and 600 mg moclobemide, a monoamine ox idase type A inhibitor, were administered in a cross-over design to ei ght healthy male volunteers. Plasma concentrations of the parent drug and of two monoamine metabolites (3,4-dihydroxyphenylglycol DHPG from noradrenaline; 5-hydroxyindoleacetic acid 5HIAA from serotonin) were m easured over time. 2 A physiological pharmacokinetic-pharmacodynamic m odel was used to describe MAO-A inhibition as reflected in the alterat ions of monoamine metabolites. Population values for the model paramet ers were obtained by a two-stage method allowing for repeated dosing p er subject. 3 Even at the lowest dose an effect of moclobemide on plas ma DHPG and 5HIAA concentrations was detectable in most subjects for u p to 24 h. In contrast to DHPG, 5HIAA formation was only partially sup pressed by moclobemide (maximum fractional extent of enzyme inhibition I-max: 0.57, CV 26%) suggesting the existence of 5HIAA formation path ways independent of those inhibitable by moclobemide. 4 Plasma moclobe mide concentrations associated with 50% of maximum enzyme inhibition ( IC50) were in the range of 100 (IC50,5HIAA at 300 mg) to 400 mu g 1(-1 ) (IC50,DHPG at 600 mg).