1. Single oral doses of 300, 450 and 600 mg moclobemide, a monoamine oxidase type A inhibitor, were administered in a cross-over design to eight healthy male volunteers. Plasma concentrations of the parent drug and of two monoamine metabolites (3,4-dihydroxyphenylglycol DHPG from noradrenaline; 5-hydroxy-indoleacetic acid 5HIAA from serotonin) were measured over time. 2. A physiological pharmacokinetic-pharmacodynamic model was used to describe MAO-A inhibition as reflected in the alterations of monoamine metabolites. Population values for the model parameters were obtained by a two-stage method allowing for repeated dosing per subject. 3. Even at the lowest dose an effect of moclobemide on plasma DHPG and 5HIAA concentrations was detectable in most subjects for up to 24 h. In contrast to DHPG, 5HIAA formation was only partially suppressed by moclobemide (maximum fractional extent of enzyme inhibition Imax: 0.57, CV 26%) suggesting the existence of 5HIAA formation pathways independent of those inhibitable by moclobemide. 4. Plasma moclobemide concentrations associated with 50% of maximum enzyme inhibition (IC50) were in the range of 100 (IC50,5HIAA at 300 mg) to 400 micrograms l-1 (IC50,DHPG at 600 mg).