PHARMACOKINETIC-PHARMACODYNAMIC INTERACTIONS BETWEEN 2 SELECTIVE MONOAMINE-OXIDASE INHIBITORS - MOCLOBEMIDE AND SELEGILINE

The objectives of this study were to assess potential pharmacokinetic and pharmacodynamic interactions between moclobemide and selegiline, T wo groups of 12 healthy male and female subjects were treated with 200 mg moclobemide or 5 mg selegiline b.i.d. for 16 days. On study day 8, the alternative active drug or placebo was added to the respective tr eatments, Concentration-time profiles of moclobemide and two of its ma in metabolites and 3,4-dihydroxyphenylglycol (DHPG, a norepinephrine m etabolite), 5-hydroxyindoleacetic acid (HIAA, a serotonin metabolite), and 3,4-dihydroxyphenylacetic acid (DOPAC, a dopamine metabolite) in plasma as well as MAO-B activity and serotonin concentration in platel ets were determined at steady state during monotreatment and combined treatment, The pharmacokinetic parameters of moclobemide and its metab olites changed on multiple dosing but were not influenced to a relevan t extent by concomitant administration of selegiline. The measured pha rmacodynamic parameters, expressed as the maximum effect on a study da y and the area under the effect-time curve, characterized the drugs' i nfluence on peripheral neurotransmitter metabolism, The most reliable variables to assess inhibition of MAO-A and -B in humans proved to be DHPG in plasma and serotonin in platelets and MAO-B activity in platel ets, respectively. Several variables (DHPG, platelet serotonin) sugges ted that selegiline has some MAO-A inhibitory activity, This became pa rticularly apparent upon addition of selegiline to moclobemide treatme nt; i.e., the effects of combined moclobemide and selegiline treatment were statistically greater than those of moclobemide monotreatment. M oclobemide alone exerted a slight inhibition of platelet MAO-B activit y, The reported pharmacodynamic interactions are not considered to be clinically relevant. However, due to the previously found supraadditiv e tyramine potentiation upon simultaneous treatment, moclobemide and s elegiline should only be combined when applying dietary restrictions w ith respect to tyramine.