Pharmacokinetic-pharmacodynamic interactions between two selective monoamine oxidase inhibitors: moclobemide and selegiline.
The objectives of this study were to assess potential pharmacokinetic and pharmacodynamic interactions between moclobemide and selegiline. Two 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 treatments. Concentration-time profiles of moclobemide and two of its main metabolites and 3,4-dihydrox/phenylglycol (DHPG, a norepinephrine metabolite), 5-hydroxy-indoleacetic 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 platelets were determined at steady state during monotreatment and combined treatment. The pharmacokinetic parameters of moclobemide and its metabolites changed on multiple dosing but were not influenced to a relevant extent by concomitant administration of selegiline. The measured pharmacodynamic parameters, expressed as the maximum effect on a study day and the area under the effect-time curve, characterized the drugs' influence 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 platelets, respectively. Several variables (DHPG, platelet serotonin) suggested that selegiline has some MAO-A inhibitory activity. This became particularly apparent upon addition of selegiline to moclobemide treatment; i.e., the effects of combined moclobemide and selegiline treatment were statistically greater than those of moclobemide monotreatment. Moclobemide alone exerted a slight inhibition of platelet MAO-B activity. The reported pharmacodynamic interactions are not considered to be clinically relevant. However, due to the previously found supraadditive tyramine potentiation upon simultaneous treatment, moclobemide and selegiline should only be combined when applying dietary restrictions with respect to tyramine.
Dingemanse
J
J
Department of Clinical Pharmacology, F. Hoffmann-La Roche, Basel, Switzerland.
Kneer
J
J
Wallnöfer
A
A
Kettler
R
R
Zürcher
G
G
Koulu
M
M
Korn
A
A
D015102:3,4-Dihydroxyphenylacetic Acid / Q000097:blood; D000328:Adult; D001549:Benzamides / Q000493:pharmacokinetics / Q000494:pharmacology*; D001792:Blood Platelets / Q000378:metabolism; D004311:Double-Blind Method; D004347:Drug Interactions; D005260:Female; D006719:Homovanillic Acid / Q000097:blood; D006801:Humans; D006897:Hydroxyindoleacetic Acid / Q000097:blood; D008297:Male; D008734:Methoxyhydroxyphenylglycol / Q000097:blood; D020912:Moclobemide; D008996:Monoamine Oxidase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D018377:Neurotransmitter Agents / Q000097:blood; D012642:Selegiline / Q000493:pharmacokinetics / Q000494:pharmacology*
D001549:Benzamides; D008996:Monoamine Oxidase Inhibitors; D018377:Neurotransmitter Agents; D015102:3,4-Dihydroxyphenylacetic Acid; D012642:Selegiline; D008734:Methoxyhydroxyphenylglycol; D006897:Hydroxyindoleacetic Acid; D020912:Moclobemide; D006719:Homovanillic Acid