Comparison of the monoamine oxidase inhibiting properties of two reversible and selective monoamine oxidase‐A inhibitors moclobemide and toloxatone, and assessment of their effect on psychometric performance in healthy subjects.

Abstract

1 The effects of two reversible, predominantly monoamine oxidase-A (MAO-A) inhibitors, moclobemide (150 mg three times daily) and toloxatone (400-200-400 mg day-1) on monoamine metabolites and psychometric performance were compared in a double-blind placebo controlled crossover study in 12 healthy subjects. 2 After 7 days of moclobemide/toloxatone/placebo administration subjects were hospitalized for 24 h on day 8. Blood samples were drawn every 2 h for determination of plasma noradrenaline (NA), 3,4-dihydroxyphenylglycol (DHPG), homovanillic acid (HVA) and 5-hydroxyindolacetic acid (5-HIAA). Urine was collected for measurements of normetanephrine and 3-methoxytyramine excretion. Psychometric performance (short-and long-term memory, critical flicker fusion frequency, choice reaction time) and subjective feelings were assessed before each drug intake (in the morning, at noon, in the evening). 3 Compared with placebo, both reversible monoamine oxidase inhibitors decreased the plasma concentration of DHPG and HVA. The overall fall in DHPG (AUC from 0 to 24 h) was 44% during moclobemide and 12% during toloxatone (P < 0.001) and the overall decrease in HVA was 38% and 20% (P < 0.005) on moclobemide and toloxatone, respectively. 4 Before the next drug intake, MAO-A inhibition, as judged by the decrease of plasma DHPG concentration, was significantly different from placebo with moclobemide but not with toloxatone. 5 Moclobemide, but not toloxatone, exerted a moderate, but significant inhibition of the deamination of 5-hydroxytryptamine (5-HT) as judged by the fall in plasma 5-HIAA concentration. Neither drug influenced plasma NA concentration. 6 A significant rise in urinary excretion of normetanephrine was observed on moclobemide and to a lesser extent on toloxatone. The urinary excretion of 3-methoxytyramine was significantly raised by moclobemide but not by toloxatone. 7 Neither moclobemide nor toloxatone altered memory function, vigilance, subjective feelings or sleep characteristics of the subjects.

Brain monoamine oxidase A inhibition in cigarette smokers

“…Estimates of the degree to which MAO A needs to be inhibited for clinical improvement vary from 20% to 80% (as assessed from peripheral measures of monoamine metabolites) (5,33,34). The level of MAO A inhibition which we measured in smokers (28%) is in the low range of these values (assuming that peripheral measures of monoamine metabolites reflect brain MAO A levels).…”

Monoamine oxidase‐A: pharmacodynamics in humans of moclobemide, a reversible and selective inhibitor.

“…method of Berlin et al [8]. The minimum quantifiable concentration of 5HIAA was 0.5 nmol l-1; in duplicate analyses the inter-day coefficient of variation was below 10%.…”

Mechanistic Pharmacokinetic and Pharmacodynamic Modeling of CHF3381 (2-[(2,3-Dihydro-1H-inden-2-yl)amino]acetamide Monohydrochloride), a Novel N-Methyl-d-aspartate Antagonist and Monoamine Oxidase-A Inhibitor in Healthy Subjects

“…A direct action model using an effect site compartment did not fit the data as well. Similarly to other reversible and selective MAO-A inhibitors (Bieck et al, 1993) like moclobemide (Holford et al, 1994), befloxatone (Patat et al, 1996), brofaromine (Gleiter et al, 1994), and toloxatone (Berlin et al, 1990), CHF3381 produces a dose-dependent inhibition of DHPG concentrations in plasma. The magnitude and the duration of the decrease in DHPG plasma concentrations were increased at steady state after multiple twice-a-day regimens for 14 days.…”