Psychopharmacology (1992) 106: S 46-S 48
Psychopharmacology © Springer-Verlag 1992
Mini-Paper Biochemical effects of high single doses of moclobemide in man: correlation with plasma concentrations J. Dingemanse 1, A. Korn 2, J.-P. Pfefen 1, and T.W. Giintert 1 i Department of Clinical Pharmacology, F. Hoffmann-La Roche Ltd, CH~4002 Basel, Switzerland z Division of Clinical Pharmacology, University Hospital, A-1090 Vienna, Austria
Abstract. The effects of high single doses of moclobemide (300, 450 and 600 mg given at the end of a standardized meal) on plasma levels of several catecholamines and their deaminated metabolites, and on plasma levels of pituitary hormones were determined in eight healthy young male volunteers in a randomised, double-blind, placebo-controlled study. Assessment o f the i.v. tyramine potentiation and determination of the plasma levels of moclobemide were also performed. The tyramine sensitivity factor at 2 h after dosing was a b o u t 2.1, with no significant differences between the doses used. The inhibitory activity of moclobemide on M A O - A was reflected in significant reductions of plasma concentrations of D H P G and 5 - H I A A . N o clear differences were detected between the moclobemide doses. Prolactin plasma concentrations were only slightly increased after the two higher doses. The plasma concentrations of moclobemide were very much in agreement with those found in previous studies under similar experimental conditions. Thus, single oral doses o f 300, 450 and 600 mg moclobemide demonstrated marked inhibition of M A O - A activity, whereas a single dose of 300 mg induced a nearm a x i m u m effect. Key words: Moclobemide centration-effect relationship
Catecholamines - Con-
The reversible M A O - A inhibitor moclobemide has been investigated with respect to its effects on m o n o a m i n e metabolism and on secretion of anterior pituitary hormones, after single doses of 100, 200 and 300 mg to healthy male volunteers (Koulu et al. 1989). Deamination of catecholamines was powerfully and dose-dependently inhibited by moclobemide, whereas the secretion of prolactin was dose-dependently stimulated. The aim of the present study was to investigate these biochemical effects after higher doses of moclobemide O(print requests to: J. Dingemanse
(300, 450, and 600 mg), in conjunction with determination of the i.v. tyramine pressor response and plasma pharmacokinetics.
Materials and methods In a randomised, double-blind, placebo-controlled, eight-way crossover study, eight healthy young male volunteers (21-34 years) received a single dose of moclobemide of 300, 450, or 600 mg and placebo at the end of a standardized meal. Each dosage was given on two occasions, once for biochemical and pharmacokinetic evaluation and once to perform i.v. tyramine potentiation tests. Biochemical measurements included determination of the plasma levels of (nor)adrenaline, the deaminated metabolites 3,4-dihydroxyphenylglycol (DHPG), homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA), as well as the pituitary hormones prolactin (PRL) and human growth hormone (hGH). The tyramine pressor test was performed pre-dose and at 2 and 24 h after drug intake. Small increasing doses of tyramine (starting with 0.5 mg) were administered i.v. until the systolic blood pressure (SBP) increased by at least 30mmHg (Korn et al. 1988). The tyramine dose which produced a rise in SBP by 30 mmHg was calculated from the dose-response curve by linear interpolation. The tyramine sensitivity factor was expressed as the ratio of tyramine dose required for increasing SBP by 30 mmHg before to the tyramine dose after moclobemide. The usual tolerability and safety parameters (adverse events, vital signs, ECG, clinical laboratory tests) were monitored during the study. Statistical evaluation of the pharmacodynamic results was based on the two-way analysis of variance according to Greenhouse Geisser.
Results and discussion Tolerability Tolerance to the different doses of moclobemide was very good. One subject had runs o f supraventricular extrasystoles during tyramine testing after 300 and 600 mg moclobemide. N o significant changes were detected in vital signs or clinical laboratory parameters.
$47 Table 1. Tyramine sensitivity factors 10
Placebo
Moclobemide 300 mg
2h 24h
0.97=k0.14 0.99±0.09
450 mg
O,
8 ~,.~
600 mg
o/
2.11+0.29 2.164-0.40 2.22=k0.33 1.184-0.10 1.21 ~0.16 1.19:50.16
o~ °
.
Psychopharmacology © Springer-Verlag 1992
Mini-Paper Biochemical effects of high single doses of moclobemide in man: correlation with plasma concentrations J. Dingemanse 1, A. Korn 2, J.-P. Pfefen 1, and T.W. Giintert 1 i Department of Clinical Pharmacology, F. Hoffmann-La Roche Ltd, CH~4002 Basel, Switzerland z Division of Clinical Pharmacology, University Hospital, A-1090 Vienna, Austria
Abstract. The effects of high single doses of moclobemide (300, 450 and 600 mg given at the end of a standardized meal) on plasma levels of several catecholamines and their deaminated metabolites, and on plasma levels of pituitary hormones were determined in eight healthy young male volunteers in a randomised, double-blind, placebo-controlled study. Assessment o f the i.v. tyramine potentiation and determination of the plasma levels of moclobemide were also performed. The tyramine sensitivity factor at 2 h after dosing was a b o u t 2.1, with no significant differences between the doses used. The inhibitory activity of moclobemide on M A O - A was reflected in significant reductions of plasma concentrations of D H P G and 5 - H I A A . N o clear differences were detected between the moclobemide doses. Prolactin plasma concentrations were only slightly increased after the two higher doses. The plasma concentrations of moclobemide were very much in agreement with those found in previous studies under similar experimental conditions. Thus, single oral doses o f 300, 450 and 600 mg moclobemide demonstrated marked inhibition of M A O - A activity, whereas a single dose of 300 mg induced a nearm a x i m u m effect. Key words: Moclobemide centration-effect relationship
Catecholamines - Con-
The reversible M A O - A inhibitor moclobemide has been investigated with respect to its effects on m o n o a m i n e metabolism and on secretion of anterior pituitary hormones, after single doses of 100, 200 and 300 mg to healthy male volunteers (Koulu et al. 1989). Deamination of catecholamines was powerfully and dose-dependently inhibited by moclobemide, whereas the secretion of prolactin was dose-dependently stimulated. The aim of the present study was to investigate these biochemical effects after higher doses of moclobemide O(print requests to: J. Dingemanse
(300, 450, and 600 mg), in conjunction with determination of the i.v. tyramine pressor response and plasma pharmacokinetics.
Materials and methods In a randomised, double-blind, placebo-controlled, eight-way crossover study, eight healthy young male volunteers (21-34 years) received a single dose of moclobemide of 300, 450, or 600 mg and placebo at the end of a standardized meal. Each dosage was given on two occasions, once for biochemical and pharmacokinetic evaluation and once to perform i.v. tyramine potentiation tests. Biochemical measurements included determination of the plasma levels of (nor)adrenaline, the deaminated metabolites 3,4-dihydroxyphenylglycol (DHPG), homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA), as well as the pituitary hormones prolactin (PRL) and human growth hormone (hGH). The tyramine pressor test was performed pre-dose and at 2 and 24 h after drug intake. Small increasing doses of tyramine (starting with 0.5 mg) were administered i.v. until the systolic blood pressure (SBP) increased by at least 30mmHg (Korn et al. 1988). The tyramine dose which produced a rise in SBP by 30 mmHg was calculated from the dose-response curve by linear interpolation. The tyramine sensitivity factor was expressed as the ratio of tyramine dose required for increasing SBP by 30 mmHg before to the tyramine dose after moclobemide. The usual tolerability and safety parameters (adverse events, vital signs, ECG, clinical laboratory tests) were monitored during the study. Statistical evaluation of the pharmacodynamic results was based on the two-way analysis of variance according to Greenhouse Geisser.
Results and discussion Tolerability Tolerance to the different doses of moclobemide was very good. One subject had runs o f supraventricular extrasystoles during tyramine testing after 300 and 600 mg moclobemide. N o significant changes were detected in vital signs or clinical laboratory parameters.
$47 Table 1. Tyramine sensitivity factors 10
Placebo
Moclobemide 300 mg
2h 24h
0.97=k0.14 0.99±0.09
450 mg
O,
8 ~,.~
600 mg
o/
2.11+0.29 2.164-0.40 2.22=k0.33 1.184-0.10 1.21 ~0.16 1.19:50.16
o~ °
.
