Relationshp between tyramine potentiation and monoamine oxidase (MAO) inhrbition: comparison between moclobemide and other MA0 inhbitors Zimmer R. Relationship between tyramine potentiation and monoamine oxidase (MAO) inhibition: comparison between moclobemide and other MA0 inhibitors. Acta Psychiatr Scand 1990: Suppl 360: 81-83. The pharmacodynamic properties of moclobemide, a reversible inhibitor of MAO-A (RIMA), were compared with the properties of other reversible as well as older irreversible MA0 inhibitors in human subjects. All the substances supposed to have MAO-A-inhibitory activity, with the exception of toloxatone, were shown by the decrease in plasma DHPG or MHPG levels to cause inhibition ranging between 50% and 85%. Toloxatone and low doses of deprenyl (a MAO-B inhibitor) caused 20% and 17% inhibition respectively; higher doses of deprenyl, however, strongly inhbited MAO-A. MAO-B inhibition was confirmed for all nonselective and selective MAO-B inhibitors. Moclobemide and clorgyline were found to be the most highly selective MAO-A inhibitors, although both also inhibited 30% of platelet MAO-B activity. Potentiation of the tyramine pressor effect is mainly influenced by the irreversibility and degree of MAO-A inhibition. Tyramine sensitivity was raised (a factor of 10-30) by all irreversible MA0 inhibitors in doses inhibiting MAO-A; it diminished with increasing reversibility. In therapeutic doses, moclobemide potentiated the intravenous tyramine pressor effect 3 times less than the old irreversible MA0 inhibitors; with the highest therapeutic dose, the tyramine sensitivity factor for moclobemide is only one-seventh to onetenth that of tranylcypromine or phenelzine. Duration of action is obviously also closely related to the reversibility of inhibition: it ranged from up to 2 days with high doses of moclobemide to 3 weeks with tranylcypromine; clorgyline and phenelzine have been shown to maintain their action for several months. The new generation of RIMAs represents a significant progress in safety. Among the RIMAs having significant pharmacodynamic activity, moclobemide appears to be the safest, the most selective and the most readily reversible.
The emergence of a new class of reversible monoamine oxidase (MAO) inhibitors (MAOIs) has greatly modified knowledge about this group of substances. The relationship between M A 0 inhibition and potentiation and duration of the tyramine (TYR) pressor effect differs according to whether a reversible or an irreversible MA01 is administered. The pharmacodynamic properties of moclobemide, a reversible MAOI, are discussed and compared with other reversible MAOIs and with the older, irreversible MAOIs.
R. Zlmmer Pharma Clinical Research, F. HoffmannLa Roche, Basle, Switzerland
Key words: antidepressant; monoamine oxidase
(MAO) inhibitor; pharmacodynamics; tyramine pressor test R. Zimmer, Pharma Clinical Research, F. Hoffmann-La Roche, CH-4002 Bask, Switzerland
Material and methods
MAO-A inhibition was estimated by the decrease in plasma 3,4-dihydroxyphenyl-ethylene glycol (DHPG) levels (1, 2) or plasma 3-methoxy-4hydroxyphenylethylene glycol (MHPG) levels (3). MAO-B activity was generally estimated in platelets using l4C-phenylethy1amine (PEA) as substrate. The potentiation of the pressor effect of tyramine administered intravenously (i.v.) was esti81
mated using either a bolus injection or the infusion technique with mostly a 30 mmHg increase in systolic blood pressure (SBP) as endpoint. The TYR dose that causes this SBP increase is termed the effective TYR dose. To allow comparisons, the TYR sensitivity factor (TSF) was used. TSF is defined as the ratio of the effective TYR dose at baseline to the effective dose during treatment. The potentiation of the TYR pressor effect by orally administered TYR was estimated under fasting conditions; TYR was ingested as capsules. The TSF was also used to assess this potentiation. The duration of action was considered important for safety reasons and was estimated by the time required to obtain baseline TSF values during i.v. or oral TYR test.
Rasults The most important findings are summarized in Table 1, together with the relevant literature references. Discussion
MAO-A inhibition, as estimated by the decrease in plasma DHPG or MHPG levels, ranged between 50% and 85% for all the MAOIs that are supposed to have MAO-A inhibitory activity. An exception was toloxatone, however, which exhibited a surprisingly poor MAO-A inhibition, similar to that observed with low doses of the MAO-B inhibitor,
deprenyl. High doses of deprenyl, however, acted as a strong MAO-A inhibitor. Only Ro 19-6327 was devoid of any effect on the MAO-A activity, providing confirmation in humans of the high selectivity observed in animals (13). MAO-B inhibition, measured in platelets, was almost complete for all nonselective and selective type-B inhibitors. It appeared that clorgyline and moclobemide are the most selective type-A inhibitors. Nevertheless, about 30% of the platelet MAO-B activity was inhibited with both compounds. The potentiation of the TYR pressor effect by i.v. TYR, as measured by the TSF, seems to be influenced mainly by 2 factors: irreversibility and degree of MAO-A inhibition. With all irreversible MAOIs, at doses producing MAO-A inhibition, TSF was high, ranging from 10 to 30. The TSFs decreased with increasing reversibility. At the highest therapeutic doses, the TSF with moclobemide was about 3. Lower TSFs were obtained with the selective MAO-B inhibitor, Ro 19-6327, and with deprenyl at doses of 5-10 mg/day, at which its action was relatively selective. The TSF observed for toloxatone is to be related to its very poor MAO-A inhibition. At therapeutic doses moclobemide potentiated the pressor effect of i.v. TYR 3 times less than did the old irreversible MAOIs. There were much larger differences between reversible and irreversible MAOIs in the potentiation of the pressor effect of oral TYR. The oral and i.v.
Table 1. Dose (mglday)
MAO-A
600 900 300 (single)
50 80
30
RO 19-6327 Toloxatone
160 5 x 200
0 20
> 90
-
1
Brofaromine
100
-
-
6
10
Cimoxatone
20 50
65 80
-
75
6
> 10
Deprenyl
5-1 0 30-60
17 70
> 90 > 90
Clorgyline
30 10
85 -
34
-
Pargyline
30
65
Tranylcypromine
20 20
75 -
> 75
-
45
-
> 80
-
-
Drug Moclobemide
Phenelzine
60
MAO-B
(%I
-
30
-
TSF i.v. 3 3.3 2.2 1
1.7 10
TSF oral
5.6
Duration of action
< 2 days < 2 days
-
5, Roche database
2
-
6, 7
-
5.4
8 days
8,9
> 4 days
6, 10
> 4 days
1, Roche database
30
-
> 15 weeks
10
(oral)
> 90
12
-
-
-
10
34 55
>22 days 4 weeks (oral)
14 55
-
> 11 weeks (oral)
82
2, 4, 5
-
-
-
Reference
3, 9
3 1, 8, 9, 11
9, 12, Roche database
TSFs differed by a factor of 2 with the reversible MAOIs and by a factor of 5 with the irreversible ones. Since oral TYR (Zimmer, Puech et al., this volume), is more relevant for safety, even under fasting conditions (9), it should be stressed that the TSF for moclobemide was 7-10 times lower than that for the irreversible MAOIs tranylcypromine and phenelzine. The duration of action is also closely related to the degree of reversibility of the inhibition. It ranged from 1 2 days with high doses of moclobemide to up to 3 weeks for tranylcypromine. When estimated by the oral TYR test, the duration of action lasted for some months with clorgyline or phenelzine (9). Conclusion
The new generation of reversible MAOIs represents a significant progress in terms of safety (estimated by the TSF) for an equivalent efficacy (MA0 inhibition) compared with the old irreversible MAOIs. Among the reversible MAOIs having a significant pharmacodynamic activity, moclobemide appears to be the safest, the most selective and the most reversible. References 1. EISENHOFER G, GOLDSTEIN D, STULLR, KEISERH, SUNDERLAND T, MURPHYD. Simultaneous liquid-chromatographic determination of 3,4-dihydroxyphenylglycol, catecholamines and 3,4-dihydroxyphenylalaninein plasma and their responses to inhibition of monoamine oxidase. Clin Chem 1986: 32: 2030-2033. 2. KOULUM, SCHEININ M, KAARTTINEN A et al. Inhibition of monoamine oxidase by moclobemide: effects on monoamine metabolism and secretion of anterior pituitary hormones and cortisol in healthy volunteers. Br J Clin PharmaCOI 1989: 27: 243-255. 3. PICKARD, COHENR, JIMERSON D, LAKEC, MURPHYD. Tyramine infusions and selective monoamine oxidase in-
hibitor treatment. Part 11. Psychopharmacology 1981: 74: 8-12. 4. KORNA, DA PRADAM, RAFFESBERG W, ALLENS, GASICS. Tyramine pressor effect in man: studies with moclobemide, a novel, reversible monoamine oxidase inhibitor. J Neural Transm 1988: Suppl 26: 57-71. 5. KETTLERR, DA PRADAM. Platelet MAO-B activity in humans and stumptail monkeys: in vivo effects of the reversible MAO-B inhibitor Ro 19-6327. In: PRZUNTEK H,RIEDERER P, eds. Early diagnosis and preventive therapy in Parkinson’s disease. Vienna: Springer-Verlag, 1989: 21 3-219. 6. DOLLERY C, BROWNM, DAVIESD, STROLINBENEDETTI M. Pressor amines and monoamine oxidase inhibitors. In: TIPTONKF, DOSTERT P, STROLIN BENEDETTI M, eds. Monoamine oxidase and disease. London: Academic Press, 1984: 429-441. 7. FERREY G, Row1 V, STROLINBENEDETTI M, GOMENIL, ORLUC A. Clinical and biochemical results with toloxatone, a short-acting MAO-A inhibitor, in depressed patients. In: TIPTONKF, DOSTERT P, STROLIN BENEDETTI M, eds. Monoamine oxidase and disease. London: Academic Press 1984: 635-637. 8. BIECKPR, ANTONIN KH, CREMER G, GLEITER C. Tyramine pressor effects of CGP 11 305 A in comparison to TCP after prolonged treatment of human volunteers. In: TIPTON KF, DOSTERT P, STROLINBENEDETTI M, eds. Monoamine oxidase and disease. London: Academic Press, 1984: 505-5 13. 9. BIECKPR, ANTONINKH. Tyramine potentiation during treatment with M A 0 inhibitors: brofaromine and moclobemide vs irreversible inhibitors. J Neural Transm 1989: SUPPI.28: 21-31. M, 10. Loo H,POIRIERMF, DENIKERP, STROLINBENEDETTI SONTAGN, LESAGEA. Selectivity of cimoxatone and its effects on prolactin release during treatment of depressed patients. In: TIPTONK, DOSTERT P, STROLIN BENEDETTI M, eds. Monoamine oxidase and disease. London: Academic Press, 1984: 353-365. 11. SIMPSONG, FREDERICKSON E, PALMERR, PI E, SLOANE R, WHITEK. Platelet monoamine oxidase inhibition by deprenyl and tranylcypromine: implications for clinical use. Biol Psychiatry 1985: 20: 680-684. 12. ROBINSON D, WIESA, RAVARIS C, IVESJ, BARLETT D. Clinical pharmacology of phenelzine. Arch Gen Psychiatry 1978: 35: 629435. 13. HAEFELY W, KETTLERR, KELLERH et al. Reversible and highly selective MAO-B inhibitor Ro 19-6327: a novel tool to explore the function of MAO-B in human brain. Adv Neurol (in press).
The emergence of a new class of reversible monoamine oxidase (MAO) inhibitors (MAOIs) has greatly modified knowledge about this group of substances. The relationship between M A 0 inhibition and potentiation and duration of the tyramine (TYR) pressor effect differs according to whether a reversible or an irreversible MA01 is administered. The pharmacodynamic properties of moclobemide, a reversible MAOI, are discussed and compared with other reversible MAOIs and with the older, irreversible MAOIs.
R. Zlmmer Pharma Clinical Research, F. HoffmannLa Roche, Basle, Switzerland
Key words: antidepressant; monoamine oxidase
(MAO) inhibitor; pharmacodynamics; tyramine pressor test R. Zimmer, Pharma Clinical Research, F. Hoffmann-La Roche, CH-4002 Bask, Switzerland
Material and methods
MAO-A inhibition was estimated by the decrease in plasma 3,4-dihydroxyphenyl-ethylene glycol (DHPG) levels (1, 2) or plasma 3-methoxy-4hydroxyphenylethylene glycol (MHPG) levels (3). MAO-B activity was generally estimated in platelets using l4C-phenylethy1amine (PEA) as substrate. The potentiation of the pressor effect of tyramine administered intravenously (i.v.) was esti81
mated using either a bolus injection or the infusion technique with mostly a 30 mmHg increase in systolic blood pressure (SBP) as endpoint. The TYR dose that causes this SBP increase is termed the effective TYR dose. To allow comparisons, the TYR sensitivity factor (TSF) was used. TSF is defined as the ratio of the effective TYR dose at baseline to the effective dose during treatment. The potentiation of the TYR pressor effect by orally administered TYR was estimated under fasting conditions; TYR was ingested as capsules. The TSF was also used to assess this potentiation. The duration of action was considered important for safety reasons and was estimated by the time required to obtain baseline TSF values during i.v. or oral TYR test.
Rasults The most important findings are summarized in Table 1, together with the relevant literature references. Discussion
MAO-A inhibition, as estimated by the decrease in plasma DHPG or MHPG levels, ranged between 50% and 85% for all the MAOIs that are supposed to have MAO-A inhibitory activity. An exception was toloxatone, however, which exhibited a surprisingly poor MAO-A inhibition, similar to that observed with low doses of the MAO-B inhibitor,
deprenyl. High doses of deprenyl, however, acted as a strong MAO-A inhibitor. Only Ro 19-6327 was devoid of any effect on the MAO-A activity, providing confirmation in humans of the high selectivity observed in animals (13). MAO-B inhibition, measured in platelets, was almost complete for all nonselective and selective type-B inhibitors. It appeared that clorgyline and moclobemide are the most selective type-A inhibitors. Nevertheless, about 30% of the platelet MAO-B activity was inhibited with both compounds. The potentiation of the TYR pressor effect by i.v. TYR, as measured by the TSF, seems to be influenced mainly by 2 factors: irreversibility and degree of MAO-A inhibition. With all irreversible MAOIs, at doses producing MAO-A inhibition, TSF was high, ranging from 10 to 30. The TSFs decreased with increasing reversibility. At the highest therapeutic doses, the TSF with moclobemide was about 3. Lower TSFs were obtained with the selective MAO-B inhibitor, Ro 19-6327, and with deprenyl at doses of 5-10 mg/day, at which its action was relatively selective. The TSF observed for toloxatone is to be related to its very poor MAO-A inhibition. At therapeutic doses moclobemide potentiated the pressor effect of i.v. TYR 3 times less than did the old irreversible MAOIs. There were much larger differences between reversible and irreversible MAOIs in the potentiation of the pressor effect of oral TYR. The oral and i.v.
Table 1. Dose (mglday)
MAO-A
600 900 300 (single)
50 80
30
RO 19-6327 Toloxatone
160 5 x 200
0 20
> 90
-
1
Brofaromine
100
-
-
6
10
Cimoxatone
20 50
65 80
-
75
6
> 10
Deprenyl
5-1 0 30-60
17 70
> 90 > 90
Clorgyline
30 10
85 -
34
-
Pargyline
30
65
Tranylcypromine
20 20
75 -
> 75
-
45
-
> 80
-
-
Drug Moclobemide
Phenelzine
60
MAO-B
(%I
-
30
-
TSF i.v. 3 3.3 2.2 1
1.7 10
TSF oral
5.6
Duration of action
< 2 days < 2 days
-
5, Roche database
2
-
6, 7
-
5.4
8 days
8,9
> 4 days
6, 10
> 4 days
1, Roche database
30
-
> 15 weeks
10
(oral)
> 90
12
-
-
-
10
34 55
>22 days 4 weeks (oral)
14 55
-
> 11 weeks (oral)
82
2, 4, 5
-
-
-
Reference
3, 9
3 1, 8, 9, 11
9, 12, Roche database
TSFs differed by a factor of 2 with the reversible MAOIs and by a factor of 5 with the irreversible ones. Since oral TYR (Zimmer, Puech et al., this volume), is more relevant for safety, even under fasting conditions (9), it should be stressed that the TSF for moclobemide was 7-10 times lower than that for the irreversible MAOIs tranylcypromine and phenelzine. The duration of action is also closely related to the degree of reversibility of the inhibition. It ranged from 1 2 days with high doses of moclobemide to up to 3 weeks for tranylcypromine. When estimated by the oral TYR test, the duration of action lasted for some months with clorgyline or phenelzine (9). Conclusion
The new generation of reversible MAOIs represents a significant progress in terms of safety (estimated by the TSF) for an equivalent efficacy (MA0 inhibition) compared with the old irreversible MAOIs. Among the reversible MAOIs having a significant pharmacodynamic activity, moclobemide appears to be the safest, the most selective and the most reversible. References 1. EISENHOFER G, GOLDSTEIN D, STULLR, KEISERH, SUNDERLAND T, MURPHYD. Simultaneous liquid-chromatographic determination of 3,4-dihydroxyphenylglycol, catecholamines and 3,4-dihydroxyphenylalaninein plasma and their responses to inhibition of monoamine oxidase. Clin Chem 1986: 32: 2030-2033. 2. KOULUM, SCHEININ M, KAARTTINEN A et al. Inhibition of monoamine oxidase by moclobemide: effects on monoamine metabolism and secretion of anterior pituitary hormones and cortisol in healthy volunteers. Br J Clin PharmaCOI 1989: 27: 243-255. 3. PICKARD, COHENR, JIMERSON D, LAKEC, MURPHYD. Tyramine infusions and selective monoamine oxidase in-
hibitor treatment. Part 11. Psychopharmacology 1981: 74: 8-12. 4. KORNA, DA PRADAM, RAFFESBERG W, ALLENS, GASICS. Tyramine pressor effect in man: studies with moclobemide, a novel, reversible monoamine oxidase inhibitor. J Neural Transm 1988: Suppl 26: 57-71. 5. KETTLERR, DA PRADAM. Platelet MAO-B activity in humans and stumptail monkeys: in vivo effects of the reversible MAO-B inhibitor Ro 19-6327. In: PRZUNTEK H,RIEDERER P, eds. Early diagnosis and preventive therapy in Parkinson’s disease. Vienna: Springer-Verlag, 1989: 21 3-219. 6. DOLLERY C, BROWNM, DAVIESD, STROLINBENEDETTI M. Pressor amines and monoamine oxidase inhibitors. In: TIPTONKF, DOSTERT P, STROLIN BENEDETTI M, eds. Monoamine oxidase and disease. London: Academic Press, 1984: 429-441. 7. FERREY G, Row1 V, STROLINBENEDETTI M, GOMENIL, ORLUC A. Clinical and biochemical results with toloxatone, a short-acting MAO-A inhibitor, in depressed patients. In: TIPTONKF, DOSTERT P, STROLIN BENEDETTI M, eds. Monoamine oxidase and disease. London: Academic Press 1984: 635-637. 8. BIECKPR, ANTONIN KH, CREMER G, GLEITER C. Tyramine pressor effects of CGP 11 305 A in comparison to TCP after prolonged treatment of human volunteers. In: TIPTON KF, DOSTERT P, STROLINBENEDETTI M, eds. Monoamine oxidase and disease. London: Academic Press, 1984: 505-5 13. 9. BIECKPR, ANTONINKH. Tyramine potentiation during treatment with M A 0 inhibitors: brofaromine and moclobemide vs irreversible inhibitors. J Neural Transm 1989: SUPPI.28: 21-31. M, 10. Loo H,POIRIERMF, DENIKERP, STROLINBENEDETTI SONTAGN, LESAGEA. Selectivity of cimoxatone and its effects on prolactin release during treatment of depressed patients. In: TIPTONK, DOSTERT P, STROLIN BENEDETTI M, eds. Monoamine oxidase and disease. London: Academic Press, 1984: 353-365. 11. SIMPSONG, FREDERICKSON E, PALMERR, PI E, SLOANE R, WHITEK. Platelet monoamine oxidase inhibition by deprenyl and tranylcypromine: implications for clinical use. Biol Psychiatry 1985: 20: 680-684. 12. ROBINSON D, WIESA, RAVARIS C, IVESJ, BARLETT D. Clinical pharmacology of phenelzine. Arch Gen Psychiatry 1978: 35: 629435. 13. HAEFELY W, KETTLERR, KELLERH et al. Reversible and highly selective MAO-B inhibitor Ro 19-6327: a novel tool to explore the function of MAO-B in human brain. Adv Neurol (in press).
