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Mod. Probl. Pharmacopsychiat., vol. 19, pp. 82-104 (Karger, Basel 1983)
Partial or Total Protection from Long-Acting
Monoamine Oxidase Inhibitors (MAOIs) by
New Short-Acting MAOIs of Type A
MD780515 and Type B MD780236
Margherita Strolin Benedetti a, Philippe Dostert a,
Christian Guffroya, Keith F. Tipton b
a Centre
de Recherche Delalande, Rueil-Malmaison, France; b Department of
Biochemistry, Trinity College, Dublin, Ireland
Short-acting inhibitors of monoamine oxidase (MAO) if administered shortly before an irreversible inhibitor, can protect the enzyme
against irreversible inactivation. The protection can be partial or total
according to the selectivity of the short-acting inhibitor towards each
of the two forms of MAO, the mechanism of inhibition of the short-acting and of the irreversible inhibitors, the doses used and their route of
administration, the interval between the administration of the two inhibitors, and their pharmacokinetic characteristics such as absorption,
tissue distribution, metabolism and elimination. There are two important reasons for carrying out investigations to determine such protection. Firstly, if the short-acting inhibitor is suitably chosen, it can not
only protect against an irreversible inhibitor, but can also enhance the
specificity of the latter. Secondly, a better knowledge of the true inhibitory potency of the reversible inhibitor can be obtained, because this is
generally underestimated by ex vivo procedures, or is not always suitably estimated by indirect in vivo methods such as measurements of the
levels of endogenous amines or their respective metabolites. However,
results obtained from this type of investigation, in spite of their interest, have to be examined critically: results similar to those expected
from simple protection might, for example, be obtained if the irreversible inhibition was due to a metabolite of the compound and if the protecting compound interfered with this metabolism.
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Introduction
Protection from Long-Acting by Short-Acting MAOIs
MD780515
(0 moxatone)
MD780236
83
)Q>-H 2CO-@-r-{"°CH3
CN
Y
°
)Q>-H 2CO-@-r-{"NHCH 3
CI
Y
°
,CH 350 3H
Several studies have been carried out to investigate the protective
effect of short-acting, reversible, selective or nonselective inhibitors on
the activity of mixed or selective irreversible inhibitors (table I).
The criteria used to demonstrate the existence or not of such a protection were, particularly in some older papers, based on pharmacodynamic determinations which were recognized as being related to MAO
inhibition, whereas in most of the more recent work the MAO-A and
MAO-B activities have either been measured directly or the concentrations of the endogenous amines and their metabolites have been determined.
The purpose of this work was to investigate the protection afforded by the two short-acting inhibitors, MD780515 and MD780236,
(fig. I) against different types of irreversible inhibitors; those chosen
were clorgyline (type A), e-deprenyl (type B) and tranylcypromine
(type A and B). MD780515 is a reversible inhibitor, both in rat and
man and has been shown to be a selective type A MAO inhibitor in vitro, ex vivo and in vivo [12, 27, 38, 39]. On the other hand, MD780236
is a selective type B MAOI in vitro, ex vivo and in vivo. It is mainly a
short-acting inhibitor in vivo and ex vivo, although it appears to be an
irreversible inhibitor in vitro with rat brain homogenates [37]. Results
of dialysis studies with rat brain mitochondria have confirmed that inhibition by MD780236 is practically irreversible in vitro [40]. In order
to better design and interpret the experiments used to demonstrate partial or total protection of MAO in the rat by orally administered
MD780515 or MD780236, against oral or intravenous irreversible inhibitors, preliminary experiments were carried out to determine the
percentage inhibition of MAO by each compound as a function of the
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Fig. 1. Chemical structures of MD780515 and MD780236.
Strolin BenedettiiDostert/Guffroy ITipton
84
Table I. Protection of MAO by short-acting MAO inhibitors from the effect of irreversible inhibitors
Reference
Short-acting
Irreversible
inhibitor
Criteria used to
prove protection
Protection
total or partial: +
weak orabsent: -
28
harmaline
iproniazid
+
34
harmaline
iproniazid
25
harmine
36
harmaline
pheniprazine
tranylcypromine
iproniazid
5-HTP-induced
tremors
concentrations of
endogenous 5-HT
MAO-A activity
33
harmaline
two phenylpropylamine derivatives
3-amino-2-oxazolidinone
4
41
mexiletine
dexamethasone
pargyline
iproniazid
tranylcypromine
18
harmaline
LY 54761
21
20
(+ )-amphetamine
p-chloramphetamine
15
harmaline
phenelzine
3-amino-2-oxazolidinone
2-hydroxyethylhydrazine
pheniprazine
pargyline
3
Ro 11-1163
pheniprazine
16
imipramine
pargyline
(+ )-amphetamine
(-)-amphetamine
phenelzine
MAO-A and -B activity
MAO-A and -B activity
MAO-A and -B activity
MAO-A and -B activity
reversal of the effect of a reserpine-
+
+
+
+
+
+
+
+
+
+
+
+
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6
concentrations of
5-HT
reversal of the effect of reserpine on
endogenous amines
MAO activity
(tryptamine,
m-iodo-benzylamine)
MAO-A activity
concentrations of
3-methoxytyramine
andHVA
MAO-A and -B activity
MAO-A activity
MAO activity
(tryptamine)
+
85
Protection from Long-Acting by Short-Acting MAOls
Table I. (continued)
MD780515
(cimoxatone)
( + )-amphetamine
p-methoxyamphetamine
harmaline
clorgyline
tranylcypromine
phenelzine
pheniprazine
clorgyline
tranylcypromine
phenelzine
17
p-methoxyamphetamine
0- and m- methoxyamphetamines
(+ )-amphetamine
caroxazone
harmine
harmaline
19
harmaline
pargyline
9
Ro 11-1163
pheniprazine
22
23
30
+
tranylcypromine
LY 51641
MAO-A and -B activity
MAO-A activity
concentrations of
endogenous epinephrine
MAO-A and -B activity
concentrations of
endogenous amines
and their metabolites
MAO-A activity
+
+
+
+
+
+
dose, at suitable times following administration. The design of the protection experiments was the following: one group of rats received the
short-acting inhibitor and a second group the irreversible inhibitor.
The animals were killed 24 h after the administration and the percentage inhibition of MAO was determined. In a third group, the shortacting inhibitor was given first and was followed 30 min, 1 h or 2 h
later by the irreversible inhibitor. The percentage inhibition of MAO
was then determined 24 h after the administration of the irreversible inhibitor.
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26
like agent on endogenous amines
MAO-A and -B ac- +
tivity
+
MAO-A activity
+
(except amphetamine
against
tranylcypromine)
MAO-A activity
+
Strolin BenedettiiDostert/Guffroy/Tipton
86
Materials and Methods
Male Sprague-Dawley rats (Charles River, CD®, France), weighing 160-190 g and
fasted for = 16 h, were used. Clorgyline hydrochloride, MD780515 and MD780236 as the
methane sulphonate were synthesized in the Department of Organic Chemistry, Delalande Research Centre, France. e-deprenyl hydrochloride was kindly supplied by Chinoin, Budapest, Hungary. Tranylcypromine hydrochloride was from Sigma, USA. 5-Hydroxy[side chain-2- 14 C]tryptamine creatinine sulphate (14C-5-HT, spec. act. 60 mCil
mmol) was purchased from The Radiochemical Centre, England, and phenylethylamine
hydrochloride (~-ethyl-I-14C) (I'C-PEA, spec. act. 50 mCilmmol) from New England
Nuclear, USA. MD780515 was administered as a suspension in 0.5% methylcellulose
whereas all other inhibitors were administered in aqueous solution. Doses are expressed
in terms of the free base.
MAO inhibition ex vivo after single administration of a reversible or irreversible
inhibitor, or after administration of a combination of both at defined time intervals, was
determined as follows. Groups of 5 animals were killed at different times after treatment
and brain, liver and heart were removed, rinsed in 9%0 NaCl, frozen in liquid nitrogen
and stored at -20°C. The tissues were then homogenized in phosphate buffer 0.1 M, pH
7.4, using an Ultra-Turrax (I g tissue/16 ml buffer in most cases, and I g/64 ml or I
g1256 ml in dilution experiments). Aliquots (0.1 ml) of tissue homogenates were taken
for the determination of MAO activity in a final volume of 0.5 ml. The reaction was
started by addition of 0.1 ml of 14C-PEA or 14C-5-HT. Final concentrations of PEA and
5-HT were 3 times the apparent K m , i.e. 12 and 480 11M for brain, 75 and 555 11M for
liver, and 90 and 375 11M for heart. The reaction was carried out at 37°C using incubation times of 2 and 10 min for PEA and 5-HT, respectively, when brain and liver were assayed, and 10 min for both substrates when heart was assayed. After incubation, the reaction was acidified with 0.2 ml of 4 N HCI and cooled in ice. The deaminated products
were extracted in 7 ml of toluene-ethyl acetate (III, v/v) and radioactivity counted in 10
ml of toluene containing PPO (0.4%).
Statistical analyses were performed on the experimental data, using the Student test
[2] when the hypothesis of equal variance was valid as evaluated by the Fisher test [2], and
the Wilcoxon non parametric test [24] when this hypothesis was rejected.
Percentage Inhibition of MA 0 as a Function of the Dose of the
Inhibitor
MD780515. The percentage inhibition of MAO I h after oral administration of MD780515 in a dose range increasing from I to 20
mg/kg is presented in table II. It is interesting to observe that even at
the smallest dose studied the percentage inhibition of MAO-A in brain
at I h was very similar to that in liver in spite of the fact that the compound was given by the oral route. This was not the case with c1orgy-
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Results and Discussion
87
Protection from Long-Acting by Short-Acting MAOIs
Table II. Ex vivo inhibition by MD780515 at different doses, of the A and B forms of
MAO in rat brain, liver and heart tissue
% inhibition of
Tissue
MAO ± SE
at 1 h
5-HT
PEA
brain
liver
heart
brain
liver
heart
MD780515, mg/kg p.o.
5
5
50 ± 2
64 ± 2
62 ± 13
7±2
11 ± 5
59 ± 10
66 ±
79 ±
78 ±
14 ±
14 ±
68 ±
10
2
3
4
2
3
2
82
89
88
23
19
72
20
± 0.4
± 0.6
±1
±2
±3
±2
86
91
91
28
26
75
±
±
±
±
±
±
0.6
0.3
2
1
2
1
MD780236. The percentage inhibition of MAO at different times
after oral administration of MD780236 is presented in table IV as a
function of the dose. 30 min after the smallest dose studied, the percentage inhibition of MAO-B in liver was about 2.2 higher than that in
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line which was several times more effective in liver than in brain [42].
This will be discussed in detail later. The strong inhibition observed
with PEA in heart is in agreement with PEA being deaminated by the A
form of the enzyme in the rat heart. However, it is important to note
that the percentage inhibition of heart MAO when 5-HT is used as substrate is, at all doses of MD780515, higher than the corresponding
value obtained with PEA.
Several dilutions of brain homogenates from rats having received
the 10 mg/kg dose were prepared (1 g/16 ml to I g1256 ml) and the
percentage inhibition of MAO determined (table III). As the percentage of MAO inhibition decreases with increase in dilution, it is clear
that MD780515 is a reversible inhibitor and that its true degree of inhibition in the tissue in vivo is underestimated by the experimental
procedure adopted. Therefore, it is highly probable that when the compound is administered at the dose of 10 mg/kg its tissue concentrations
are so high that the values of MAO-A inhibition tend asymptotically to
100%. In this asymptotic region, the effect of an irreversible inhibitor,
up to a certain dose, can be insignificant, even if it binds to the negligible amout of free enzyme and displaces the equilibrium towards the
dissociation of the enzyme-MD780515 complex.
Strolin BenedettiiDostertiGuffroy /Tipton
88
Table III. Effect of dilution of rat brain homogenates on the inhibition of MAO-A and
-B by MD780515
MD780515 (10 mg/kg p.o.)
% inhibition of MAO ± SE at I h
Brain dilution
in buffer, g/ml
5-HT
82
1/16
1/64
1/256
PEA
23 ± 2
± 0.4
65 ± 1
7±4
9±3
40 ± 4
Table III. Effect of dilution of rat brain homogenates on the inhibition of MAO-A and
-B by MD780515
-B by MD780515
Brain
Brain
Brain
Brain Brain BrainBrain
10
5-HT
5-HT
5-HT
5-HT
5-HT
5-HT
5-HT
5-HT
brain
liver
heart
brain
liver
heart
brain
liver
heart
brain
liver
heart
brain
liver
brain
liver
heart
brain
brain
liver
10
brain
liver
heart
brain
liver
heart
brain
liver
heart
brain
liver
heart
10
10
brain
liver
brain
liver
brain
liver
heart
brain
brain
liver
heart
brain
brain
liver
brain
liver
brain. A comparison of central and peripheral inhibition after oral deprenyl shows that MD780236 and deprenyl behave in a similar way
[42] (table IX), in contrast to MD7805l5 and clorgyline which differ
considerably in this respect (table II, VII). From these data, it appears
that MD780236 is essentially a short-acting inhibitor of type B MAO in
ex vivo experiments, even though a residuum of inhibition still exists at
24 h and, as known from previous work, even later [37], which suggests
that there is a small irreversible component. As a consequence of this
residual inhibition it seemed preferable not to use doses of MD780236
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Brain dilution
in buffer, g/ml
Protection from Long-Acting by Short-Acting MAOIs
89
Table V. Effect of dilution of rat brain homogenates on the inhibition of MAO-B by
MD780236
MD780236 (2.5 mg/kg p.o.)
± SE at I h (PEA)
Brain dilution
in buffer, g/ml
% inhibition MAO
1/16
1/64
11256
77
74
66
±3
±3
±4
Clorgyline. The percentage inhibitions of MAO at two different
times after intravenous and oral administration of clorgyline are respectively presented in tables VI and VII as a function of the dose.
When clorgyline is administered intravenously the percentage inhibition of MAO-A in brain is much higher than in liver, i.e. at a dose of 0.1
mg/kg of clorgyline, the ratio of percentage inhibition in brain to percentage inhibition in liver at 1 h was about 17. Similar results have been
obtained by other workers who administered clorgyline subcutaneously [42]. Total inhibition of brain MAO-A at 1 h is obtained with intravenous doses of clorgyline of > 0.1 mg/kg, whereas the doses necessary to inhibit completely liver MAO-A at this time were ::::,. S mg/kg. A
higher inhibition of heart MAO activity is obtained with S-HT as substrate than with PEA at almost all doses, intravenously or orally, of
clorgyline. This is probably due to the fact that PEA is also a substrate
for clorgyline-resistant amine oxidase (CRAO), an enzyme also found
in rat heart [14, 29].
As mentioned above, a similar observation was made for
MD780S1S (table II) which suggests that MD780S1S possesses little in-
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which would have produced total inhibition of MAO- B in the protection experiments.
Dilution experiments have been carried out using brains from rats
which had received a dose of 2.S mg/kg of MD780236 and the results
are expressed in table V. These data, as well as those from dilution experiments carried out previously both on MD780236 and e-deprenyl
[37], confirm that MD780236 is at least partially reversible in vivo,
even if the effect of dilution with this compound is much smaller, at
least at 1 h, than that observed in analogous experiments with
MD780S1S, an inhibitor which can be considered as fully reversible.
Strolin 8enedetti/Dostert/Guffroy /Tipton
90
Table VI. Ex vivo inhibition by clorgyline injected at different doses, of the A and B forms of MAO in rat
brain, liver and heart tissue
% inhibition
Tissue
Clorgyline, mg/kg i.v.
MAO ±SEat
5-HT
Ih
brain
liver
heart
brain
liver
heart
24h
PEA
Ih
brain
liver
heart
brain
liver
heart
24h
0.01
0.05
0.1
0.5
12 ± 2
50 ± 2
87 ± 2
5±5
81 ± 4
76 ± 2.5
4±5
59 ± 7
99
40
99
92
27
83
2±3
6±3
52 ± 5
2±3
4±3
43 ± 5
5±2
3± I
57 ± 5
9±2
7±5
54 ± 3
o ± 13
9±3
34 ± 12
44 ± 4
14 ± 9
15 ± 13
0±2
0±2
o ±9
0±3
25 ± 9
0±4
14 ± 5
15 ± 9
5
0.5
±
±
±
±
±
±
0.2
4
0.8
0.2
3
2
99 ±
62 ±
100 ±
95 ±
36 ±
84 ±
10
0.2 100 ± 0.2 100 ± 0.1
3
94 ± 0.4 96 ± 0.2
0.1 100 ± 0.1 100 ± 0.1
0.8 90 ± 0.5 90 ± 0.2
67 ± I
77 ± I
4
2
87 ± I
93 ± I
10 ± 2
6±4
60 ± 4
12 ± 3
8±4
55 ± 3
29 ±
20 ±
62 ±
17 ±
12 ±
57 ±
2
4
4
2
2
3
45
30
77
30
16
68
±
±
±
±
±
±
3
3
2
2
3
5
Table VII. Ex vivo inhibition by clorgyline given orally at different doses, of the A and B
forms of MAO in rat brain, liver and heart tissue
% inhibition
Tissue
Clorgyline, mg/kg p.o.
MAO ± SEat
5-HT
Ih
24h
PEA
Ih
24h
0.5
brain
liver
heart
brain
liver
heart
7±3
41 ± 3
-16 ± 17
I±3
29 ± 5
- 8 ± 16
brain
liver
heart
brain
liver
heart
2±2
I±3
-26±1419±13
0±4
3± 5
- 4 ± 13 19 ± 8
6±2
53 ± 2
18 ± II
11 ± 4
37 ± 3
21 ± 7
10
5
85
91
98
79
63
86
±7
±2
±2
±4
±3
±4
10 ± 3
15 ± 2
74 ± 7
9±3
7±3
62 ± 6
20
93 ± 2
98 ± 0.4
93 ± I
95 ± 0.2
100±0.1100±0.5
89 ± 0.7 92 ± 0.4
75 ± 2
80 ± I
92 ± 0.8 96 ± 0.6
15 ±
19 ±
73 ±
18 ±
15 ±
64 ±
2
3
2
3
3
3
24 ±
22 ±
77 ±
22 ±
23 ±
74 ±
3
3
3
4
3
2
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0.5
Protection from Long-Acting by Short-Acting MAOIs
91
e-Deprenyl. The percentage inhibitions of MAO measured at two
different times after intravenous and oral administration of e-deprenyl
are presented as a function of the dose in tables VIII and IX respectively. After an intravenous dose of 0.027 mg/kg of -deprenyl the percentage inhibition of MAO-B in brain at 1 h was 4-5 times higher than
in liver: the difference observed between brain and liver inhibition is
less than that observed after the treatment with c1orgyline. Practically
total inhibition of brain MAO-B is obtained for doses of> 1.35 mg/kg
at I h, whereas total inhibition of liver MAO-B was not yet reached at
the maximum dose studied (2.7 mg/kg). These results are similar to
those obtained by Philips [32] who found that doses of e-deprenyl of <
1 mg/kg i.p. given to mice could not produce an inhibition of brain
MAO sufficient to allow PEA concentrations to increase. It is again
apparent that for brain, the percentage inhibitions of MAO-B produced by deprenyl at 1 and 24 h did not differ as much as in case of
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hibitory activity on CRAO_ The doses of intravenous c10rgyline necessary to inhibit completely heart MAO with 5-HT were> 0_1 mg/kg at
I h.
It can be observed that in the case of brain, the percentage inhibitions of MAO-A at I and 24 h do not differ as much as is the case for
liver. This is probably due to the fact that the half-life of the enzyme appears to vary between different organs, the turnover of MAO in the
brain being slower than in the liver [11, l3]. The situation in rat heart is
more complicated, since the half-life of the enzyme increases with age
[10]: rats used in this study should have a half-life value for the enzyme
situated between those for liver and brain.
When c10rgyline is administered orally, the difference observed
between liver and brain for the inhibition obtained with small doses
(percentage inhibition in liver 9 times higher than in brain at 1 mg/kg),
does not exist at higher doses.
Total inhibition of MAO-A in both brain and liver was obtained 1
h after administration of doses of > 10 mg/kg. Our data are in agreement with those obtained by Christmas et al. [5] who measured inhibition of brain MAO 18 h after an oral dose of c10rgyline given to rats.
The results obtained with heart preparations were similar to those from
the intravenous experiments and a higher inhibition was obtained with
5- HT as substrate than with PEA. The doses necessary to completely
inhibit MAO with 5- HT were> 5 mg/kg at 1 h.
Strolin Benedetti/Dostert/Guffroy /Tipton
92
Table VI II. Ex vivo inhibition by e-deprenyl injected at different doses, of the A and B
forms of MAO in rat brain and liver tissue
% inhibition
Tissue
e-deprenyl, mg/kg i.v.
MAO ± SEat
0.027
5-HT
Ih
24h
PEA
Ih
24h
brain
liver
brain
liver
brain
liver
brain
liver
3±2
3±4
2±2
4±2
52
II
44
13
±
±
±
±
4
5
2
4
0.27
0.54
1.35
9±2
10 ± 4
9±2
8±2
II ± 3
10 ± 5
10 ± 2
6±3
30
12
23
II
±
±
±
±
3
4
2
2
50 ±
16 ±
46 ±
16 ±
2
3
3
2
91
61
82
45
92
69
84
53
94
86
86
67
±
±
±
±
0.4
I
0.4
2
96
89
89
75
0.1
0.7
0.4
2
±
±
±
±
0.3
4
0.4
3
±
±
±
±
0.1
4
0.3
2
2.7
±
±
±
±
Table IX. Ex vivo inhibition by e-deprenyl given orally at different doses, of the A and B
forms of MAO in rat brain and liver tissue
% inhibition
Tissue
e-Deprenyl, mg/kg p.o.
MAO ± SEat
5-HT
Ih
24h
PEA
Ih
24h
2.7
1.35
brain
liver
brain
liver
-I ± 0.7
o± I
3±3
o± I
3±2
7±3
o± I
4±2
brain
liver
brain
liver
8±3
55 ± 6
6±4
45 ± 3
36 ±
79 ±
44 ±
65 ±
4
2
4
3
5.4
10.8
3±
18 ±
o±
14 ±
4
I
2
7 ± 0.8
32 ± 2
6±2
21 ± 2
16
42
16
38
82
89
71
74
3
I
3
I
92
92
83
77
94 ±
94 ±
86 ±
82 ±
±
±
±
±
I
±
±
±
±
0.3
0.2
I
0.8
±
±
±
±
2
3
3
2
0.2
0.2
0.7
0.3
liver and it is probable that the different turnover rates of MAO-B in
different organs can explain these results [11, 13]. The turnover rates of
both MAO-A and MAO-B in brain are slower that in liver, although
there is no significant difference between the half-lives of the two
forms in either of these organs [II, 13].
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0.27
93
Protection from Long-Acting by Short-Acting MAOIs
Table X. Ex vivo inhibition by tranylcypromine given orally at different doses, of the A
and B forms of MAO in rat brain, liver and heart tissue
% inhibition
MAO ± SEat
Tissue
Tranylcypromine, mg/kg p.o.
0.0384
5-HT
Ih
24h
PEA
1h
24h
0.096
brain
liver
heart
brain
liver
heart
5±2
- 2±2
9±3 18 ± 2
-21 ± 12 15 ± 7
4±2
0±2
9±2
6±3
19 ± 13 21 ± 11
brain
liver
heart
brain
liver
heart
7±3
14 ± 4
-14 ± 10
11 ± 3
13 ± 2
20 ± 10
16 ±
39 ±
11 ±
13 ±
25 ±
24 ±
2
2
5
3
2
9
0.384
0.96
42
64
49
33
43
48
±3
±3
±8
±2
±2
±6
91
94
94
70
60
75
±
±
±
±
±
±
2
0.4
0.6
0.6
1
3
99
98
98
87
78
86
± 0.1
±0.3
± 0.4
± 1
±2
±3
71
87
51
62
68
45
±
±
±
±
±
±
97
98
80
83
77
66
±
±
±
±
±
±
0.4
0.1
1
0.6
0.8
4
99
99
85
93
89
74
±
±
±
±
±
±
3
2
6
2
2
6
3.84
0.1
0.1
1
0.5
1
3
Tranylcypromine. The percentage inhibitions of MAO at different
times after oral administration of tranylcypromine are presented as a
function of the dose in table X. The central and peripheral inhibition
by this compound of both MAO-A and MAO-B were, as for
MD780515, rather similar even at small doses. A total inhibition of
brain and liver MAO-A and MAO-B was obtained at doses of > 0.96
mg/kg at 1 h. In contrast to clorgyline, a not too different degree of inhibition with the heart preparation was obtained when either 5-HT or
PEA were used as substrate which raises the question as to whether tranylcypromine has some inhibitory effect on CRAO: a recent paper
supports the view that tranylcypromine produces partial inhibition of
this enzyme [31]. The dose necessary to completely inhibit at 1 h heart
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The percentage inhibition of MAO- B 1 h after an oral dose of 1.35
mg/kg of deprenyl was about 2.2 times higher in liver than in brain:
this difference disappears at higher doses. Total inhibition of MAO-B
is practically reached at 1 h both in brain and liver for doses of > 10.8
mg/kg.
94
Strolin BenedettiiDostertiGuffroy/Tipton
Table XI. Protection of MAO in rat brain, liver and heart tissue by MD 780515 given orally, from the inhibitory effect of c10rgyline given orally
% inhibition Tissue
MAO ± SE
at 24h
5-HT
brain
liver
heart
PEA
heart
Interval, MD780515
Clorgyline
MD780515
10 mg/kg p.o. 5 mg/kg p.o. + c10rgyline
h
0.5
I
2
0.5
0.5
2
0.5
0.5
2
0.5
I
0.5
2
5±3
7±5
8±3
10 ± 5
8±4
13 ± 4
-37 ± 22
13 ± 19
- I ± II
-26 ± 16
II ± 14
7±9
84 ± 2
82 ± 2
74 ± 6
66 ± 4
67 ± I
65 ± 2
84 ± 3
90 ± 2
85 ± 2
59 ± 5
68 ± 5
56 ± 3
II ± 3
20 ± 7
16 ± 4
30 ± 5
16 ± 4
31 ± 5
o ± 14
-I ± 24
3 ± 15
o ± II
3 ± 16
7 ± II
** p < 0.01: MD780515 + c10rgyline compared to c1orgyline; + p < 0.05;
MD780515 + c10rgyline compared to MD780515; n.s. = not significant.
**
**
**
**
**
**
**
**
**
**
**
**
++
n.s.
n.s.
++
n.s.
++
n.s.
n.s.
n.s.
n.s.
P < 0.01:
Protection Experiments
MD780515 and Clorgyline. Results obtained in a preliminary study
[26] in which 5 mg/kg of oral clorgyline was given 30 min after an
oral dose of 10 mg/kg of MD780515, showed total protection by
MD780515 from the irreversible inhibition of MAO-A, at least in rat
brain and heart. In order to check whether the protective effect of oral
MD780515 towards oral clorgyline could be partially due to impaired
absorption of clorgyline in the presence of MD780515, clorgyline
(5 mg/kg, p.o.) has been administered 30 min, 1 hand 2 h after
MD780515 (10 mg/kg, p.o.): the MD780515 being administered at a
dose which should produce total inhibition of MAO-A in vivo at 1 h
and the clorgyline at a dose of less than that required to produce total
MAO-A inhibition. The results presented in table XI show that the ab-
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MAO using 5-HT is> 0.96 mg/kg, but when PEA is used the dose is>
3.84 mg/kg. These data are in agreement with those obtained by Christmas et al. [5] when they measured brain MAO inhibition 18 h after oral
administration of tranylcypromine to rat.
95
Protection from Long-Acting by Short-Acting MAOIs
Table XII. Protection of MAO in rat brain and heart tissue by MD780515 given orally,
from the inhibitory effect of clorgyline injected intravenously at 0.05 and 0.1 mg/kg
% inhibition Tissue
MAO± SE
at24h
5-HT
PEA
brain
heart
brain
heart
Interval
h
**
**
**
**
MD780515
Clorgyline
10 mg/kg p.o. 0.05 mg/kg
i.v.
0.5 ± 3
-13 ± 13
4±3
o± 10
44±4
20 ± 13
2±3
15 ± 11
MD780515
+ clorgyline
11 ±
-3 ±
-4 ±
-1 ±
2
13
2
11
** n.s.
n.s. n.s.
* n.s.
n.s. n.s.
Clorgyline MD780515
MD780515
IOmg/kgp.o. 0.1 mg/kgi.v. + clorgyline
5-HT
PEA
brain
heart
brain
heart
**
**
**
**
0.5 ± 3
-13 ± 13
4±3
o ± 10
71 ± 2
50 ± 7
4±2
40 ± 7
10 ± 3
-5 ± 16
-2 ± 2
2 ± 13
**
**
**
**
n.s.
n.s.
n.s.
* p < 0.05; ** P < 0.01: MD780515 + clorgyline compared to clorgyline; + p < 0.05:
+ clorgyline compared to MD780515; n.s. = not significant.
sorption of c10rgyline is not impaired by MD780515, which means that
the protection observed in the experiments with the inhibitors is due to
a real competition of the two inhibitors for the enzyme. In table XI, a
dose ratio of 2 for oral MD 780515 to oral c10rgyline produces total
protection in brain and heart. However, protection can be obtained at
a lower ratio of about 1, as has been shown in our earlier work [26],
where starting with a dose of 21 mg/kg of MD780515, total protection
of rat brain MAO-A was obtained after a dose of 28.2 mg/kg of c1orgyline administered 30 min later. When the doses are expressed in terms
of mmollkg, the dose ratio varies between 0.8 and 1.6.
The tissue concentrations and disposition of c10rgyline can be influenced by its route of administration. It was therefore thought interesting to study whether MD780515 produces partial or total protection
against the irreversible inhibition of MAO-A after intravenous injection of c10rgyline at doses which do not produce total inhibition. Results are presented in table XII which show that MD780515 also produces total protection of MAO-A against c10rgyline injected intravenously. In a further experiment c10rgyline was administered intraven-
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MD780515
Strolin BenedettiiDostertl Guffroy ITipton
96
Table XIII. Protection of MAO in rat brain, liver and heart tissue by MD780515 given
orally, from the inhibitory effect of c10rgyline injected intravenously at a dose of 5
mg/kg
% inhibition Tissue
MAO ± SE
at24h
5-HT
PEA
brain
liver
heart
brain
liver
heart
Interval
h
**
**
**
**
**
**
**
**
MD780515
Clorgyline
10 mg/kg p.o. 5mg/kgi.v.
MD780515
+ c10rgyline
7±5
8±4
13 ± 19
2±3
5±3
11 ± 14
68 ± 5
20 ± 4
45 ± 15
9±8
6±2
34 ± II
90 ± 0.3
57 ± 2
92 ± 2
17 ± 3
7±2
67 ± 5
** p < 0.01: MD780515 + c10rgyline compared to c1orgyline; + p < 0.05;
MD780515 + c10rgyline compared to MD780515; n.s. = not significant.
**
**
**
++
+
n.s. n.s.
n.s. n.s.
**
++
++
P < 0.01:
M D 780515 and Tranylcypromine. Protection experiments with tranylcypromine were carried out, as for c1orgyline, using the same oral
dose of MD780515 followed 1 h later by oral doses of tranylcypromine
which were less than required to produce total MAO inhibition. The results are presented in table XIV. For the smaller dose of tranylcypromine, total protection of the A form of the enzyme was observed, indi-
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ously at a much higher dose which produced practically a total inhibition of MAO with 5-HT 1 h after injection (table VI). In this case, the
protection by MD780515 was only partial (table XIII) because
MD780515 and c10rgyline compete for the free enzyme. The decreased
protection by MD780515 when the dose of c10rgyline is suitably increased is due to displacement of the reversible inhibitor by the irreversible one to such an extent that a no longer negligible amount of enzyme is dissociated from its complex with MD780515 to bind with c1orgyline in a process that finally results in irreversible inhibition. In tables VI and XIII, it is interesting to note that although heart MAO
should be completely inhibited by c1orgyline, there will still be residual
activity when PEA is used probably due to the presence of CRAO. This
explains why, in spite of the lack of total inhibition when PEA is used
as substrate (62 and 57-67% at 1 and 24 h, respectively), MD780515
protects only partially (table XIII).
97
Protection from Long-Acting by Short-Acting MAOIs
Table XIV. Protection of MAO in rat brain, liver and heart tissue by MD780515 given orally, from the inhibitory effect oftrancylcypromine given orally
% inhibition Tissue
MAO±SE
at24h
5-HT
PEA
5-HT
PEA
brain
liver
heart
brain
liver
heart
brain
liver
heart
brain
liver
heart
Interval
h
**
**
**
**
**
**
**
**
**
**
**
**
**
**
**
**
MD780515
Tranylcy10 mg/kg p.o. promine
0.48 mg/kg
p.o.
MD780515
+ tranylcypromine
10 ± 4
7±4
16 ± 7
-4 ± 2
-3 ± 7
13 ± 6
15 ± 4
10 ± 4
-4 ± 18
71 ± 1
60 ± 3
4± 14
44
42
43
68
67
39
±
±
±
±
±
±
3
2
6
3
2
5
MD780515
Trancyl10 mg/kg p.o. cypromine
0.96mg/kg
p.o.
MD780515
+ tranylcypromine
10 ± 4
7±4
16 ± 7
-4 ± 2
-3 ± 7
13 ± 6
19 ± 4
19 ± 3
13 ± 11
82 ± 1
77 ± 1
19 ± 7
73
59
75
84
77
63
± I
±2
±2
± 0.8
±1
±2
**
**
*
n.s.
n.s.
n.s.
n.s.
n.s.
++
*
n.s.
**
**
**
++
n.s.
n.s.
++
**
++
n.s.
++
n.s.
* p < 0.05; ** p < 0.01: MD780515 + tranylcypromine compared to tranylcypromine; + p
+ tranylcypromine compared to MD780515; n.s.
=
not
eating, as for clorgyline, a competition for the enzyme. At the higher
dose there is significant protection of the A form even though is not total in brain and liver. The absence of protection by MD780515 in brain
and liver, but not in heart, against inhibition by tranylcypromine of
PEA deamination was expected. Therefore, the selectivity of tranylcypromine as a type B MAO inhibitor is increased in the presence of
MD780515.
In these experiments, a dose ratio of about 10 for oral MD780515
to oral tranylcypromine produces practically total protection of
MAO-A. When the doses are expressed in terms of mmollkg, the dose
ratio becomes 4. This is in agreement with results obtained in an earlier
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< 0.05; ++ P < 0.01: MD780515
significant.
Strolin Benedetti/Dostert/Guffroy /Tipton
98
Table XV. Protection of MAO-B in rat brain and liver tissue by MD780236 given orally,
from the inhibitory effect of e-deprenyl injected intravenously
Tissue
Brain
Liver
Brain
Liver
Brain
Liver
Interval
h
0.5
0.5
0.5
0.5
0.5
0.5
% inhibition MAO ±SE (PEA) at 24 h
MD780236
2.5 mg/kg p.o.
e-deprenyl
MD780236
0.054 mg/kg i.v. + e-deprenyl
23 ± 2
20 ± 5
61 ± 3
11 ± 5
53 ± 4
23 ± 5
MD780236
2.5 mg/kg p.o.
e-deprenyl
0.27 mg/kg i.v.
MD780236
e-deprenyl
23 ± 2
20 ± 5
83 ± 0.4
41 ± 4
70 ± 3
30 ± 4
MD780236
2.5 mg/kg p.o.
e-deprenyl
2.7 mg/kg i.v.
MD780236
+ e-deprenyl
25 ± 2
26 ± 4
89 ± 0.6
73 ± 2
84 ± 0.6
64 ± 4
n.s.
++
**
n.s.
**
++
**
++
n.s.
n.s.
++
** p < 0.01: MD780236 + e-deprenyl compared to e-deprenyl; + p < 0.05 ; ++ p < 0.01:
MD780236 + e-deprenyl compared to MD780236; n.s. = not significant.
study [26] where it was found that oral doses of MD780515 of ~ 42
mg/kg totally protected rat brain MAO against an oral dose of 4.8
mg/kg of tranylcypromine administered 30 min later (dose ratio ::::,. 9).
carried out using an oral dose of 2.5 mg/kg of MD780236 because with
higher doses of the compound the values of residual inhibition at 24 h
make it difficult to interpret the results. This dose of MD780236 does
not produce total inhibition of MAO-B (table IV). Experiments were
carried out with e-deprenyl administered intravenously 30 min after
(table XV), or intravenously or orally I h after MD780236 (table XVI).
No dose of e-deprenyl produced total inhibition except for the dose of
2.7 mg/kg i.v. in the experiment with brain tissue (table VIII, IX). It is
very difficult to interpret the results of these protection experiments. At
the time when the e-deprenyl is administered, it is not known to what
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MD780236 and e-Deprenyl. MAO protection experiments were
Protection from Long-Acting by Short-Acting MAOIs
99
Table XVI. Protection of MAO-B in rat brain and liver tissue by MD780236 given orally,
from the inhibitory effect of e-deprenyl given by the intravenous or oral routes
Tissue
Interval
% inhibition MAO ± SE (PEA) at 24 h
h
Brain
Liver
Brain
Liver
**
n.s.
**
n.s.
MD780236
2.5 mg/kg p.o.
e-deprenyl
0.27 mg/kg i.v.
MD780236
+ e-deprenyl
24 ± 2
20 ± 3
83 ± I
38 ± 3
61 ± I
34 ± 2
MD780236
2.5 mg/kg p.o.
e-deprenyl
2.7 mg/kg p.o.
MD780236
e-deprenyl
24 ± 2
20 ± 3
72 ± I
75 ± 2
55 ± 2
60 ± 3
**
++
n.s.
++
**
**
++
++
** p < 0.01: MD780236 + e-deprenyl compared to e-deprenyl; ++ p < 0.01: MD780236 +
=
not significant.
extent the residual irreversible inhibition due to MD780236 is already
present. As shown in tables XV and XVI there is partial protection of
MAO-B in brain for the two smallest doses of e-deprenyl (0.054 and
0.27 mg/kg i.v.), this protection being statistically significant only with
the dose of 0.27 mg/kg. For the statistical analysis it was assumed that
at the time when the e-deprenyl was administered only a negligible
amount of the enzyme was irreversibly inhibited by MD780236. If the
residual irreversible inhibition by MD780236 is totally present at 30
min, the results obtained with the two smallest doses of e-deprenyl
might simply be explained as follows: at the time of e-deprenyl injection, there is an activity due to the free enzyme (residual MAO-B activity) of about 37 and 19% in brain and liver respectively (table IV), and
e-deprenyl, at the small doses mentioned above, inhibits only this residual activity. Therefore, the percentage inhibition observed with
MD780236 and the two smallest doses of e-deprenyl in brain is due to
the irreversible inhibition of MD780236 plus the residual MAO-B activity inhibited by e-deprenyl, there being practically no competitive
displacement. Alternatively, if the irreversible inhibition due to
MD780236 is not yet present at 30 min, the percentage inhibition observed with MD780236 and the two smallest doses of e-deprenyl in
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e-deprenyl compared to MD780236; n.s.
Strolin BenedettilDostert/Guffroy /Tipton
100
Table XVII. Protection of MAO in rat brain and liver tissue by MD780236 given orally,
from the inhibitory effect of tranylcypromine given orally
% inhibition Tissue
MAO ± SE
at 24h
5-HT
PEA
brain
liver
brain
liver
TranylInterval MD780236
MD780236
2.5 mg/kg p.o. cypromine
h
+ tranyl0.48 mg/kg p.o. cypromine
**
**
**
**
3±4
-3 ± 3
24 ± 2
20 ± 4
44
42
68
67
±
±
±
±
3
2
3
2
43
41
61
52
±
±
±
±
3
2
2
3
n.s.
n.s.
n.s.
++
**
++
TranylMD780236
MD780236
2.5 mg/kg p.o. cypromine
+ tranyl0.96 mg/kg p.o. cypromine
5-HT
PEA
brain
liver
brain
liver
**
**
**
**
3±4
-3 ± 3
24 ± 2
20 ± 4
73
59
84
77
±
±
±
±
1
2
0.8
1
69
54
77
70
±
±
±
±
3
3
2
2
n.s.
n.s.
++
**
n.s.
brain would be due to inhibition of the residual MAO-B activity and to
partial displacement by e-deprenyl of the reversible inhibitor from its
complex with the enzyme. However, when the intravenous dose of
e-deprenyl is increased to 2.7 mg/kg, the protection by MD780236 was
decreased which shows conclusively that e-deprenyl can displace the
reversible inhibitor. Partial protection of MAO activity in brain and
liver tissue was shown when e-deprenyl was given orally at 2.7 mg/kg
(table XVI).
These results lend further support to those previously obtained
[37], which suggest that MD780236 is a short-acting inhibitor of type B
MAO, and that the inhibition is probably composed, as is generally the
case for irreversible inhibitors, of a rapidly reversible step leading to
the formation of an enzyme inhibitor complex. This can then react further, probably by way of an imine derivative, to form an irreversibly
inhibited species. Metabolism of the inhibitor can, however, also occur
to yield an inactive form and/or a truly reversible inhibitor.
MD780236 might thus present some similarities with phenelzine which
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** p < 0.01: MD780236 + tranylcypromine compared to tranylcypromine; ++ p < 0.01:
MD780236 + tranylcypromine compared to MD780236; n.s. = not significant.
Protection from Long-Acting by Short-Acting MAOIs
101
is an irreversible inhibitor of MAO as well as a substrate for the enzyme [1, 7,8,35]_ It is possible that enzymes other than MAO may be
responsible, either wholly or partly, for the metabolism of MD780236.
A knowledge of the relative rates of metabolism and elimination of
free MD780236 and e-deprenyl from tissues would be necessary in order to interpret fully the results of these experiments.
MD780236 and Tranylcypromine. Protection experiments were
carried out using an oral dose of 2.5 mg/kg of MD780236 followed 1 h
later by an oral dose of 0.48 mg/kg or 0.96 mg/kg tranylcypromine.
Results are presented in table XVII. They show that MD780236 protects only to a limited extent against tranylcypromine, probably for the
same reasons discussed above in case of e-deprenyl.
MD780515 is definitely a reversible inhibitor of type A MAO. The
in vivo inhibitory potency of this compound orally, estimated by
means of the protection of MAO-A against irreversible inhibition by
c1orgyline, is very similar to that of oral c1orgyline. This is in agreement
with a previous in vitro study [27] which compared the potency of these
molecules for the displacement of labelled harmaline which binds specifically to MAO-A in rat brain, even if comparison of in vitro data
concerning reversible and irreversible inhibitors has to be carried out
cautiously.
On the contrary, the in vivo inhibitory potency of oral MD780515,
estimated through the protection of MAO-A against irreversible inhibition by oral tranylcypromine, is inferior to that of the latter. The
comparison of the corresponding potencies of the two molecules in vitro in displacing harmaline has given opposite results [27].
The same discrepancy between in vitro and in vivo results seems to
exist in case of harmaline and tranylcypromine: harmala alkaloids are
not very effective in protecting rat brain MAO in vivo from inhibition
by tranylcypromine [22, 25] (table I), in spite of the strong potency of
harmaline as compared to tranylcypromine in in vitro experiments
[27]. This emphasizes again the need to know, for reversible as well as
for irreversible inhibitors, the rate and extent of absorption, existence
or not of a first-pass effect, degree of metabolism, tissue distribution,
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Conclusions
Strolin BenedettiiDostert/GuffroyITipton
102
rate of elimination and, for the reversible inhibitor, its inducing or inhibitory properties on drug-metabolizing enzymes, in order to estimate
correctly the inhibitory potency of reversible compounds from protection experiments.
In spite of the fact that MD780236 is an irreversible inhibitor in in
vitro conditions, in these protection experiments it behaves mainly as a
reversible inhibitor.
Acknowledgements
The authors would like to thank Ms. M. Farny for help in the preparation of the manuscript, Ms. C. Papillon for the statistical analysis of the data and Dr. M. Mitchard for
useful discussions during the preparation of the paper.
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6
7
8
9
10
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F-92500 Rueil-Malmaison (France)
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