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The addition of a dopamine agonist and of a monoamine oxidase type B inhibitor to I-dopa has been suggested in the therapy of Parkinson's disease. The plasma pharmacokinetics of both cabergoline and I-dopa have previously been shown to remain unaffected when the two drugs are given concomitantly. This study aimed at examining whether the plasma pharmacokinetic parameters of cabergoline and selegiline are modified when given in combination. Selegiline is hardly detectable in plasma. Therefore, the plasma levels of its metabolites amphetamine, methamphetamine and desmetylselegiline were used to assess the effect of cabergoline co-administration. Plasma levels of the selegiline metabolites were determined first after selegiline administration (10 mg/day) for 8 days, and then after administration of both drugs for 22 additional days (day 30). Cabergoline plasma levels were measured on day 30, and then after administration of cabergoline (1 mg/day) alone for further 22 days. No statistical difference was found between the Cmax.ss, tmax.ss, AUC0-24h.ss, C0h.ss, C24h.ss values of cabergoline and of the selegiline metabolites when the two drugs were given alone or in combination, indicating the absence of pharmacokinetic interaction between cabergoline and selegiline.

The effects of the potent anticonvulsant FCE 26743 ((S)-2-(4-3-fluorobenzyloxy)benzylamino)propionamide) on monoamine oxidase (MAO) activity were measured in-vitro and ex-vivo using rat tissue homogenates. In-vitro, FCE 26743 showed potent and selective inhibitory properties towards liver MAO-B, with IC50 values about 10(-7) M for MAO-B and higher than 10(-5) M for MAO-A. When determined ex-vivo in brain, the ED50 value for the inhibition of MAO-B was 1.1 mg kg-1 (p.o.) 1 h post-dosing, whereas MAO-A remained virtually unaffected after administration of 60 mg kg-1. Similar effects were seen in liver. Following oral administration of 5 mg kg-1 FCE 26743 to rats, brain MAO-B inhibition was 79% after 1 h and 13% after 24 h, indicating that FCE 26743 behaves as a short-acting MAO-B inhibitor. The ability of FCE 26743 to act as a MAO substrate was assessed in mice by measuring the urinary excretion of alaninamide, a potential metabolite of FCE 26743 which would result from the action of MAO. No alaninamide was detectable in the 0-8 h urines after administration of a 119 mg kg-1 dose, suggesting that FCE 26743 is not, or only to a small degree, a substrate of MAO. The effects of FCE 26743 on cytochrome P450 enzymes involved in testosterone hydroxylation were determined in rats after repeated administration. No induction of the cytochrome P450 system was noted.

Milacemide, a secondary amine derivative, was previously demonstrated to be a substrate of MAO-B and to be insensitive to the action of copper-dependent amine oxidases. In the present study, it was investigated whether the FAD-dependent secondary amine metabolizing enzyme polyamine oxidase (PAO), could participate in the metabolism of milacemide. For this purpose, the urinary metabolic pattern of oral 14C-milacemide was determined in rats with and without pretreatment with the irreversible PAO inhibitor MDL 72527 and, for comparison, after inhibition of MAO-B by l-deprenyl. While l-deprenyl was shown to significantly decrease the urinary excretion of glycinamide and of an unknown metabolite (UK1), pretreatment with MDL 72527 did not modify the elimination of milacemide as glycinamide but produced a decrease in UK1 equal to that induced by l-deprenyl. The percent of the dose of milacemide eliminated as unchanged drug was slightly but significantly increased after PAO inhibition, though considerably less than after l-deprenyl. These data suggest that milacemide might be a substrate of PAO. If confirmed, this result would constitute the first example of the involvement of the FAD-dependent PAO in drug metabolism.

Milacemide was found to protect Swiss albino CD1 mice but not Sprague Dawley rats against bicuculline-induced lethality. Since it had been previously suggested that the anticonvulsant activity of milacemide might be related to MAO-B- mediated glycine formation, brain and liver MAO-A and-B activities and the urinary metabolic pattern of milacemide were determined in the same mice and rat strains. Similar brain and liver MAO activities were found in the two species, except for liver MAO-A activity which was higher in rats. After the same oral dose of milacemide, the percent of the dose excreted as glycinamide was significantly higher in mice than in rats, whereas that excreted as metabolite UK1 was significantly higher in rats. These results support the hypothesis of a glycine-mediated anticonvulsant activity for milacemide and suggest that the increased formation of UK1 to the detriment of glycinamide might account for the lack of protection against bicuculline-induced lethality by milacemide in rats.

In a previous paper a possible relationship had been suggested to exist between age-induced changes in total MAO activity and amino acid levels in some rat brain areas. To further investigate the possible involvement of MAO activity in changes of brain amino acid levels with aging, moclobemide and Ro 19-6327, short acting MAO-A and MAO-B inhibitors, respectively, were administered to female Wistar rats for their whole life-span. Brain amino acid levels in animals treated with MAO inhibitors were compared to those of young and old nontreated rats. The age-induced changes in brain amino acid concentrations found in the present study were in good agreement with those previously reported. Treatment with both moclobemide and Ro 19-6327 was found to restore taurine and serine concentrations in cortex and glutamine concentrations in cerebellum, to the same values as in young rats, to decrease cerebellum concentrations of serine and to increase taurine concentrations in hypothalamus. Administration of moclobemide brought aspartate concentrations in accumbens and cortex back to the same values as in young rats. A similar effect was observed on hypothalamus glutamate concentrations in rats treated with Ro 19-6327. Some possible causes and consequences of the correction of age-induced brain amino acid levels by chronic administration of MAO inhibitors are discussed.

Cimoxatone is a fully reversible inhibitor selective for the A form of monoamine oxidase. The inhibition is so potent against this enzyme form that it acts as a tight-binding inhibitor. Use of this inhibitor indicates that in rat brain homogenates the concentration of monoamine oxidase A is approximately 8-11 pmol . mg protein-1. Values similar to this were obtained by clorgyline titration, and both methods gave values similar to those found with a [3H]harmaline binding assay.

The pharmacokinetics of the reversible MAO-A inhibitor, cimoxatone, and its O-demethyl metabolite MD 770222 were investigated in eight healthy adult volunteers following single doses of 20- and 40-mg tablets, and 40-mg aqueous suspension. Cimoxatone plasma conc./time curves were fitted using a one-compartment open model, with absorption and elimination half-lives of about 0.5 and 12.0 h, respectively. Visual fittings, parameter estimates, and statistical analysis (Akaike information criterion) showed that data were better fitted by first-order than by zero-order absorption rate. A lag time of 20-25 min was observed for both formulations. MD 770222, which is also a selective and reversible inhibitor of MAO A although less potent than cimoxatone, is the major plasma metabolite and its plasma elimination half-life is about three times longer than cimoxatone. Although cimoxatone solubility in water is only 5 ppm, the drug appears to be well absorbed as indicated by the tight conformity of the pharmacokinetic parameters. Cmax and AUC values doubled from the 20- to the 40-mg dose. A statistical analysis showed that the systemic availability of cimoxatone from the 40-mg tablet is higher than from the suspension (p less than 0.05), and this difference is even more pronounced on analysis of the metabolite data (p less than 0.01). Particle size analysis of cimoxatone pronounced on analysis of the metabolite data (p less than 0.01). Particle size analysis of cimoxatone powder showed the formation of agglomerates for the suspension which, by reduction of surface area, could decrease the availability of the drug.

In-vivo studies on the metabolism of [14C]MD 780236 a short-acting selective type B MAO inhibitor in the rat showed the acid to be the major metabolite in plasma and urine, whereas it was minor in brain, where the alcohol was the major metabolite. Pretreatment with SKF 525-A did not modify the metabolite profile in brain, but benserazide decreased the alcohol. Pretreatment with (-)-selegiline had no effect, but clorgyline or clorgyline with (-)-selegiline significantly decreased the alcohol and increased the primary amine metabolite in brain. In-vivo results suggest that MAO-A is the enzyme responsible for the metabolism of MD 780236. This was confirmed by in-vitro studies. Rat brain homogenates extensively metabolized the drug, with the aldehyde being the major metabolite formed (28% of the total radioactivity in the incubation mixture after 60 min incubation). The acid (12%) was more important than the alcohol (4%) in-vitro. The addition of all metabolites originating from possible MAO activity gave 46% when the incubation was carried out at pH 7.4 and 82% at pH 8.8. The presence of NADPH or NAD+ did not alter the relative amounts of metabolites formed. Total metabolites originating from MAO activity in the presence of (-)-selegiline accounted for 40% of total radioactivity, whereas in the presence of clorgyline they accounted for 8% and in the presence of both clorgyline and (-)-selegiline they were reduced to 3%, compared with 45% in controls. As a further proof of the importance of MAO-A in the metabolism of MD 780236, rats were pretreated with clorgyline 1 h before the drug and MAO-B inhibition measured at different times ex-vivo in brain and liver. The short-lasting phase of inhibition of MAO-B disappeared after pretreatment with clorgyline, and inhibition at 24 h was as high as that at 1 h. These results demonstrate the importance of the A form of MAO for the metabolism of MD 780236.

In the rat, suitable oral doses of tricyclic antidepressants (amitriptyline 20 mg kg-1, imipramine, desipramine 2.5 mg kg-1) are able to antagonize the increase of cardiac levels of intravenous tyramine after a pharmacologically active dose (3.5 mg kg-1 orally) of a reversible and specific type A MAO inhibitor, MD780515 (3-[4-(3-cyanophenylmethoxy)phenyl]-5-(methoxymethyl)-2-oxazolidinone). MD780515, in oral doses up to 35 mg kg-1, does not alter the liver microsomal drug metabolizing enzymes in the rat. Therefore, when given with tricyclic antidepressants, it should not interfere with their metabolism.

Binding of a new selective reversible type A MAO inhibitor cimoxatone (MD 780515) to plasma proteins was studied in vitro by equilibrium dialysis. Binding to 580 microM human serum albumin (HSA) and to total plasma proteins was 93-96% and independent of cimoxatone concentration (0.15-207 microM). The drug was mainly bound to HSA with two binding sites and a moderate association constant (K = 2.9 X 10(4) M-1). Free fatty acids did not modify cimoxatone binding to HSA. Cimoxatone was also moderately bound to isolated lipoprotein fractions; alpha 1-acid glycoprotein and gamma-globulins did not play an important role in the binding of cimoxatone. MD 770222, the O-demethyl metabolite, appeared to be bound to HSA at the same binding sites as cimoxatone. However, no interaction occurred between the two compounds for 580 microM HSA. L-Tryptophan, bilirubin, the benzodiazepines flunitrazepam and oxazepam, imipramine and aspirin, did not displace cimoxatone from its binding sites. On the other hand, warfarin and phenylbutazone decreased cimoxatone binding to 29 microM HSA but no interaction occurred with 580 microM HSA.

In rat, histamine metabolism is altered by some nonspecific inhibitors of monoamine oxidase (MAO) such as iproniazid, and, to a lesser extent, tranylcypromine. Type A MAO inhibitors, such as clorgyline and MD780515, do not seem to interfere with the metabolism of histamine. Deprenyl, a type B MAO inhibitor, shows some inhibition which is, however, much lower than that observed with iproniazid. The strong effect of iproniazid is probably due to its DAO inhibiting properties.

The inhibiton of type A and B MAO in rat forebrain crude membrane preparation by MD780515, (3-(4-[(3-cyanophenyl)methoxy]phenyl)-5-(methoxymethyl)-2-oxazolidinone-Centre de Recherche Delalande, France) has been investigated in vitro with 5-hydroxytryptamine and beta-phenylethylamine as substrates. The inhibition of the high-affinity binding of [3H]harmaline, a specific marker of type A MAO, was also studied. In the experimental conditions used, MD780515 appeared to be a pure mixed MAO inhibitor (MAOI) of 5-HT deamination, both Km and Vmax being altered [Ki (Dixon) = Ki, (slope) = 2 nM; Ki (intercept) = 12 nM]. Phenylethylamine oxidation could be considered to be noncompetitively inhibited by MD780515 (Ki (slope) = 78 nM; Ki (intercept) = 103 nM). Dixon and intercept replots were hyperbolic, suggesting that, at high concentrations, PEA could be deaminated by both forms of MAO. This hypothesis was confirmed by biphasic inhibition curves of 80 microM-PEA obtained when MD780515, clorgyline, harmaline and deprenyl were used at MAOIs. MD780515 was a potent inhibitor (IC50 = 1-2 nM) of [3H]harmaline binding. Comparatively, clorgyline, 'cold' harmaline and Lilly 51641 inhibited 3H ligand binding, with IC50 of 5, 7 and 40 nM respectively. In conclusion, MD780515 is a reversible, specific and potent type A MAOI.

The inhibition of cytochrome P-450 dependent hydroxylations of bufuralol (BH) and antipyrine, and O-deethylation of 7-ethoxycoumarin (7-ECOD) by several monoamine oxidase inhibitors (MAOIs) was investigated in rat liver microsomes. According to their IC50 values, clorgyline was the most potent inhibitor while toloxatone, the only reversible MAOI in this study, was the least potent. A great variability of inhibitory potencies was found, even in the same chemical class of MAOIs. Irreversible inhibition of BH and 7-ECOD has been studied. Rapid irreversible inhibition occurred in some cases, and this could be responsible for in vivo inhibition after repeated dosing of these MAOIs.

Cimoxatone is a new monoamine oxidase inhibitor (MAOI) in comparison to the existing non-selective and irreversible MAOIs used in the therapy of depression. A clinical study has been carried out in 10 depressed patients. Cimoxatone was given from 0.32 to 0.78 mg/kg/day for 28 days. The drug was shown to be effective against depression and well tolerated at the given doses. The inhibition of monoamine oxidase and its reversibility were assessed by urinary excretion of 3-methoxy-4-hydroxy- phenylethyleneglycol sulphate. The treatment had no effect on the plasma prolactin levels. The plasma concentrations of cimoxatone reached a plateau after 3 to 4 days of therapy. The study confirmed earlier findings in healthy volunteers that the principal metabolite is also active as a type A MAOI. The plasma elimination of cimoxatone and its metabolite is almost complete 4 days after the last dosing.

Prolactin (PRL) secretion is stimulated by serotonin (5-HT) and inhibited by dopamine (DA). 5-HT is generally recognized as a substrate for type A monoamine oxidase (MAO), whereas DA is considered as a substrate for either A or B, or both forms of MAO, depending on the species and tissues used. The effect of cimoxatone, a reversible, selective MAO-A inhibitor, on diurnal variation in plasma PRL level was investigated in healthy adults after a single 40 mg oral dose, as an indirect approach to investigating whether DA is preferentially a substrate for Type A or B MAO in man. The circadian rhythm in PRL, stress conditions and diet were taken into account in the present study, which was placebo-controlled. There was a slight but significant reduction in circulating PRL in the six subjects, which persisted for at least 9 h after cimoxatone. However, the duration of the decrease in plasma PRL was shorter than the inhibition of MAO-A. The results are not inconsistent with the presence of both forms of MAO in the human hypothalamus and with DA as a substrate for both forms in this region, if it is assumed that the hypothalamic concentrations of the drug during the period 0-9 hours was sufficiently high to inhibit DA deamination by both forms of MAO.

MD 780236, a selective inhibitor of the B form of MAO behaves as an irreversible inhibitor in in-vitro conditions and mainly as a short-acting inhibitor in ex-vivo experiments. The enantiomer with the R absolute configuration (MD 240928) is fully reversible in ex-vivo conditions, whereas the S-enantiomer (MD 240931) has kept the irreversible component of the inhibition seen with MD 780236. The corresponding racemic alcohol derivative (MD 760548) is also a short-acting inhibitor of the B form of MAO; its S-enantiomer, which has an absolute configuration corresponding to that of MD 240928, has a selectivity towards the B form superior to that of the other enantiomer. The mechanism of the MAO inhibition by MD 780236 is discussed.

In the rat brain, dopamine is metabolised by both A and B forms of monoamine oxidase (MAO), although the A form of the enzyme is the major component. The Km of MAO-A toward dopamine (120 microM) is lower than the Km of MAO-B toward this substrate (340 microM). The activity of MAO-A was lower in old rats than in young rats, and the same degree of decrease was found for 5-hydroxytryptamine as for dopamine as substrates for this enzyme form. The activity of MAO-B was higher in the old rats, the degree of increase being the same for dopamine as for beta-phenethylamine as substrates for this enzyme form. The Ki values of the inhibition of MAO-A by cimoxatone and MD770222 (the principal plasma metabolite of cimoxatone) were independent of the substrate used to assay for activity, but were lower than the Ki values for the inhibition of MAO-B by these compounds.

In both rat brain and heart, noradrenaline and 5-hydroxytryptamine are metabolised predominantly by monoamine oxidase-A. The Km values for 14C-noradrenaline in the rat brain and heart are 290 microM and 300 microM, respectively, whereas for 14C-5-hydroxytryptamine the values are 180 microM and 140 microM, respectively. In the rat brain, mixed substrate experiments suggested that 14C-noradrenaline and 14C-5-hydroxytryptamine are metabolised at the same active centre. Both substrates are inhibited with similar Ki values by the reversible inhibitors cimoxatone, toloxatone and MD 770222.

The purpose of the present work was to study the semicarbazide-sensitive amine oxidase (SSAO) inhibitory properties of MD 240931 and MD 240928 (the two enantiomers of MD 780236) as well as those of the corresponding primary amines, MD220662 and MD220661, in rat heart and aorta. MD240928 and MD240931 are rather weak SSAO inhibitors, MD 240931 being more potent than MD 240928. Of the four compounds studied, the most potent inhibitor of SSAO is MD 220662, its IC50 value ranging from 2.10(-6) to 6.10(-6)M. The SSAO inhibitory potency of this compound does not change significantly with the time of preincubation in both the absence and presence of clorgyline (10(-4)M). MD 220661 is also an inhibitor of SSAO; however, its SSAO inhibitory potency, which without preincubation is comparable to that of MD 220662, does decrease with the time of preincubation to the same extent in both the absence and presence of clorgyline (10(-4)M). These results suggest that MD 220661 is not only an inhibitor of SSAO, but is also a substrate of the enzyme.

Rats were administered toloxatone 100 mg kg-1 p.o., and killed 0.5 to 8 hours later. Toloxatone reversibly inhibited type A MAO, but did not affect the activity of type B MAO in whole brain. Cerebral concentrations of noradrenaline, dopamine and 5-hydroxytryptamine were increased after toloxatone, while their metabolite concentrations were reduced. Synaptosomal uptake processes of these amines were not altered by tolaxatone.

3-(4-[(3-Chlorophenyl)methoxy]phenyl)-5-[(methylamino)methyl]-2- oxazolidinone methanesulphonate (compound MD 780236) is a selective inhibitor of the B-form of monoamine oxidase. Inhibition involves an initial non-covalent interaction between enzyme and inhibitor followed by a time-dependent process resulting in irreversible inhibition. The initial, reversible, phase of inhibition was found to be competitive with respect to phenethylamine and 5-hydroxytryptamine, and a comparison of the Ki values indicated the affinity of the inhibitor for the B-form of the enzyme to be some 7-fold greater than its affinity for the A-form. This selectivity was considerably enhanced by preincubation of the enzyme and inhibitor. Time courses showed that complete inhibition was not achieved under conditions where the inhibitor concentration was over 100-fold greater than that of the enzyme. Assay of the activity of monoamine oxidase by determining the release of hydrogen peroxide fluorometrically showed compound MD 780236 to be a substrate for, as well as an inhibitor of, monoamine oxidase, and kinetic analysis revealed that the rate of product formation was some 530-fold greater than that of the process leading to irreversible inhibition of the B-form of the enzyme.

Cimoxatone is a reversible mixed-type selective inhibitor of monoamine oxidase-A. For a mixed-type inhibitor, it can be shown that (vo-vi)/Vi is proportional to the inhibitor concentration. This relationship has been used to estimate the t 1/2 of the elimination of cimoxatone in rat brain after a single dose of inhibitor. t 1/2 values, estimated with three monoamine oxidase substrates, were in the range 3.9-4.8 h, in reasonable agreement with t 1/2 values determined from the plasma and brain concentration/time curves of cimoxatone.

In this paper an overview of the present state of monoamine oxidase inhibitors (MAOIs) is presented. The irreversible inhibitors are firstly considered. They have been divided into four chemical types: substituted hydrazine, cyclopropylamine, propargylamine and allylamine derivatives. Moreover, a tetrahydropyridine derivative (MPTP), recently described as an irreversible inhibitor of MAO-B, has been included among the irreversible MAOIs. The reversible inhibitors such as tetrahydro-beta-carbolines and salsolinol, phenylalkylamines: amphetamine, amiflamine and 2,3-dichloro-alpha-methyl-benzylamine. Among the short acting or reversible inhibitors the 4-(2-benzofuranyl) piperidine series and the morpholinoethylamino derivatives are discussed. Finally the oxazolidinone series is presented separately, as in this series reversible or irreversible inhibitors of the A or B form of MAO have been obtained.