P. R. Bieck

Tyramine kinetics and pressor sensitivity during monoamine oxidase inhibition by selegiline

The effect of the monoamine oxidase inhibitor selegiline on tyramine metabolism and intravenous and oral tyramine pressor sensitivity was studied in healthy subjects. After oral doses of tyramine, which caused systolic blood pressure to increase by 30 mm Hg, we determined plasma concentrations of p‐hydroxyphenylacetic acid (HPAA) and of conjugated and unconjugated tyramine. When 20 mg/day of selegiline was administered, the AUCspec of HPAA decreased from 86% to 64% and the AUCspec of conjugated tyramine increased from 13% to 35% of the sum of total tyramine and HPAA. Pressor sensitivity was enhanced more with oral administration of tyramine than with intravenous administration of tyramine. After the drug was discontinued, initial values were reached within 4 days (one subject) and 2 weeks (two subjects). Fifty‐five percent of the selegiline dose was eliminated in urine as amphetamine and methamphetamine. The findings support the assumption that selegiline does not selectively inhibit monoamine oxidase‐B (MAO‐B) when administered in doses of 20 mg/day and higher.

Monoamine oxidase inhibition by phenelzine and brofaromine in healthy volunteers

The two monoamine oxidase (MAO) inhibitors phenelzine and brofaromine given for 2 to 3 weeks were compared in six volunteers. Blood pressure sensitivity to intravenous tyramine increased 2.6‐fold during phenelzine (60 mg/day) and 4.8‐fold during brofaromine, whereas sensitivity to oral tyramine increased more during phenelzine (15.7‐fold vs 8.5‐fold). After withdrawal of phenelzine, pressor sensitivity to oral tyramine returned to control values within 2 and for more than 8 weeks. Relative bioavailability of conjugated tyramine was elevated sixfold by brofaromine and 11.6‐fold by phenelzine. Urinary elimination of tryptamine increased during phenelzine and brofaromine to 12.7‐fold and threefold, respectively. 3‐Methoxy‐4‐hydroxyphenylglycol (MHPG) and 3‐methoxy‐4‐hydroxymandelic acid (VMA) excretion decreased during brofaromine significantly by 72% and 49%, respectively. The nonsignificant decrease of MHPG excretion and the increase of intravenous tyramine pressor sensitivity caused by phenelzine are significantly related. The data suggest that the selective reversible MAO‐A inhibitor brofaromine has a larger therapeutic safety than phenelzine.

Effect of brofaromine and pargyline on human plasma melatonin concentrations

1. Plasma melatonin was used to determine the influence of two monoamine oxidase inhibitor drugs in 11 normal subjects. 2. Acute oral administration of the selective reversible MAO-A inhibitor brofaromine but not of the - in low doses - selective MAO-B inhibitor pargyline increased daytime melatonin with large variations in onset, degree and duration. 3. Further investigation of this selective action on melatonin might help to better understand the action of the therapeutically effective antidepressive therapy with selective MAO-A inhibitors.

Role of cytochrome P4502D6 in the metabolism of brofaromine

SummaryThe metabolic fate of brofaromine (CGP 11 305 A), a new, reversible, selective MAO-A inhibitor, has been assessed in poor (PM) and extensive (EM) metabolizers of debrisoquine.Compared to EM, PM had significantly longer t1/2 (136%) and larger AUC(0−∞) (110%) of the parent compound brofaromine and a lower Cmax (69%) and AUC (0–72 h) (40%) of its O-desmethyl metabolite. The mean metabolite/substrate ratio (based on urine excretion) was about 6-times greater in EM than in PM. Treatment with quinidine converted all EM into phenocopies of PM. All pharmacokinetic parameters of brofaromine and O-desmethyl-brofaromine in EM treated with quinidine were similar to those of untreated PM, including the metabolite/substrate ratio. Quinidine treatment of PM did not alter the pharmacokinetics of brofaromine or of its metabolite, nor the metabolite/substrate ratio.The results indicate a role for the debrisoquine type of oxidation polymorphism in the O-demethylation and pharmacokinetics of brofaromine.

Clinical pharmacology of the new COMT inhibitor CGP 28 014

CGP 28 014 is a specific inhibitor of catechol-O-methyltransferase (COMT) in vivo. In humans, the inhibition was assessed by measuring urinary excretion of isoquinolines and with the levodopa test. Following administration of CGP 28 014, urinary excretion of isoquinolines was significantly increased. In rats, CGP 28 014 reduced plasma and striatal concentrations of 3-O-methyldopa (30MD) in a dose-dependent manner. Acute and subchronic administration of CGP 28 014 alone or in combination with the peripherally acting decarboxylase inhibitor benserazide decreased plasma 30MD as an index of COMT inhibition by about 50%. There seems to be a close relationship between the time-course of plasma concentrations of CGP 28 014 and the extent of COMT inhibition assessed by the 30MD/DOPA ratio in plasma.

Urinary Excretion of Tryptamine in Comparison to Normetanephrine and Beta-Phenylethylamine in Human Volunteers After Subchronic Treatment with Different Monoamine Oxidase Inhibitors

Measurement of urinary tryptamine excretion has been used extensively in the past as indicator for monoamine oxidase (MAO) inhibition in man. Basal tryptamine excretion (ug/g creatinine) differs between sexes (p< 0.001). The values obtained (x ± SD) were: 66 ± 26 in 13 males (n = 90) and 112 ± 42 in 9 females (n = 60). The higher basal tryptamine excretion and the larger tryptamine/indole acetic acid ratios in females, together with the greater effect of MAO inhibitors suggest a lower basal MAO-A activity in women. Different hormonal influences could explain the large interindividual and intraindividual seasonal variation of tryptamine excretion in females. By comparison of urinary tryptamine, normetanephrine and beta-phenylethylamine during subchronic treatment with three different MAO inhibitors it could be shown that tryptamine is a MAO-A substrate. MAO-A inhibition by the new reversible selective inhibitor CGP 11 305 A (150mg/d) caused parallel increases of tryptamine (320%) and normetanephrine (360%), but did not change urinary phenylethylamine. Selective MAO-B inhibition with deprenyl (10mg/d) enhanced phenylethylamine excretion (2600%), but did not affect tryptamine. During treatment with tranylcypromine (20mg/d), the unspecific inhibitor of both MAO-A+B, all three metabolites increased significantly (between 440% and 720%).

Intravenous amine pressor tests in healthy volunteers

SummaryThe pressor effect of intravenous tyramine (TYR) and noradrenaline (NA) has been evaluated, respectively, in 157 tests in 19 healthy unmedicated subjects, and in 202 tests in 24 similar subjects, all of whom took part in ≥3 test sessions.The pressor dose (PD) that raised systolic blood pressure by 30 mm Hg (PD30) ranged from 2 to 8 mg for TYR, and from 3.5 to 17 μg · min−1 for NA. Coefficients of variation ranged from 3 to 47% and from 6 to 38% for TYR and NA, respectively, in the intra-subject comparison. The average inter-subject variation in the TYR PD30 was 22% for 8 females and 30% for 11 males; the corresponding variation in the NA PD30 was 27% (8 females) and 26% (16 males).While the average PD30 for NA was similar for males (10.8 μg/min) and females (10.9 μg/min), a sex-related difference was found for the PD30 of i.v. TRY: 4.4 mg for 11 males and 3.8 mg for 8 females.Additional results from volunteers who took part in fewer than 3 pressor test sessions supported this observation; PD30 of TYR 4.6 mg in 34 males vs 3.5 mg in 21 females.The large intra- and inter-subject variations in the i.v. TYR and NA pressor test results, and the sex difference in the systolic blood pressure response to i.v. TYR, should be considered in assessing the number and gender of subjects required in studies intended to show “significant” differences in the blood pressure response in amine pressor tests.

Metabolic fate of CGS 8216, a benzodiazepine receptor antagonist, in rat and in man.

Conclusion1.CGS 8216 is metabolised to the hydroxy metabolite CGS 11 361 in rat and in man with a much higher metabolite/parent drug ratio in man (2.5 vs 0.1).2.The brain/plasma concentration ratio of the parent drug in the rat 30 min after 10 and 25 mg/kg IP is low, suggesting slow penetration of the drug into the brain tissue.3.No hydroxy metabolite of CGS 8216 was found in the brain of treated rats.4.The discrepancy between our results and those of Lister et al. i.e. 12–20 times lower drug concentrations in plasma and no detectable drug in brain tissue, are hard to explain. It does not seem likely that it is caused by the use of two different strains of rats with apparently differing age. One explanation might be the better bioavailability of CGS 8216 given in polyethylene glycol/water and the 10-fold lower limit of quantitation of the HPLC method we used.5.The findings of Lister et al. are not supported by our data.

Monoamine oxidase inhibition by the MAO-A inhibitors brofaromine and clorgyline in healthy volunteers

The present study compared the extent and duration of MAO inhibition by the selective and reversible MAO-A inhibitor brofaromine with the selective and irreversible MAO-A inhibitor clorgyline using amine pressor tests and excretion of urinary amine metabolites (MHPG, tryptamine). The pharmacological characterization of clorgyline as an irreversible and brofaromine as a reversible MAO-A inhibitor in clinically effective doses was confirmed in humans.

Effect of the new selective COMT inhibitor CGP 28014 A on the formation of 3-O-methyldopa (3OMD) in plasma of healthy subjects

CGP 28014 A is a specific inhibitor of catechol-O-methyl transferase (COMT). The effect on COMT was assessed with the levodopa test in 5 unmedicated subjects and after pretreatment with 200-600 mg CGP 28014 p.o. Plasma concentrations of DOPA, 3-O-methyldopa (3OMD), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid were measured. CGP 28014 A decreased 3OMD not dose-related by 67% (p less than 0.05). This, and an increase of DOPAC shows COMT inhibition by this compound in humans.