K. H. Antonin

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.

An interaction study with cimetidine and the new angiotensin II antagonist valsartan

AbstractObjective: This was a randomised, open, three-way crossover study in 12 healthy male volunteers to determine the effect of a single oral dose of cimetidine on the pharmacokinetics of a single oral dose of the angiotensin II receptor antagonist valsartan – and vice versa. The volunteers received either valsartan alone (160 mg), or cimetidine alone (800 mg), or valsartan 1 h after cimetidine. The study was designed primarily to detect a possible influence of cimetidine on the rate and extent of absorption of valsartan. Methods: Plasma concentrations of valsartan and cimetidine, measured by means of high-performance liquid chromatography, were used to calculate pharmacokinetic parameters. The rate of absorption of valsartan and the fraction of the dose absorbed and systemically available after oral administration were calculated using data from an i.v. study with valsartan in healthy young volunteers. Results: The pharmacokinetics of cimetidine – area under curve (AUC0–48 h), maximum concentration (Cmax), time to reach Cmax (tmax) and apparent terminal plasma half-life (t1/2) – was not changed by co-administration of valsartan. For valsartan, the AUC0–48 h increased by 7% and the Cmax by 51% (ratio of geometric means) with co-administration of cimetidine. The higher value for Cmax was attributed to the initial increase in the rate of absorption of valsartan: ka was increased 2.7-fold and another indicator for the rate of absorption, Cmax/tmax, 2.2-fold. This effect was ascribed to inhibition of acid secretion by cimetidine, which leads to a higher gastric pH, thereby increasing the solubility of valsartan; the t1/2 of valsartan was not changed. After valsartan alone, 19% of the dose was absorbed, 23% with co-administration of cimetidine. It was estimated that only 2.2% of the possible change in AUC might be missed by giving a single high dose of cimetidine instead of multiple doses, with the aim to optimally inhibit formation of the inactive metabolite of valsartan. Cimetidine-related changes in the rate of elimination of valsartan were not anticipated, since the clearance from plasma occurs mainly by biliary excretion of unchanged valsartan; metabolism and renal excretion are only minor contributors. Therefore, even in the clinically relevant situation with multiple doses of valsartan and cimetidine, notable changes in the pharmacokinetics of valsartan, except for an increase in Cmax, are not to be expected. This increase in Cmax appears to be of no clinical significance.Valsartan alone and in combination with cimetidine was well tolerated by healthy subjects.

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.

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.

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.

Tryptamine Kinetics in Human Volunteers

In 6 healthy, young volunteers the kinetics of L-tryptophan (TRP) following 3 different single oral doses (1.5, 3, 6 g) simultaneously with urinary tryptamine (TA) excretion were examined. Blood and urine samples were collected hourly before and for 14 h after TRP. TRP in plasma and TA in urine were analysed by specific and sensitive HPLC methods using UV and fluorometric detection, respectively. The measurements were repeated in one volunteer after pretreatment with the decarboxylase inhibitor benserazide (3 × 125 mg/d for 15 days), and in 2 volunteers after pretreatment with the selective and reversible inhibitor of MAO-A, brofaremine (150 mg/d for 10 days).

Transdermally applied scopolamine does not impair psychomotor performance

ConclusionThese results demonstrate that vigilance and sensorimotor abilities during continuous transdermal administration of scopolamine are not impaired. This is due to the dose of scopolamine being high enough to evoke an antiemetic effect but with minimal elicitation of undersired side effects. Wesnes and Warburton (1984), who used two oral doses in a pulse mode, showed either no effect on a rapid visual information-processing performance task (0.6 mg scopolamine) or a nearly 20% decrease in psychomotor performance (1.2 mg scopolamine) 30 min after drug intake. This is consistent with data from a recent publication (Muir and Metcalfe 1983) showing peak plasma concentrations after an oral dose of 415 μg scopolamine at approximately 30 min. Such peak concentrations are know to be responsible for unpleasant CNS side effects such as drowsiness, giddiness, confusion, and memory disturbancies (Shaw and Urquart 1980). The conclusion of Wesnes and Warburton that “the effects of scopolamine are... of relevance for example to sea-borne personnel engaged in tasks requiring sustained mental alertness” holds true only for scopolamine given in a pulse mode butnot for TTS-scopolamine.