Failure to detect amphetamine or 1-amino-3-phenylpropane in humans or rats receiving the MAO inhibitor tranylcypromine.

BACKGROUND: There have been conflicting reports in the literature about whether or not tranylcypromine is metabolized to amphetamine. In the current report, we investigated this possible route of metabolism in both rats and humans. Body fluid samples from patients and rats and brain, liver and heart samples from rats were analyzed for levels of amphetamine and 1-amino-3-phenylpropane, another potential product of cleavage of the cyclopropyl ring of tranylcypromine after administration of tranylcypromine. Extracted samples were reacted with pentofluorobenzenesulfonyl chloride and analyzed using electron-capture gas chromatography. RESULTS: Amphetamine or 1-amino-3-phenylpropane were not found in any of the samples, indicating that opening of the cyclopropyl ring of tranylcypromine is not a significant route of metabolism for this drug at usual doses. LIMITATIONS: The assay procedure did not permit analysis of 1-amino-2-phenylpropane (another possible product of cleavage of the cyclopropyl ring of tranylcypromine) or of N-methylamphetamine. CONCLUSIONS: These studies support the growing body of evidence indicating that opening of the cyclopropyl ring of tranylcypromine to form amphetamine, a drug of abuse, is not significant at usual doses of tranylcypromine.

The pharmacokinetics of tranylcypromine enantiomers in healthy subjects after oral administration of racemic drug and the single enantiomers.

The pharmacokinetics of the two enantiomers of tranylcypromine were evaluated in six healthy subjects after oral dosage of the racemate (20 mg of the sulphate) and the single enantiomers (10 mg of the sulphate) using an enantiospecific assay. Significant differences in AUC, Cmax, lambda(z), and CLR of the two enantiomers were observed both on administration of the racemate and of the individual enantiomers. The plasma concentrations and urinary excretion rates of (-)-tranylcypromine exceeded those of (+)-tranylcypromine. AUCs of the (-)-enantiomer [arithmetical means 197 ng ml(-1) h after the racemate, 130 ng ml(-1) h after the enantiomer] were greater than those of the (+)-enantiomer [26 ng ml(-1) h after the racemate, 28 ng ml(-1) h after the enantiomer] (P = 0.0001). No in vivo racemisation was detected. The power of the study was insufficient to establish any enantiomer-enantiomer interaction except for a possible interaction at the level of renal clearance (P = 0.013 for both enantiomers).

Postmortem changes in blood tranylcypromine concentration: competing redistribution and degradation effects.

Site and temporal changes in tranylcypromine (TCP) and lithium concentrations in blood were studied in a human poisoning case. Blood samples from peripheral vessels and six central vessels were obtained at 0, 6, 24, 48 and 72 h after starting the autopsy. Nine tissue samples were obtained on completion. TCP showed preferential concentration in liver (2.21 micrograms/g) and brainstem (2.46 micrograms/g). There was a moderate post mortem redistribution phenomenon with TCP concentrations lowest in peripheral blood (0.17 micrograms/ml) at 0 h and highest in central vessels at 24 h (0.52 micrograms/ml). At 72 h blood TCP concentrations fell below those at 0 time but the samples showed marked putrefactive changes. Control blood samples spiked with TCP and incubated for 48 h at 37 degrees C showed a 58% fall in drug concentration. By contrast with TCP, lithium, which has a small Vd (0.8 l/kg) and is chemically stable, did not show this pattern of change in blood concentration. The site and temporal differences in TCP concentration in blood can be explained by the competing effects of post mortem redistribution and drug degradation. Redistribution is an early post mortem phenomenon characterised by diffusion, along a concentration gradient, from drug reservoirs in solid organs into adjacent blood vessels. Drug degradation is a later phenomenon associated with putrefactive change.

Enantiospecific high-performance liquid chromatographic assay with fluorescence detection for the monoamine oxidase inhibitor tranylcypromine and its applicability in pharmacokinetic studies.

In order to be able to measure low concentrations of tranylcypromine enantiomers in biological material, chiral fluorescent derivatization and high-performance liquid chromatography (HPLC) were employed. The internal standard S-(+)-amphetamine and borate-sodium hydroxide buffer pH 11 were added to plasma or urine sample aliquots. o-Phthaldialdehyde was used for precolumn derivatization in combination with the chiral mercaptan N-acetylcysteine. HPLC resolution of the diastereoisomeric derivatives was possible on an octadecylsilane column. The mobile phase consisted of sodium phosphate buffer solution pH 6.5, methanol and tetrahydrofuran. The fluorescence of the eluate was monitored at 344/442 nm. The intra-day coefficients of variation were below 10%, the limit of determination was 0.5 ng/ml. The assay was found to be applicable for routine analyses in a preliminary pharmacokinetic study, in which an oral dose of 20 mg racemic tranylcypromine sulfate was administered to three healthy volunteers. The plasma concentrations were generally low, and those of S-(-)-tranylcypromine significantly exceeded those of the R-(+)-enantiomer. Average maximum concentrations were 57.5 and 6.3 ng/ml for S- and R-tranylcypromine, respectively. While S-tranylcypromine was well detectable within the whole study period (8 h), R-tranylcypromine concentrations fell below the detection limit after 4 h in two out of the three studied volunteers.

Liquid chromatographic estimation of tranylcypromine in human plasma.

A simple, selective and quantitative estimation of tranylcypromine using liquid chromatography and electrochemical detection with apomorphine as internal standard in human plasma is described. Sample preparation is done by liquid-liquid extraction. The absolute mean recovery of apomorphine is 95%, the recovery of tranylcypromine is 81%. This method gives a simple estimation method to assay plasma concentrations of tranylcypromine in the therapeutic range (5-200 ng/ml) with good reproducibility and linearity.

Acute cardiovascular effects of tranylcypromine: correlation with plasma drug, metabolite, norepinephrine, and MHPG levels.

BACKGROUND: Recent case reports, small series, and uncontrolled, unblinded studies have suggested that tranylcypromine may produce pressor reactions in some patients. However, the physiologic mechanism underlying this cardiovascular change is unknown. METHOD: The authors studied the acute cardiovascular effects of tranylcypromine in 13 patients and attempted to correlate these changes with plasma measures of parent drug, possible pressor metabolites, norepinephrine, and 3-methoxy-4-hydroxyphenylglycol. RESULTS: Significant elevations in supine blood pressure occurred after administration of tranylcypromine and correlated with tranylcypromine dose. Similar changes were not observed in standing blood pressure measurements. In fact, an orthostatic decrease in blood pressure and increase in heart rate were observed. Amphetamine-like metabolites were not found. CONCLUSIONS: The authors speculate on possible mechanisms underlying these opposite cardiovascular effects.

A comparative study of the electrocardiographic effects of tranylcypromine and amitriptyline when prescribed singly and in combination.

The authors treated 53 in-patients aged between 18 and 65 years who were suffering from major depression with either tranylcypromine, amitriptyline or a combination of tranylcypromine and amitriptyline. Electrocardiograms taken before and after treatment were compared. In clinically effective doses amitriptyline gave rise to a significant increase in heart rate when prescribed alone and in combination with tranylcypromine. Single tranylcypromine treatment had little effect on heart rate and gave rise to no change in cardiac conduction as measured by the electrocardiogram. Amitriptyline when prescribed in combination with tranylcypromine was associated with significant lengthening of the PR interval. None of the patients developed pathological changes in their electrocardiograms under the carefully monitored treatment conditions of the study.

Pharmacokinetics of tranylcypromine in patients who are depressed: relationship to cardiovascular effects.

We investigated the pharmacokinetics of tranylcypromine, as well as the relationship between plasma levels of this agent and its effects on blood pressure and pulse rate. Tranylcypromine was absorbed rapidly after oral dosing, with the peak level being attained within 0.67 to 3.50 hours. Absorption was biphasic in seven of nine subjects. Elimination of tranylcypromine also was rapid, with a t 1/2 between 1.54 and 3.15 hours. From 2 to 7 hours after dosing, standing systolic and diastolic blood pressures were lowered and standing pulse was raised, compared with baseline. Onset of the effect on standing systolic blood pressure was correlated with the time of peak plasma tranylcypromine concentration. Maximum orthostatic drop of blood pressure and rise of pulse rate occurred 2 hours after dosing. Mean plasma tranylcypromine concentrations were correlated with mean orthostatic drop of systolic blood pressure and rise of pulse rate. Patients who have clinically significant hypotensive reactions to this agent may benefit from changes in their dose regimen aimed at minimizing peak tranylcypromine levels.

Activated alpha-alkyl-alpha-arylacetic acid enantiomers for stereoselective thin-layer chromatographic and high-performance liquid chromatographic determination of chiral amines.

The separation of racemic benoxaprofen into the two benoxaprofen enantiomers by preparative high-performance liquid chromatography and the application of the activated enantiomers as derivatization reagents for the simultaneous stereoselective determination of chiral amines in biological material is described. Activated (+)- and (-)-benoxaprofen are both shown to be very sensitive and stable chiral fluorescence markers, applicable to thin-layer chromatography as well as to high-performance liquid chromatography.

Determination of tranylcypromine in human plasma and urine using high-resolution gas--liquid chromatography with nitrogen-sensitive detection.

A precise and sensitive method is described for the determination of the antidepressant drug tranylcypromine in human plasma and urine using high-resolution gas chromatography. The drug, together with an added internal standard, is extracted from the plasma or urine sample, derivatized with heptafluorobutyric anhydride and analysed on an OV-225 support-coated open-tubular glass capillary column with nitrogen-sensitive detection. The method has been applied to the measurement of tranylcypromine levels in plasma and urine from both healthy volunteers and from psychiatric patients receiving a therapeutic dosage of the drug.

Tranylcypromine ('Parnate') overdose: measurement of tranylcypromine concentrations and MAO inhibitory activity and identification of amphetamines in plasma.

A case of tranylcypromine overdose is reported. Tranylcypromine, amphetamine methamphetamine and phenylethylamine were detected in the plasma by gas chromatography and their identity confirmed by mass spectrometry. The data suggested that the amphetamines were metabolic products of tranylcypromine. Platelet monoamine oxidase activity was more than 95% inhibited during the 72 h after the overdose despite complete clinical recovery by that time. The possible role of amphetamines and phenylethylamine in causing the clinical manifestations of tranylcypromine overdose is discussed.

[Determination and comparison of the plasma and urine concentrations in men given tranylcypromine stereoisomers]. / Bestimmung und Vergleich der Plasma- und Urinkonzentrationen nach Gabe von (+)- und (-)-Tranylcypromin.

The (+) and (-)isomers of DL-trans-2-phenylcyclopropylamine (tranylcypromine, Parnate, Jatrosom) were tested under cross-over conditions on 10 volunteers. (-)Tranylcypromine entered blood circulation more rapidly, reached significantly higher concentrations and was metabolized more slowly than (+)tranylcypromine. These results indicate a difference in the pharmacokinetics of the tranylcypromine isomers. In the urine collected over a period of 24 h the excretion of unmetabolized (4)tranylcypromine was lower probably resulting from the greater metabolization rate of this isomer. There is a conformity between the findings in plasma and urine.

[Fluorimetric determination of tranylcypromine in plasma as its 1-dimethylamino-naphthaline-5-sulfonic acid chloride by direct measurement of TLC-plates (author's transl)]. / Fluorimetrische Bestimmung von Tranylcypromin in plasma als 1-Dimethylamino-naphthalin-5-sulfonsäure-Derivat durch direkte quantitative Dünnschichtchromatographie.

A fluorimetric method for analysis of tranylcypromine from plasma is described. After extraction from plasma tranylcypromine reacts with 1-dimethylamino-naphthaline-5-sulfonic acid chloride (DANS-Cl) in order to form the highly fluorescent DANS-tranylcypromine. After chromatographic separation on silicagel plates quantitation is achieved by in situ fluorescence determination. The recovery of tranylcypromine from plasma is 64% with a coefficient of variance of about +/- 6%.