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A fatal overdose involving tranylcypromine (Parnate) where blood, urine and tissues were quantitated using a pentafluoroproprionic anhydride (PFPA) derivative and gas-chromatography/mass spectroscopy (GCMS). The samples were re-quantified over several weeks demonstrating a significant loss of drug in tissues but not blood or urine specimens. The urine was positive for methamphetamine which has been a suspected metabolite.

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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.

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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.

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Two simple and sensitive spectrophotometric methods are described for the assay of three MAO inhibitors: isocarboxazid, tranylcypromine sulphate and iproniazid phosphate. The first method is based on the formation of a highly coloured stable radical anion between the drug as an n-donor and 7,7,8,8-tetracyanoquinodimethane (TCNQ) as a pi-electron acceptor. Beer's law is obeyed in the concentration range 0.2-3, 0.2-4 and 0.5-4 micrograms ml-1 for isocarboxazid, tranylcypromine sulphate and iproniazid phosphate, respectively. The second method involves the use of iodine monochloride (ICl) as an sigma-acceptor. It was found that ICl reacts quantitatively only with isocarboxazid and tranylcypromine sulphate; with iproniazid phosphate results were very poor. Beer's law is obeyed in the concentration range 2-20 micrograms ml-1 for both drugs. The optimum experimental parameters for colour production in each case were determined. The percentage recoveries obtained were in accordance with those obtained by the official methods. The proposed methods are characterized by high sensitivity.

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A rapid and simple method for the simultaneous determination of trifluoperazine dihydrochloride and tranylcypromine sulphate by first- and fourth-derivative UV spectrophotometry is presented. The procedure consists of extraction in 0.2 m hydrochloric acid, filtration and measurement of the amplitudes of the first- and fourth-derivative spectra at 260 and 274 nm, respectively. A zero-crossing technique is used for the determination of trifluoperazine. Good linearity, accuracy, precision and selectivity were found, and the method is proposed for routine quality control purposes, even for the uniformity of contents test.

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Optimum experimental conditions were developed for determination of the optical purity of samples of tranylcypromine sulfate by proton magnetic resonance spectroscopy after complexation with the chiral lanthanide chelate Eu(hfc)3. At a substrate concentration of 0.25M (0.125M as sulfate) in CDCl3 and an Eu(hfc)3 to substrate molar ratio of 1, the methine proton geminal to the amino group in the cyclopropane ring showed the largest induced shift and largest enantiomeric induced shift difference. From the relative intensities of the resolved (+)-CH-NH2 protons (15.77 ppm) and (-)-CH-NH2 proton (16.04 ppm), the enantiomeric purity and percentage compositions were readily calculated. The mean +/- SD recovery of (+)-tranylcypromine sulfate from synthetic enantiomeric mixtures was 101.02 +/- 2.59 (n = 6).

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Use of proton nuclear magnetic resonance spectroscopy and the lanthanide shift reagent, Eu(hfc)3, resulted in a simple and reliable method for determination of the diastereomeric purity of trans-2-phenylcyclopropylamine sulfate (tranylcypromine sulfate). Eu(hfc)3 effectively simplified the complex overlapping pattern of the 5 non-equivalent phenyl protons to a virtually first order pattern. At a shift reagent to substrate molar ratio of 0.75, and a substrate concentration of 0.25M (as the free base) in CDCl3, the resonances for the cis- and trans-ortho-phenyl protons at 11.39 and 9.99 ppm, respectively, were sufficiently resolved to be of use in quantitative work. Analysis of synthetic diastereomeric mixtures of 2-phenylcyclopropylamine sulfate by the proposed method yielded results that were in close agreement with the expected values. The mean recovery (SD) of trans-diastereomer was 100.51% (0.40) (n = 6). Levels of less than 2% of cis-diastereomer were measurable in cis-trans mixtures.

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The effects of short- and long-term administration of a low dose of tranylcypromine on brain and urine levels of several biogenic amines and on brain activity of monoamine oxidases (MAO) A and B were investigated. MAO-A and MAO-B were inhibited by greater than 85% on day 1, and this inhibition continued to increase over the course of the study (42 days). Levels of 5-hydroxytryptamine in brain continued to increase up to day 21 and did not decline from day 21 to day 42, and levels of tranylcypromine itself continued to increase up to day 42. Dopamine concentrations peaked at day 10 and were not significantly different from that value by day 42. Brain levels of tryptamine and beta-phenylethylamine showed dramatic elevations after the first dose of the drug and remained essentially unchanged from those high values throughout the course of the drug treatment. Brain and urine increases in tryptamine and beta-phenylethylamine showed similar patterns, whereas urinary 5-hydroxytryptamine excretion reached maximal levels earlier than did brain levels.

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The formation of p-hydroxytranylcypromine from intraperitoneally injected tranylcypromine was confirmed using two types of experiments. In the first, tranylcypromine levels were shown to be increased in brains of rats pretreated with agents known to be inhibitors of ring hydroxylation compared to rats pretreated with physiological saline. For the second set of experiments, p-hydroxytranylcypromine was identified in brain and urine (following intraperitoneal injection) by derivatizing with perfluoroacylating reagents and analyzing by electron-capture gas chromatography and by combined gas chromatography-mass spectrometry. In experiments in vitro, p-hydroxytranylcypromine was demonstrated to inhibit monoamine oxidase, although it was weaker than TCP in this regard and was a much stronger inhibitor of MAO-A than of MAO-B.

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Aqueous trichloracetylation followed by electron-capture gas chromatography has been employed for the rapid, sensitive and simultaneous analysis of the endogenous trace amine beta-phenylethylamine and the anti-depressant tranylcypromine.

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Activated R,S-benoxaprofen is described as a new reagent for fluorescent derivatization of drugs with primary or secondary amino groups or with hydroxyl groups. Separation of the reaction products is demonstrated by thin-layer chromatography and high-performance liquid chromatography. The sensitivity of the detection is in the picomole range. Derivatization procedures can be easily and rapidly performed.

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