1. The objective was to use modern mass spectrometric techniques to update current information on the metabolism of trimetazidine in human subjects found by previous studies. 2. Urine and plasma samples were taken from four healthy human volunteers taking part in a larger kinetic study. Each subject received an oral dose of 80-mg trimetazidine daily for 4 days. 3. Identification and quantitation of trimetazidine and its metabolites in urine and plasma were achieved using modern liquid chromatography-mass spectrometric methods. 4. The major drug-related component observed in urine and plasma was unchanged trimetazidine. In addition to the parent drug, 10 metabolites were detected in urine in concentrations ranging from 0.008 (0.01% dose) to 1.094 micrograms.ml-1 (1.4% dose). Metabolic profiles following acute and chronic doses of trimetazidine were qualitatively similar.

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The application of liquid chromatography/mass spectrometry (LC/MS) and LC/MS/MS with electrospray ionization to drug metabolism studies was investigated using S 9788 and various synthesized metabolic products as model compounds to assess the response characteristics with regard to compound lipophilicity and the influence of biological matrix components. The results obtained demonstrate the versatility of the electrospray ionization technique to analyse compounds of widely varying polarity and the power of MS/MS to identify unequivocally metabolic products. These techniques offer a very rapid screening procedure that can be used to identify metabolic products and thus provide important early metabolic information that can be used in the candidate drug selection programme. These procedures were then applied to an in vivo study sample and, using neutral loss MS/MS, it was possible to detect metabolites of S 9788 directly from a crude biological matrix (bile) without prior extraction or chromatography to confirm positively the identity of five important metabolites of S 9788 in the rat.

1. The comparative metabolism of fenfluramine was investigated in mouse, rat, dog and man following a single oral dose of 14C-(+/-)-fenfluramine hydrochloride (1 mg/kg), and also in rat after eight consecutive 12-h subcutaneous doses (24 mg/kg). 2. Main route of excretion of radioactivity in all species and at all doses was into urine (> 80%), with only minor amounts of radioactivity found in faeces. 3. From all species examined a total of 11 metabolites were observed in urine and plasma by t.l.c. and h.p.l.c. analysis and no metabolite was present in the plasma which was not present in urine. 4. All species dealkylate fenfluramine to the active metabolite norfenfluramine, to a relative greater or lesser extent, with plasma metabolic ratios (norfenfluramine/fenfluramine) showing inter-animal variation (rat >> dog >> mouse = man). 5. These differences are due to the efficient deamination of both compounds to polar inactive metabolites in man, with less dealkylation and lower plasma levels of norfenfluramine compared with the other species studied. 6. In conclusion, major species differences in the metabolism of (+/-)-fenfluramine, both qualitative and quantitative were observed, and no one species had a similar metabolic profile to that found in man.

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