The structure of the urinary metabolites formed after moclobemide administration in humans was elucidated, and the pattern compared with that in the plasma. The metabolic pathways of moclobemide were also compared with those of structurally related substances. After oral moclobemide administration, on average 95% of the dose was recovered in the urine within 4 days, with a mean of 92% being excreted during the first 12 h. The drug is extensively metabolized: less than 1 % of the dose was excreted unchanged. A total of 19 metabolites, accounting together for about 64% of the dose, was isolated and all metabolites accounting for more than 170 of the dose were identified. Consistent with other morpholinecontaining compounds, metabolic pathways of moclobemide include mainly oxidative attack on the morpholine moiety, leading to a multitude of oxidation products. Four primary metabolic reactions were identified: morpholine N-oxidation, aromatic hydroxylation, morpholine C-oxidation and deamination. The major metabolites in urine are 4 carboxylic acids (M7A and M7B, M8, M9) that account for 49% of the dose. Only 2 metabolites (M3, MlO) were found to be hydroxylated on the aromatic nucleus. They were excreted completely as conjugates of glucuronic and/ or sulfuric acid. Conjugation in general, however, seems to be of minor importance in the overall biotransformation of the drug. The metabolite pattern in plasma was found to be qualitatively but not quantitatively similar to that observed in urine. Almost all of the main urinary metabolites were found in plasma as well. The unchanged parent compound and 2 primary oxidation products of the morpholine ring (Ml, MlS), which were present in urine only in trace amounts, could easily be detected in I plasma.Moclobemide belongs to a new generation of monoamine oxidase (MAO) inhibitors of the benzamide type and contains a morpholine ring as a characteristic part of its structure.The aim of this study was to elucidate the structures of the urinary metabolites formed from moclobemide after its administration to humans and to compare the metabolite pattern in urine and plasma. In addition, a comparison of metabolic pathways between moclobemide and structurally related drugs was attempted. Material and methods Drug administration and sample collectionTwo healthy young volunteers received 50 mg 14Clabelled moclobemide (2 pCi/mg; position of radiolabel, see Fig. 1) orally in a hard gelatine capsule. Blood was taken by puncture of an arm vein at different time points up to 10 h after administration and plasma was obtained by centrifugation.Urine and faeces were collected quantitatively in fractions up to 96 h after administration. Isolating and identifying the metabolitesMetabolites were isolated from pooled 0-12 h urine by chromatography on Amberlite XAD-2 resin and subsequent extractions with ethyl acetate at pH 9 and pH 3. These extractions were made before and after enzymatic hydrolysis with a mixture of beta-glucuronidase and arylsulfatase. Separation and purification of the metabo...

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1. Following intravenous administration of 14C-remikiren to the male rat, 78% of the administered radioactivity was recovered in faeces, indicating high biliary elimination. Of the 25 +/- 0.1% of the dose recovered in urine, the majority (16.5% of dose) was intact drug. 2. After oral administration to the male rat the urinary recovery was markedly reduced (8.5 +/- 2.0% of dose), and virtually all of the material was excreted as an inactive hydrolysis product. Intact drug was non-detectable, suggesting extensive first-pass metabolism. 3. Perfusion of isolated rat liver confirmed high biliary elimination, coupled with extensive metabolism. Although intact remikiren was the major component in bile (20% of the 'dose'), the majority of the radioactivity was recovered as a series of mono- and di-hydroxylated metabolites. 4. When screened against human renin, only one of the metabolites in bile and urine (mono-hydroxylated in the t-butyl side chain, and synthesized as Ro 44-0444) showed comparable activity to remikiren. The remaining ten metabolites tested were at least one order of magnitude less active than the parent drug. 5. In comparative in vitro studies Ro 44-0444 was formed by rat, but not human or cynomolgus monkey, liver microsomes. The primate microsomes also produced more of the remaining mono- and di-hydroxy products, suggesting that metabolites make little contribution to the oral activity of remikiren which is observed in these species in vivo.

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