flavin-adenine-dinucleotide and milacemide

1. It has previously been established that monoamine oxidase (MAO)-B participates in the metabolism of milacemide [2-(pentylamino)acetamide]. Furthermore, in rats, inhibition of FAD-dependent polyamine oxidase (PAO) was found to decrease the urinary excretion of two milacemide metabolites, termed UK1 and UK2. 2. Using gas chromatography-mass spectrometry, UK1 was identified as oxamic acid and UK2 as 2-hydroxyacetamide, confirming that PAO is involved in the metabolism of milacemide. 3. Thus, two FAD-dependent amine-oxidizing enzymes, MAO and PAO, contribute to the metabolism of milacemide. Milacemide appears to be the first non-polyamine xenobiotic in the metabolism of which PAO participates.

Topics: Acetamides; Animals; Anticonvulsants; Flavin-Adenine Dinucleotide; Gas Chromatography-Mass Spectrometry; Male; Oxamic Acid; Oxidoreductases Acting on CH-NH Group Donors; Polyamine Oxidase; Rats; Rats, Inbred Strains

Milacemide, a secondary amine derivative, was previously demonstrated to be a substrate of MAO-B and to be insensitive to the action of copper-dependent amine oxidases. In the present study, it was investigated whether the FAD-dependent secondary amine metabolizing enzyme polyamine oxidase (PAO), could participate in the metabolism of milacemide. For this purpose, the urinary metabolic pattern of oral 14C-milacemide was determined in rats with and without pretreatment with the irreversible PAO inhibitor MDL 72527 and, for comparison, after inhibition of MAO-B by l-deprenyl. While l-deprenyl was shown to significantly decrease the urinary excretion of glycinamide and of an unknown metabolite (UK1), pretreatment with MDL 72527 did not modify the elimination of milacemide as glycinamide but produced a decrease in UK1 equal to that induced by l-deprenyl. The percent of the dose of milacemide eliminated as unchanged drug was slightly but significantly increased after PAO inhibition, though considerably less than after l-deprenyl. These data suggest that milacemide might be a substrate of PAO. If confirmed, this result would constitute the first example of the involvement of the FAD-dependent PAO in drug metabolism.

Topics: Acetamides; Animals; Flavin-Adenine Dinucleotide; Glycine; Male; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Oxidoreductases Acting on CH-NH Group Donors; Pargyline; Polyamine Oxidase; Putrescine; Rats; Rats, Inbred Strains; Selegiline