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Does FAD-dependent polyamine oxidase contribute to the metabolism of milacemide?
M Strolin Benedetti1, G Cocchiara, M Colombo
1Research and Development, Erbamont Group, Farmitalia Carlo Erba, Milan, Italy.
Abstract:
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.
Insights
Milacemide metabolism may involve polyamine oxidase (PAO), an FAD-dependent enzyme. Inhibition of PAO altered milacemide
Area of Science:
- Biochemistry
- Pharmacology
- Drug Metabolism
Background:
- Milacemide, a secondary amine, is metabolized by monoamine oxidase B (MAO-B).
- Its interaction with copper-dependent amine oxidases is negligible.
- The role of FAD-dependent polyamine oxidase (PAO) in milacemide metabolism was unexplored.
Purpose of the Study:
- To investigate the potential involvement of polyamine oxidase (PAO) in the metabolic pathways of milacemide.
- To compare the effects of PAO inhibition with MAO-B inhibition on milacemide's urinary metabolic profile.
Main Methods:
- Oral administration of 14C-milacemide to rats.
- Assessment of urinary metabolic patterns following pretreatment with a PAO inhibitor (MDL 72527).
- Comparison with results obtained after MAO-B inhibition using l-deprenyl.
Main Results:
- PAO inhibition with MDL 72527 decreased an unknown metabolite (UK1) similarly to MAO-B inhibition.
- PAO inhibition slightly increased the excretion of unchanged milacemide.
- l-deprenyl significantly reduced glycinamide and UK1 excretion.
Conclusions:
- The findings suggest that milacemide may be a substrate for the FAD-dependent enzyme polyamine oxidase (PAO).
- This study presents the first evidence for PAO's potential role in the metabolism of a drug.
- Further studies are needed to confirm PAO's involvement in milacemide biotransformation.