Summary
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 1-deprenyl.
While 1-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 1-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 1-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.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Barrand MA, Callingham BA (1982) Monoamine oxidase activities in brown adipose tissue of the rat: some properties and subcellular distribution. Biochem Pharmacol 31:2177–2184.
Bolkenius FN, Bey P, Seiler N (1985) Specific inhibition of polyamine oxidase in vivo is a method for the elucidation of its physiological role. Biochim Biophys Acta 838:69–76.
Guffroy C, Fowler CJ, Strolin Benedetti M (1983) The deamination of n-pentylamine by monoamine oxidase and a semicarbazide-sensitive amine oxidase of rat heart. J Pharm Pharmacol 35:416–420.
Hölltä E (1977) Oxidation of spermidine and spermine in rat liver: purification and properties of polyamine oxidase. Biochemistry 16:91–100.
Janssens de Varebeke P, Cavalier R, David-Remacle M, Youdim MBH (1988) Formation of the neurotransmitter glycine from the anticonvulsant milacemide is mediated by brain monoamine oxidase. J Neurochem 50:1011–1016.
Janssens de Varebeke P, Pauwels G, Buyse C, David-Remacle M, De Mey J, Roba J, Youdim MBH (1989) The novel neuropsychotropic agent milacemide is a specific enzyme-activated inhibitor of brain monamine oxidase B. J Neurochem 53:1109–1116.
Seiler N (1987) Inhibition of enzymes oxidizing polyamines. In: McCann PP, Pegg AE, Sjoerdsma A (eds) Inhibition of polyamine metabolism. Academic Press, Orlando, pp 49–77.
Seiler N, Bolkenius FN, Knödgen B, Mamont P (1980) Polyamine oxidase in rat tissues. Biochim Biophys Acta 615:480–488.
Strolin Benedetti M (1989) Oxidative drug metabolism not cytochrom P-450 dependent. Actual Chim Thér 16:337–356.
Strolin Benedetti M, Sontag N, Boucher T, Kan JP (1981) Aliphatic amines as MAO substrates in the rat: the effect of selective inhibitors on the deamination of n-pentylamine. In: Usdin E, Weiner N, Youdim MBH (eds) Function and regulation of monoamine enzymes. Macmillan, London, pp 527–538.
Strolin Benedetti M, Dostert P, Guffroy C, Tipton KF (1983) Partial or total protection from long-acting monoamine oxidase inhibitors by new short-acting MAOIs of type A MD 780515 and type B MD 780236. Mod Probl Pharmacopsychiatry 19:82–104.
Strolin Benedetti M, Marrari P, Moro E, Dostert P, Roncucci R (1988) Do amineoxidases contribute to the metabolism of milacemide?. Pharmacol Res Commun 20 [Suppl] 4:135–136.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 1990 Springer-Verlag
About this paper
Cite this paper
Strolin Benedetti, M., Cocchiara, G., Colombo, M., Dostert, P. (1990). Does FAD-dependent polyamine oxidase contribute to the metabolism of milacemide?. In: Riederer, P., Youdim, M.B.H. (eds) Amine Oxidases and Their Impact on Neurobiology. Journal of Neural Transmission, vol 32. Springer, Vienna. https://doi.org/10.1007/978-3-7091-9113-2_48
Download citation
DOI: https://doi.org/10.1007/978-3-7091-9113-2_48
Publisher Name: Springer, Vienna
Print ISBN: 978-3-211-82239-5
Online ISBN: 978-3-7091-9113-2
eBook Packages: Springer Book Archive