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Metabolism of Monoamine Oxidase Inhibitors

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Abstract

1. The principal routes of metabolism of the following monoamine oxidase inhibitors (MAOIs) are described: phenelzine, tranylcypromine, pargyline, deprenyl, moclobemide, and brofaromine.

2. Acetylation of phenelzine appears to be a minor metabolic pathway. Phenelzine is a substrate as well as an inhibitor of MAO, and major identified metabolites of phenelzine include phenylacetic acid and p-hydroxyphenylacetic acid. Phenelzine also elevates brain GABA levels, and as yet unidentified metabolites of phenelzine may be responsible for this effect. β-Phenylethylamine is a metabolite of phenelzine, and there is indirect evidence that phenelzine may also be ring-hydroxylated and N-methylated.

3. Tranylcypromine is ring-hydroxylated and N-acetylated. There is considerable debate about whether or not it is metabolized to amphetamine, with most of studies in the literature indicating that this does not occur.

4. Pargyline and R(−)-deprenyl, both propargylamines, are N-demethylated and N-depropargylated to yield arylalkylamines (benzylamine, N-methylbenzylamine, and N-propargylbenzylamine in the case of pargyline and amphetamine, N-methylamphetamine and N-propargylamphetamine in the case of deprenyl). These metabolites may then undergo further metabolism, e.g., hydroxylation.

5. Moclobemide is biotransformed by C- and N-oxidation on the morpholine ring and by aromatic hydroxylation. An active metabolite of brofaromine is formed by O-demethylation. It has been proposed that another as yet unidentified active metabolite may also be formed in vivo.

6. Preliminary results indicate that several of the MAOIs mentioned above are substrates and/or inhibitors of various cytochrome P450 (CYP) enzymes, which may result in pharmacokinetic interactions with some coadministered drugs.

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Authors and Affiliations

  1. Neurochemical Research Unit, Department of Psychiatry, University of Alberta, Edmonton, Alberta, T6G 2B7, Canada

    G. B. Baker, L. J. Urichuk & K. F. McKenna

  2. Clarke Institute, Division of the Centre for Addiction and Mental Health, University of Toronto, Ontario, Canada

    S. H. Kennedy

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  1. G. B. Baker
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  2. L. J. Urichuk
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  3. K. F. McKenna
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  4. S. H. Kennedy
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Baker, G.B., Urichuk, L.J., McKenna, K.F. et al. Metabolism of Monoamine Oxidase Inhibitors. Cell Mol Neurobiol 19, 411–426 (1999). https://doi.org/10.1023/A:1006901900106

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