An evaluation of potential mechanism-based inactivation of human drug metabolizing cytochromes P450 by monoamine oxidase inhibitors, including isoniazid

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dc.contributor.authorPolasek, T.
dc.contributor.authorElliot, D.
dc.contributor.authorSomogyi, A.
dc.contributor.authorGillam, E.
dc.contributor.authorLewis, B.
dc.contributor.authorMiners, J.
dc.date.issued2006
dc.descriptionThe definitive version is available at www.blackwell-synergy.com
dc.description.abstractAIMS: To characterize potential mechanism-based inactivation (MBI) of major human drug-metabolizing cytochromes P450 (CYP) by monoamine oxidase (MAO) inhibitors, including the antitubercular drug isoniazid. METHODS: Human liver microsomal CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A activities were investigated following co- and preincubation with MAO inhibitors. Inactivation kinetic constants (KI and kinact) were determined where a significant preincubation effect was observed. Spectral studies were conducted to elucidate the mechanisms of inactivation. RESULTS: Hydrazine MAO inhibitors generally exhibited greater inhibition of CYP following preincubation, whereas this was less frequent for the propargylamines, and tranylcypromine and moclobemide. Phenelzine and isoniazid inactivated all CYP but were most potent toward CYP3A and CYP2C19. Respective inactivation kinetic constants (KI and kinact) for isoniazid were 48.6 µm and 0.042 min1 and 79.3 µm and 0.039 min1. Clorgyline was a selective inactivator of CYP1A2 (6.8 µm and 0.15 min1). Inactivation of CYP was irreversible, consistent with metabolite-intermediate complexation for isoniazid and clorgyline, and haeme destruction for phenelzine. With the exception of phenelzine-mediated CYP3A inactivation, glutathione and superoxide dismutase failed to protect CYP from inactivation by isoniazid and phenelzine. Glutathione partially slowed (17%) the inactivation of CYP1A2 by clorgyline. Alternate substrates or inhibitors generally protected against CYP inactivation. CONCLUSIONS: These data are consistent with mechanism-based inactivation of human drug-metabolizing CYP enzymes and suggest that impaired metabolic clearance may contribute to clinical drug–drug interactions with some MAO inhibitors
dc.description.statementofresponsibilityThomas M. Polasek, David J. Elliot, Andrew A. Somogyi, Elizabeth M. J. Gillam, Benjamin C. Lewis and John O. Miners
dc.identifier.citationBritish Journal of Clinical Pharmacology, 2006; 61(5):570-584
dc.identifier.doi10.1111/j.1365-2125.2006.02627.x
dc.identifier.issn0306-5251
dc.identifier.issn1365-2125
dc.identifier.orcidSomogyi, A. [0000-0003-4779-0380]
dc.identifier.urihttp://hdl.handle.net/2440/35989
dc.language.isoen
dc.publisherBlackwell Publishing Ltd
dc.source.urihttp://www.blackwell-synergy.com/doi/abs/10.1111/j.1365-2125.2006.02627.x
dc.subjectMicrosomes, Liver
dc.subjectHumans
dc.subjectClorgyline
dc.subjectIsoniazid
dc.subjectPhenelzine
dc.subjectCytochrome P-450 Enzyme System
dc.subjectAryl Hydrocarbon Hydroxylases
dc.subjectCytochrome P-450 CYP1A2
dc.subjectMixed Function Oxygenases
dc.subjectMonoamine Oxidase Inhibitors
dc.subjectUltrafiltration
dc.subjectTissue Culture Techniques
dc.subjectCytochrome P-450 CYP3A
dc.subjectCytochrome P-450 CYP2A6
dc.subjectCytochrome P-450 Enzyme Inhibitors
dc.subjectCytochrome P-450 CYP2C9
dc.subjectCytochrome P-450 CYP2C19
dc.subjectCytochrome P-450 CYP2D6 Inhibitors
dc.titleAn evaluation of potential mechanism-based inactivation of human drug metabolizing cytochromes P450 by monoamine oxidase inhibitors, including isoniazid
dc.typeJournal article
pubs.publication-statusPublished

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