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|Title:||An evaluation of potential mechanism-based inactivation of human drug metabolizing cytochromes P450 by monoamine oxidase inhibitors, including isoniazid|
|Citation:||British Journal of Clinical Pharmacology, 2006; 61(5):570-584|
|Publisher:||Blackwell Publishing Ltd|
|Thomas M. Polasek, David J. Elliot, Andrew A. Somogyi, Elizabeth M. J. Gillam, Benjamin C. Lewis and John O. Miners|
|Abstract:||AIMS: 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|
|Keywords:||Microsomes, Liver; Humans; Clorgyline; Isoniazid; Phenelzine; Cytochrome P-450 Enzyme System; Aryl Hydrocarbon Hydroxylases; Cytochrome P-450 CYP1A2; Mixed Function Oxygenases; Monoamine Oxidase Inhibitors; Ultrafiltration; Tissue Culture Techniques; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP2A6; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 CYP2C9; Cytochrome P-450 CYP2C19; Cytochrome P-450 CYP2D6 Inhibitors|
|Description:||The definitive version is available at www.blackwell-synergy.com|
|Appears in Collections:||Pharmacology publications|
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