An evaluation of potential mechanism-based inactivation of human drug metabolizing cytochromes P450 by monoamine oxidase inhibitors, including isoniazid.
Article Details
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Polasek TM, Elliot DJ, Somogyi AA, Gillam EM, Lewis BC, Miners JO
An evaluation of potential mechanism-based inactivation of human drug metabolizing cytochromes P450 by monoamine oxidase inhibitors, including isoniazid.
Br J Clin Pharmacol. 2006 May;61(5):570-84. doi: 10.1111/j.1365-2125.2006.02627.x.
- PubMed ID
- 16669850 [ View in PubMed]
- 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 microm and 0.042 min-1 and 79.3 microm and 0.039 min-1. Clorgyline was a selective inactivator of CYP1A2 (6.8 microm and 0.15 min-1). 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.
DrugBank Data that Cites this Article
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Iproniazid Cytochrome P450 2C9 Protein Humans UnknownInhibitorDetails Iproniazid Cytochrome P450 2D6 Protein Humans UnknownInhibitorDetails Phenelzine Cytochrome P450 2C19 Protein Humans UnknownInhibitorDetails Phenelzine Cytochrome P450 2D6 Protein Humans UnknownInhibitorDetails Phenelzine Cytochrome P450 3A Subfamily (Protein Group) Protein group Humans UnknownInhibitorDetails Phenelzine Cytochrome P450 3A5 Protein Humans UnknownInhibitorDetails Phenelzine Cytochrome P450 3A7 Protein Humans UnknownInhibitorDetails