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

Polasek, TM, Elliot, DJ, Somogyi, AA, Gillam, EMJ, Lewis, BC and Miners, JO (2006) An evaluation of potential mechanism-based inactivation of human drug metabolizing cytochromes P450 by monoamine oxidase inhibitors, including isoniazid. British Journal of Clinical Pharmacology, 61 5: 570-584. doi:10.1111/j.1365-2125.2006.02627.x


Author Polasek, TM
Elliot, DJ
Somogyi, AA
Gillam, EMJ
Lewis, BC
Miners, JO
Title An evaluation of potential mechanism-based inactivation of human drug metabolizing cytochromes P450 by monoamine oxidase inhibitors, including isoniazid
Journal name British Journal of Clinical Pharmacology   Check publisher's open access policy
ISSN 0306-5251
Publication date 2006
Sub-type Article (original research)
DOI 10.1111/j.1365-2125.2006.02627.x
Volume 61
Issue 5
Start page 570
End page 584
Total pages 15
Editor E. Begg
J. Ritter
M. Lennard
Place of publication United Kingdom
Publisher Blackwell Publishing Ltd.
Collection year 2006
Language eng
Subject C1
270108 Enzymes
320504 Toxicology (incl. Clinical Toxicology)
780105 Biological sciences
Abstract 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. Human liver microsomal CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A activities were investigated following co- and preincubation with MAO inhibitors. Inactivation kinetic constants (K-I and k(inact)) were determined where a significant preincubation effect was observed. Spectral studies were conducted to elucidate the mechanisms of inactivation. 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 (K-I and k(inact)) for isoniazid were 48.6 mu M and 0.042 min(-1) and 79.3 mu M and 0.039 min(-1). Clorgyline was a selective inactivator of CYP1A2 (6.8 mu M 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. 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.
Keyword Pharmacology & Pharmacy
Cytochrome P450
Isoniazid
Mao Inhibitors
Mechanism-based Inactivation
Human Liver-microsomes
In-vitro
Intermediate Complex
N-demethylation
Prediction
Phenelzine
Pharmacokinetics
Oxidation
Cyp2c19
Q-Index Code C1

 
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