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An evaluation of potential mechanism‐based inactivation of human drug metabolizing cytochromes P450 by monoamine oxidase inhibitors, including isoniazid
Author(s) -
Polasek Thomas M.,
Elliot David J.,
Somogyi Andrew A.,
Gillam Elizabeth M. J.,
Lewis Benjamin C.,
Miners John O.
Publication year - 2006
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/j.1365-2125.2006.02627.x
Subject(s) - clorgyline , chemistry , phenelzine , isoniazid , moclobemide , pharmacology , tranylcypromine , monoamine oxidase , cyp1a2 , glutathione , cyp3a , cyp2a6 , cytochrome p450 , biochemistry , enzyme , biology , medicine , endocrinology , tuberculosis , pathology , hippocampus , antidepressant
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 ( K I and k inact ) 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 ( K I and k inact ) for isoniazid were 48.6 µ m and 0.042 min −1 and 79.3 µ m and 0.039 min −1 . Clorgyline was a selective inactivator of CYP1A2 (6.8 µ 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. 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.