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

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

SUBMITTER: Polasek TM 

PROVIDER: S-EPMC1885050 | biostudies-literature | 2006 May

REPOSITORIES: biostudies-literature