Isoniazid is a mechanism-based inhibitor of cytochrome P450 1A2, 2A6, 2C19 and 3A4 isoforms in human liver microsomes

  title={Isoniazid is a mechanism-based inhibitor of cytochrome P450 1A2, 2A6, 2C19 and 3A4 isoforms in human liver microsomes},
  author={Xia Wen and Jun-sheng Wang and Pertti J. Neuvonen and Janne T. Backman},
  journal={European Journal of Clinical Pharmacology},
Abstract.Objective: In order to evaluate the inhibitory effects of isoniazid on cytochrome P450 (CYP) mediated drug metabolism, the in vitro inhibitory potency and specificity as well as the reduced nicotinamide adenine dinucleotide phosphate (NADPH)-, time- and concentration dependency of isoniazid as an inhibitor of the activity of the major human CYP isoforms were studied. Methods: Using pooled human liver microsomes, the in vitro inhibitory effects of isoniazid on CYP1A2 (phenacetin O… 

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

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.

Inhibition of cytochrome P450 by ethambutol in human liver microsomes.

Mechanism-Based Inhibition of Cytochrome P450 3A4 by Therapeutic Drugs

It appears that the chemical properties of a drug critical to CYP3A4 inactivation include formation of reactive metabolites by CYP isoenzymes, preponderance of CYP inducers and P-glycoprotein (P-gp) substrate, and occurrence of clinically significant pharmacokinetic interactions with coadministered drugs.

Inhibitory effect of antituberculosis drugs on human cytochrome P450-mediated activities.

The results suggested that pyrazinamide and ethionamide did not seem to cause drug interactions mediated by the inhibition of CYP, and isoniazid might contribute to the severe drug interactions by a different inhibitory mechanism depending on each of the CYP isozymes, in addition to the reported observations.

More potent inhibition of human CYP2A6 than mouse CYP2A5 enzyme activities by derivatives of phenylethylamine and benzaldehyde

Data from a rapid 96-well plate assay method was developed and validated to measure liver microsomal coumarin 7-hydroxylation in vitro and novel potent inhibitors were found for CYP2A6 and, except for 4-methoxybenzaldehyde, all the compounds inhibited CYP 2A5 and CYP1A6 enzymes differentially.

Clinically Important Drug Interactions Potentially Involving Mechanism-based Inhibition of Cytochrome P450 3A4 and the Role of Therapeutic Drug Monitoring

To minimize drug-drug interactions involving mechanism-based CYP3A4 inhibition, it is necessary to choose safe drug combination regimens, adjust drug dosages appropriately, and conduct therapeutic drug monitoring for drugs with narrow therapeutic indices.

Mechanism-Based Inactivation of Human Cytochrome P 4502 C 8 by Drugs in Vitro

The majority of studies performed to date have focused on CYP3A4, the principal isoform involved in the metabolic clearance of drugs in humans, but it is now apparent that the function of other P450 isoforms may also be significantly impaired by drugs that act as mechanism-based inactivators (MBIs).

Mechanism-Based Inactivation of Human Cytochrome P4502C8 by Drugs in Vitro

Several tricyclic antidepressants, calcium channel blockers, monoamine oxidase inhibitors, and various other known CYP3A4 inhibitors exhibited greater inhibition of CYP2C8 (paclitaxel 6α-hydroxylation) following preincubation, consistent with mechanism-based inactivation.