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

Eur J Clin Pharmacol. 2002 Jan;57(11):799-804. doi: 10.1007/s00228-001-0396-3.


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-deethylation), CYP2A6 (coumarin 7-hydroxylation), CYP2C9 (tolbutamide hydroxylation), CYP2CI9 (S-mephenytoin 4'-hydroxylation), CYP2D6 (dextromethorphan O-demethylation), CYP2E1 (chlorzoxazone 6-hydroxylation) and CYP3A4 (midazolam 1'-hydroxylation) activities were examined.

Results: After a 15-min preincubation without NADPH, isoniazid reversibly inhibited microsomal CYP2C19- and CYP3A4-mediated reactions with apparent Ki values of 36 microM and 73 microM, respectively. However, isoniazid had only weak inhibitory effects on the five other CYP-mediated reactions (Ki > 110 microM). After a 15-min preincubation with NADPH, isoniazid showed an increased inhibitory potency toward CYP1A2, CYP2A6, CYP2C19 and CYP3A4 activities (Ki = 56, 60, 10 and 36 microM, respectively). In addition, the inactivation of CYP1A2, CYP2A6, CYP2C19 and CYP3A4 by isoniazid was NADPH-, time- and concentration dependent, and was characterised by Kinact values of 0.11, 0.13, 0.09 and 0.08 min(-1), and K1 values of 285, 173, 112 and 228 microM, respectively.

Conclusions: As the peak plasma concentrations of isoniazid are around 30-50 microM, isoniazid at clinically relevant concentrations reversibly inhibits CYP2C19 and CYP3A4 activities, and mechanistically inactivates CYP1A2, CYP2A6, CYP2C19 and CYP3A4 in human liver microsomes. Co-administration of isoniazid and drugs that are primarily metabolised by these CYP isoforms, particularly by CYP2C19 and CYP3A4, may result in significant drug interactions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antitubercular Agents / pharmacology*
  • Aryl Hydrocarbon Hydroxylases*
  • Biomarkers
  • Chromatography, High Pressure Liquid
  • Cytochrome P-450 CYP1A2 Inhibitors
  • Cytochrome P-450 CYP2A6
  • Cytochrome P-450 CYP2C19
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme Inhibitors*
  • Female
  • Humans
  • In Vitro Techniques
  • Isoenzymes / antagonists & inhibitors
  • Isoniazid / pharmacology*
  • Kinetics
  • Male
  • Microsomes, Liver / drug effects
  • Microsomes, Liver / enzymology*
  • Mixed Function Oxygenases / antagonists & inhibitors
  • NADP / metabolism


  • Antitubercular Agents
  • Biomarkers
  • Cytochrome P-450 CYP1A2 Inhibitors
  • Cytochrome P-450 Enzyme Inhibitors
  • Isoenzymes
  • NADP
  • Mixed Function Oxygenases
  • Aryl Hydrocarbon Hydroxylases
  • CYP2A6 protein, human
  • CYP2C19 protein, human
  • CYP3A protein, human
  • Cytochrome P-450 CYP2A6
  • Cytochrome P-450 CYP2C19
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • Isoniazid