Accurate prediction of dose-dependent CYP3A4 inhibition by itraconazole and its metabolites from in vitro inhibition data

Clin Pharmacol Ther. 2010 Oct;88(4):499-505. doi: 10.1038/clpt.2010.119. Epub 2010 Aug 25.


Inhibitory drug metabolites may contribute to drug-drug interactions (DDIs). The aim of this study was to determine the importance of inhibitory metabolites of itraconazole (ITZ) in in vivo cytochrome P450 (CYP) 3A4 inhibition. The pharmacokinetics of ITZ and midazolam (MDZ) were determined in six healthy volunteers in four sessions after administration of MDZ with and without oral ITZ. After doses of 50, 200, and 400 mg of ITZ, the clearance of orally administered MDZ decreased by 27, 74, and 83%, respectively. The in vivo half maximal inhibitory concentration (IC(50)) for ITZ ranged from 5 to 132 nmol/l in the six subjects. The metabolites of ITZ were estimated to account for ~50% of the total CYP3A4 inhibition, with the relative contribution increasing with time after ITZ dosing. Of the total of 18 interactions observed, 15 (84%) could be predicted within a twofold error margin, with improved accuracy observed when ITZ metabolites were included in the predictions. This study shows that the metabolites of ITZ contribute to CYP3A4 inhibition and need to be accounted for in quantitative rationalization of ITZ-mediated DDIs.

Publication types

  • Clinical Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Area Under Curve
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 CYP3A Inhibitors*
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Enzyme Inhibitors / pharmacology*
  • Female
  • Humans
  • In Vitro Techniques
  • Inhibitory Concentration 50
  • Itraconazole / pharmacology*
  • Male
  • Metabolic Clearance Rate
  • Midazolam / pharmacokinetics*
  • Young Adult


  • Cytochrome P-450 CYP3A Inhibitors
  • Enzyme Inhibitors
  • Itraconazole
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • Midazolam