Plasma concentrations of inhaled budesonide and its effects on plasma cortisol are increased by the cytochrome P4503A4 inhibitor itraconazole

Clin Pharmacol Ther. 2002 Oct;72(4):362-9. doi: 10.1067/mcp.2002.127397.


Objective: Our objective was to examine the effects of itraconazole on the pharmacokinetics and cortisol-suppressant activity of budesonide administered by inhalation.

Methods: In a randomized, double-blind, 2-phase crossover study, 10 healthy subjects took 200 mg itraconazole or placebo orally once a day for 5 days. On day 5, 1 hour after the last dose of itraconazole or placebo, 1000 microg budesonide was administered by inhalation. Plasma budesonide and cortisol concentrations were measured up to 23 hours.

Results: Itraconazole increased the mean total area under the plasma concentration-time curve of inhaled budesonide 4.2-fold (range, 1.7-fold to 9.8-fold; P <.01) and the peak plasma concentration 1.6-fold (P <.01) compared with placebo. The mean terminal half-life of budesonide was prolonged from 1.6 to 6.2 hours (ie, 3.7-fold; range, 1.5-fold to 9.3-fold; P <.001) by itraconazole. The suppression of cortisol production after inhalation of budesonide was significantly increased by itraconazole as compared with placebo, as shown by a 43% reduction in the area under the plasma cortisol concentration-time curve from 0.5 to 10 hours (P <.001) and a 12% decrease in the cortisol concentration measured 23 hours after administration of budesonide, at 8 am (P <.05).

Conclusions: Itraconazole markedly increased systemic exposure to inhaled budesonide, probably by inhibiting the cytochrome P4503A4-mediated metabolism of budesonide during both the first-pass and the elimination phases. This interaction resulted in enhanced systemic effects of budesonide, as shown by suppression of cortisol production. Long-term coadministration of budesonide and a potent CYP3A4 inhibitor may be associated with an increased risk of adverse effects of budesonide.

Publication types

  • Clinical Trial
  • Comparative Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Inhalation
  • Adult
  • Analysis of Variance
  • Area Under Curve
  • Budesonide / blood*
  • Budesonide / pharmacology
  • Cross-Over Studies
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme Inhibitors*
  • Cytochrome P-450 Enzyme System / metabolism
  • Double-Blind Method
  • Drug Synergism
  • Enzyme Inhibitors / blood
  • Enzyme Inhibitors / pharmacology*
  • Female
  • Humans
  • Hydrocortisone / blood*
  • Itraconazole / blood
  • Itraconazole / pharmacology*
  • Male
  • Statistics, Nonparametric


  • Cytochrome P-450 Enzyme Inhibitors
  • Enzyme Inhibitors
  • Itraconazole
  • Budesonide
  • Cytochrome P-450 Enzyme System
  • CYP3A protein, human
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • Hydrocortisone