Effect of itraconazole on the pharmacokinetics of atorvastatin

Clin Pharmacol Ther. 1998 Jul;64(1):58-65. doi: 10.1016/S0009-9236(98)90023-6.


Background: Itraconazole, a potent inhibitor of CYP3A4, increases the risk of skeletal muscle toxicity of some 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors by increasing their serum concentrations. The aim of this study was to characterize the effect of itraconazole on the pharmacokinetics of atorvastatin, a new HMG-CoA reductase inhibitor that is metabolized at least in part by CYP3A4.

Methods: In a randomized, double-blind, two-phase crossover study, 10 healthy volunteers took 200 mg itraconazole or matched placebo orally once daily for 4 days. On day 4, 40 mg atorvastatin was administered orally, and a further dose of 200 mg itraconazole or placebo was taken 24 hours after atorvastatin intake. Serum concentrations of atorvastatin acid, atorvastatin lactone, 2-hydroxyatorvastatin acid and lactone, 4-hydroxyatorvastatin acid and lactone, active and total HMG-CoA reductase inhibitors, itraconazole, and hydroxyitraconazole were measured up to 72 hours.

Results: Itraconazole increased the area under the concentration--time curve from time zero to 72 hours [AUC(0-72)] and the elimination half-life of atorvastatin acid about threefold (p < 0.001), whereas the peak serum concentration was not significantly changed. The AUC(0-72) of atorvastatin lactone was increased about fourfold (p < 0.001), and the peak serum concentration and half-life were increased more than twofold (p < 0.01). Itraconazole decreased the peak serum concentration and AUC(0-72) of 2-hydroxyatorvastatin acid (p < 0.01) and 2-hydroxyatorvastatin lactone (p < 0.01). Itraconazole significantly (p < 0.01) increased the half-life of 2 hydroxyatorvastatin lactone. The AUC(0-72) values of active and total HMG-CoA reductase inhibitors were increased 1.6-fold (p < 0.001) and 1.7-fold (p < 0.001), respectively.

Conclusions: Itraconazole has a significant interaction with atorvastatin. The mechanism of increased serum concentrations of atorvastatin and HMG-CoA reductase inhibitors is inhibition of CYP3A4-mediated metabolism of atorvastatin and its metabolites by itraconazole. Concomitant use of itraconazole and other potent inhibitors of CYP3A4 with atorvastatin should be avoided or the dose of atorvastatin should be reduced accordingly.

Publication types

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

MeSH terms

  • Adult
  • Anticholesteremic Agents / metabolism
  • Anticholesteremic Agents / pharmacokinetics*
  • Antifungal Agents / administration & dosage
  • Antifungal Agents / metabolism
  • Antifungal Agents / pharmacology*
  • Area Under Curve
  • Atorvastatin
  • Cross-Over Studies
  • Double-Blind Method
  • Drug Interactions
  • Female
  • Heptanoic Acids / metabolism
  • Heptanoic Acids / pharmacokinetics*
  • Humans
  • Hydroxymethylglutaryl CoA Reductases / drug effects*
  • Hydroxymethylglutaryl CoA Reductases / metabolism
  • Itraconazole / administration & dosage
  • Itraconazole / metabolism
  • Itraconazole / pharmacology*
  • Male
  • Pyrroles / metabolism
  • Pyrroles / pharmacokinetics*
  • Smoking / adverse effects


  • 2-hydroxyatorvastatin
  • Anticholesteremic Agents
  • Antifungal Agents
  • Heptanoic Acids
  • Pyrroles
  • Itraconazole
  • 4-hydroxyatorvastatin
  • Atorvastatin
  • Hydroxymethylglutaryl CoA Reductases