Inhibition of in vitro metabolism of simvastatin by itraconazole in humans and prediction of in vivo drug-drug interactions

Pharm Res. 2001 May;18(5):622-31. doi: 10.1023/a:1011077109233.


Purpose: To evaluate an interaction between simvastatin and itraconazole in in vitro studies and to attempt a quantitative prediction of in vivo interaction in humans.

Methods: The inhibitory effect of itraconazole on simvastatin metabolism was evaluated using human liver microsomes and the Ki values were calculated for the unbound drug in the reaction mixture. A physiologically-based pharmacokinetic model was used to predict the maximum in vivo drug-drug interaction.

Results: Itraconazole competitively inhibited the metabolism of simvastatin to M-1 and M-2 with Ki values in the nM range. The area under the curve (AUC) of simvastatin after concomitant dosing with itraconazole was predicted to increase ca. 84-101-fold compared with that without administration of itraconazole. Taking into consideration the fact that this method predicts the maximum interaction, this agrees well with the clinical observation of a 19-fold increase. A similar prediction, based on the Ki value without taking into account the drug adsorption to microsomes, led to an underevaluation of the interaction.

Conclusions: It was demonstrated that the competitive inhibition of CYP3A4-mediated simvastatin metabolism by itraconazole is the main cause of the drug interaction and that a Ki value corrected for drug adsorption to microsomes is the key factor in quantitatively predicting the maximum in vivo drug interactions.

MeSH terms

  • Anticholesteremic Agents / metabolism*
  • Anticholesteremic Agents / pharmacokinetics
  • Antifungal Agents / pharmacology*
  • Binding, Competitive / drug effects
  • Biotransformation
  • Blood Proteins / metabolism
  • Cytochrome P-450 Enzyme System / metabolism
  • Depression, Chemical
  • Drug Interactions
  • Humans
  • In Vitro Techniques
  • Isoenzymes / metabolism
  • Itraconazole / pharmacology*
  • Kinetics
  • Microsomes, Liver / drug effects
  • Microsomes, Liver / metabolism
  • Protein Binding
  • Simvastatin / metabolism*
  • Simvastatin / pharmacokinetics


  • Anticholesteremic Agents
  • Antifungal Agents
  • Blood Proteins
  • Isoenzymes
  • Itraconazole
  • Cytochrome P-450 Enzyme System
  • Simvastatin