ArticlePharmaceutical research2001
Inhibition of in vitro metabolism of simvastatin by itraconazole in humans and prediction of in vivo drug-drug interactions.
Article in Pharmaceutical research, 2001. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 58 citations in OpenAlex.
- A Review on New Frontiers in Drug-Drug Interaction Predictions and Safety Evaluations with In Vitro Cellular Models.Pharmaceutics · 2025Review
- How Science Is Driving Regulatory Guidances.Methods in molecular biology (Clifton, N.J.) · 2021Article
- Time-dependent enzyme inactivation: Numerical analyses of in vitro data and prediction of drug-drug interactions.Pharmacology & therapeutics · 2020Review
- Preincubation With Everolimus and Sirolimus Reduces Organic Anion-Transporting Polypeptide (OATP)1B1- and 1B3-Mediated Transport Independently of mTOR Kinase Inhibition: Implication in Assessing OATP1B1- and OATP1B3-Mediated Drug-Drug Interactions.Journal of pharmaceutical sciences · 2019Article
- Impact of Lipid Partitioning on the Design, Analysis, and Interpretation of Microsomal Time-Dependent Inactivation.Drug metabolism and disposition: the biological fate of chemicals · 2019Article
- Quantifying Hepatic Enzyme Kinetics of (-)-∆Drug metabolism and disposition: the biological fate of chemicals · 2019Article
- Development of a Physiologically Based Pharmacokinetic Model for Itraconazole Pharmacokinetics and Drug-Drug Interaction Prediction.Clinical pharmacokinetics · 2016Article
- Comparison of the inhibitory profiles of itraconazole and cimetidine in cytochrome P450 3A4 genetic variants.Drug metabolism and disposition: the biological fate of chemicals · 2011Article
- The quantitative prediction of CYP-mediated drug interaction by physiologically based pharmacokinetic modeling.Pharmaceutical research · 2008Article
- The enzymatic basis of drug-drug interactions with systemic triazole antifungals.Clinical pharmacokinetics · 2008Review
- Dynamically simulating the interaction of midazolam and the CYP3A4 inhibitor itraconazole using individual coupled whole-body physiologically-based pharmacokinetic (WB-PBPK) models.Theoretical biology & medical modelling · 2007Article
Corrections and comments
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Authors and funding
10 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
purposeTo evaluate an interaction between simvastatin and itraconazole in in vitro studies and to attempt a quantitative prediction of in vivo interaction in humans.
methodsThe 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.
resultsItraconazole 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.
conclusionsIt 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.
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