ArticleDrug metabolism and disposition: the biological fate of chemicals2010
Physiologically based pharmacokinetic model of mechanism-based inhibition of CYP3A by clarithromycin.
Article in Drug metabolism and disposition: the biological fate of chemicals, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
35 citing papers in PubMed, 78 citations in OpenAlex.
- Evaluation of the cytochrome P450-mediated drug interaction profile of olorofim.Antimicrobial agents and chemotherapy · 2026Trial
- Rate of onset of inhibition of gut-wall and hepatic CYP3A by clarithromycin.European journal of clinical pharmacology · 2013Trial
- Effect of clarithromycin and fluconazole on the pharmacokinetics of montelukast in human volunteers.European journal of clinical pharmacology · 2012Trial
- Verification of a Physiologically-based Pharmacokinetic Model for Predicting CYP3A4-mediated Simvastatin and Simvastatin Acid Drug-drug Interactions.The AAPS journal · 2026Article
- Elevated Serum Concentrations of Lacosamide and Perampanel in a Pediatric Patient Following Coadministration of Clarithromycin forThe journal of pediatric pharmacology and therapeutics : JPPT : the official journal of PPAG · 2026Article
- Physiologically-based pharmacokinetic model for predicting drug-drug interactions perpetrated by posaconazole in healthy subjects with normal weight and obesity: Concomitant use and washout.Journal of pharmacokinetics and pharmacodynamics · 2025Article
- Drug-Drug Interactions in Nosocomial Infections: An Updated Review for Clinicians.Pharmaceutics · 2024Review
- Prediction of Pharmacokinetic Drug-Drug Interactions Involving Anlotinib as a Victim by Using Physiologically Based Pharmacokinetic Modeling.Drug design, development and therapy · 2024Article
- Dual Inhibition of CYP3A4 by Voriconazole and Clarithromycin Influences Tacrolimus Pharmacokinetics: Case Series Study.European journal of drug metabolism and pharmacokinetics · 2022Article
- Competitive Metabolism of Polycyclic Aromatic Hydrocarbons (PAHs): An Assessment Using In Vitro Metabolism and Physiologically Based Pharmacokinetic (PBPK) Modeling.International journal of environmental research and public health · 2022Article
- Atrioventricular block after fingolimod resumption: a consequence of sphingosine-1-phosphate axis alteration due to COVID-19?Journal of neurology · 2021Article
- Evidence-Based Guidelines for Drug Interaction Studies: Model-Informed Time Course of Intestinal and Hepatic CYP3A4 Inhibition by Clarithromycin.The AAPS journal · 2021Article
- Drug-Drug Interaction Predictions via Knowledge Graph and Text Embedding: Instrument Validation Study.JMIR medical informatics · 2021Article
- Irreversible Enzyme Inhibition Kinetics and Drug-Drug Interactions.Methods in molecular biology (Clifton, N.J.) · 2021Article
- Predicting Clinical Effects of CYP3A4 Modulators on Abemaciclib and Active Metabolites Exposure Using Physiologically Based Pharmacokinetic Modeling.Journal of clinical pharmacology · 2020Article
- A hybrid model to evaluate the impact of active uptake transport on hepatic distribution of atorvastatin in rats.Xenobiotica; the fate of foreign compounds in biological systems · 2020Article
- Time-dependent enzyme inactivation: Numerical analyses of in vitro data and prediction of drug-drug interactions.Pharmacology & therapeutics · 2020Review
- Population Modeling Highlights Drug Disposition Differences Between Tenofovir Alafenamide and Tenofovir Disoproxil Fumarate in the Blood and Semen.Clinical pharmacology and therapeutics · 2019Article
- Improved Predictions of Drug-Drug Interactions Mediated by Time-Dependent Inhibition of CYP3A.Molecular pharmaceutics · 2018Article
- Development of an Adult Physiologically Based Pharmacokinetic Model of Solithromycin in Plasma and Epithelial Lining Fluid.CPT: pharmacometrics & systems pharmacology · 2017Article
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 3 countries.
Funding
Abstract
The prediction of clinical drug-drug interactions (DDIs) due to mechanism-based inhibitors of CYP3A is complicated when the inhibitor itself is metabolized by CYP3Aas in the case of clarithromycin. Previous attempts to predict the effects of clarithromycin on CYP3A substrates, e.g., midazolam, failed to account for nonlinear metabolism of clarithromycin. A semiphysiologically based pharmacokinetic model was developed for clarithromycin and midazolam metabolism, incorporating hepatic and intestinal metabolism by CYP3A and non-CYP3A mechanisms. CYP3A inactivation by clarithromycin occurred at both sites. K(I) and k(inact) values for clarithromycin obtained from in vitro sources were unable to accurately predict the clinical effect of clarithromycin on CYP3A activity. An iterative approach determined the optimum values to predict in vivo effects of clarithromycin on midazolam to be 5.3 microM for K(i) and 0.4 and 4 h(-1) for k(inact) in the liver and intestines, respectively. The incorporation of CYP3A-dependent metabolism of clarithromycin enabled prediction of its nonlinear pharmacokinetics. The predicted 2.6-fold change in intravenous midazolam area under the plasma concentration-time curve (AUC) after 500 mg of clarithromycin orally twice daily was consistent with clinical observations. Although the mean predicted 5.3-fold change in the AUC of oral midazolam was lower than mean observed values, it was within the range of observations. Intestinal CYP3A activity was less sensitive to changes in K(I), k(inact), and CYP3A half-life than hepatic CYP3A. This semiphysiologically based pharmacokinetic model incorporating CYP3A inactivation in the intestine and liver accurately predicts the nonlinear pharmacokinetics of clarithromycin and the DDI observed between clarithromycin and midazolam. Furthermore, this model framework can be applied to other mechanism-based inhibitors.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.