ArticlePharmaceutical research2013
Mechanistic modeling to predict the transporter- and enzyme-mediated drug-drug interactions of repaglinide.
Article in Pharmaceutical research, 2013. 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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Who cites it
35 citing papers in PubMed, 102 citations in OpenAlex.
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- Interplay of UDP-Glucuronosyltransferase and CYP2C8 for CYP2C8 Mediated Drug Oxidation and Its Impact on Drug-Drug Interaction Produced by Standardized CYP2C8 Inhibitors, Clopidogrel and Gemfibrozil.Clinical pharmacokinetics · 2024Article
- Non-uniformity of Changes in Drug-Metabolizing Enzymes and Transporters in Liver Cirrhosis: Implications for Drug Dosage Adjustment.Molecular pharmaceutics · 2021Article
- Quantitative prediction of breast cancer resistant protein mediated drug-drug interactions using physiologically-based pharmacokinetic modeling.CPT: pharmacometrics & systems pharmacology · 2021Article
- Physiologically based pharmacokinetic modeling to assess metabolic drug-drug interaction risks and inform the drug label for fedratinib.Cancer chemotherapy and pharmacology · 2020Article
- Prediction of Cyclosporin-Mediated Drug Interaction Using Physiologically Based Pharmacokinetic Model Characterizing Interplay of Drug Transporters and Enzymes.International journal of molecular sciences · 2020Article
- Physiologically-Based Pharmacokinetic Models for Evaluating Membrane Transporter Mediated Drug-Drug Interactions: Current Capabilities, Case Studies, Future Opportunities, and Recommendations.Clinical pharmacology and therapeutics · 2020Review
- Physiologically Based Pharmacokinetic Modelling to Identify Pharmacokinetic Parameters Driving Drug Exposure Changes in the Elderly.Clinical pharmacokinetics · 2020Article
- Effects of mongolian medicineInternational journal of clinical and experimental pathology · 2020Article
- An Informatics-based Approach to Identify Key Pharmacological Components in Drug-Drug Interactions.AMIA Joint Summits on Translational Science proceedings. AMIA Joint Summits on Translational Science · 2020Article
- Impact of Intracellular Concentrations on Metabolic Drug-Drug Interaction Studies.The AAPS journal · 2019Article
- CYP450s-Activity Relations of Celastrol to Interact with Triptolide Reveal the Reasons of Hepatotoxicity ofMolecules (Basel, Switzerland) · 2019Article
- Use of Physiologically Based Pharmacokinetic Modeling to Evaluate the Effect of Chronic Kidney Disease on the Disposition of Hepatic CYP2C8 and OATP1B Drug Substrates.Clinical pharmacology and therapeutics · 2019Article
- Clinical Investigation of Coproporphyrins as Sensitive Biomarkers to Predict Mild to Strong OATP1B-Mediated Drug-Drug Interactions.Clinical pharmacokinetics · 2018Article
- When Does the Rate-Determining Step in the Hepatic Clearance of a Drug Switch from Sinusoidal Uptake to All Hepatobiliary Clearances? Implications for Predicting Drug-Drug Interactions.Drug metabolism and disposition: the biological fate of chemicals · 2018Article
- Clopidogrel Pharmacokinetics in Malaysian Population Groups: The Impact of Inter-Ethnic Variability.Pharmaceuticals (Basel, Switzerland) · 2018Article
- Guiding dose adjustment of amlodipine after co-administration with ritonavir containing regimens using a physiologically-based pharmacokinetic/pharmacodynamic model.Journal of pharmacokinetics and pharmacodynamics · 2018Article
- Implications of intercorrelation between hepatic CYP3A4-CYP2C8 enzymes for the evaluation of drug-drug interactions: a case study with repaglinide.British journal of clinical pharmacology · 2018Article
- Prediction of Drug-Drug Interactions with Bupropion and Its Metabolites as CYP2D6 Inhibitors Using a Physiologically-Based Pharmacokinetic Model.Pharmaceutics · 2017Article
- Physiologically Based Pharmacokinetic Modeling Suggests Limited Drug-Drug Interaction Between Clopidogrel and Dasabuvir.Clinical pharmacology and therapeutics · 2017Article
Corrections and comments
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
purposeQuantitative prediction of complex drug-drug interactions (DDIs) is challenging. Repaglinide is mainly metabolized by cytochrome-P-450 (CYP)2C8 and CYP3A4, and is also a substrate of organic anion transporting polypeptide (OATP)1B1. The purpose is to develop a physiologically based pharmacokinetic (PBPK) model to predict the pharmacokinetics and DDIs of repaglinide.
methodsIn vitro hepatic transport of repaglinide, gemfibrozil and gemfibrozil 1-O-β-glucuronide was characterized using sandwich-culture human hepatocytes. A PBPK model, implemented in Simcyp (Sheffield, UK), was developed utilizing in vitro transport and metabolic clearance data.
resultsIn vitro studies suggested significant active hepatic uptake of repaglinide. Mechanistic model adequately described repaglinide pharmacokinetics, and successfully predicted DDIs with several OATP1B1 and CYP3A4 inhibitors (<10% error). Furthermore, repaglinide-gemfibrozil interaction at therapeutic dose was closely predicted using in vitro fraction metabolism for CYP2C8 (0.71), when primarily considering reversible inhibition of OATP1B1 and mechanism-based inactivation of CYP2C8 by gemfibrozil and gemfibrozil 1-O-β-glucuronide.
conclusionsThis study demonstrated that hepatic uptake is rate-determining in the systemic clearance of repaglinide. The model quantitatively predicted several repaglinide DDIs, including the complex interactions with gemfibrozil. Both OATP1B1 and CYP2C8 inhibition contribute significantly to repaglinide-gemfibrozil interaction, and need to be considered for quantitative rationalization of DDIs with either drug.
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