ArticlePharmaceutical research2008
Multiple inhibition mechanisms and prediction of drug-drug interactions: status of metabolism and transporter models as exemplified by gemfibrozil-drug interactions.
Article in Pharmaceutical research, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 73 citations in OpenAlex.
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- In Vitro Assessment of Transporter Mediated Perpetrator DDIs for Several Hepatitis C Virus Direct-Acting Antiviral Drugs and Prediction of DDIs with Statins Using Static Models.The AAPS journal · 2022Article
- A computational approach to predict multi-pathway drug-drug interactions: A case study of irinotecan, a colon cancer medication.Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society · 2020Article
- In Silico Prediction of Major Clearance Pathways of Drugs among 9 Routes with Two-Step Support Vector Machines.Pharmaceutical research · 2018Article
- Prediction of pharmacokinetics and drug-drug interactions when hepatic transporters are involved.Clinical pharmacokinetics · 2014Review
- Stereoselective inhibition of CYP2C19 and CYP3A4 by fluoxetine and its metabolite: implications for risk assessment of multiple time-dependent inhibitor systems.Drug metabolism and disposition: the biological fate of chemicals · 2013Article
- ITC recommendations for transporter kinetic parameter estimation and translational modeling of transport-mediated PK and DDIs in humans.Clinical pharmacology and therapeutics · 2013Review
- Disposition pathway-dependent approach for predicting organic anion-transporting polypeptide-mediated drug-drug interactions.Clinical pharmacokinetics · 2013Article
- Mechanistic modeling to predict the transporter- and enzyme-mediated drug-drug interactions of repaglinide.Pharmaceutical research · 2013Article
- Cyclosporine inhibition of hepatic and intestinal CYP3A4, uptake and efflux transporters: application of PBPK modeling in the assessment of drug-drug interaction potential.Pharmaceutical research · 2013Article
- Importance of multi-p450 inhibition in drug-drug interactions: evaluation of incidence, inhibition magnitude, and prediction from in vitro data.Chemical research in toxicology · 2012Review
- Physiologically based modeling of pravastatin transporter-mediated hepatobiliary disposition and drug-drug interactions.Pharmaceutical research · 2012Article
- Assessment of algorithms for predicting drug-drug interactions via inhibition mechanisms: comparison of dynamic and static models.British journal of clinical pharmacology · 2011Article
- Repaglinide-gemfibrozil drug interaction: inhibition of repaglinide glucuronidation as a potential additional contributing mechanism.British journal of clinical pharmacology · 2010Article
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
purposeTo assess the consequences of multiple inhibitors and differential inhibition mechanisms on the prediction of 12 gemfibrozil drug-drug interactions (DDIs). In addition, qualitative zoning of transporter-related gemfibrozil and cyclosporine DDIs was investigated.
methodsThe effect of gemfibrozil and its acyl-glucuronide on different enzymes was incorporated into a metabolic prediction model. The impact of CYP2C8 time-dependent inhibition by gemfibrozil acyl-glucuronide was assessed using repaglinide, cerivastatin, loperamide, rosiglitazone and pioglitazone DDIs. Gemfibrozil and cyclosporine inhibition data obtained in human embryonic kidney cells expressing OATP1B1 and hepatic input concentration ([I]in) were used for qualitative zoning of 14 transporter-mediated DDIs.
resultsIncorporation of time-dependent inhibition by gemfibrozil glucuronide showed no significant improvement in the prediction, as CYP2C8 contributed <65% to the overall elimination of the victim drugs investigated. Qualitative zoning of OATP1B1 DDIs resulted in no false negative predictions; yet the magnitude of observed interactions was significantly over-predicted.
conclusionsTime-dependent inhibition by gemfibrozil glucuronide is only important for victim drugs eliminated predominantly (>80%) via CYP2C8. Qualitative zoning of OATP1B1 inhibitors based on [I]in/K (i) is valid in drug screening to avoid false negatives. Refinement of the transporter model by incorporating the fraction of drug transported by a particular transporter is recommended.
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