ArticleBritish journal of clinical pharmacology2010
Repaglinide-gemfibrozil drug interaction: inhibition of repaglinide glucuronidation as a potential additional contributing mechanism.
Article in British journal of clinical pharmacology, 2010. 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, 40 citations in OpenAlex.
- A Phenotyping Tool for Seven Cytochrome P450 Enzymes and Two Transporters: Application to Examine the Effects of Clopidogrel and Gemfibrozil.Clinical pharmacology and therapeutics · 2025Trial
- Drug-drug interactions of plant alkaloids derived from herbal medicines on the phase II UGT enzymes: an introductory review.Naunyn-Schmiedeberg's archives of pharmacology · 2025Review
- Investigation of Biotransformation Pathways in a Chimeric Mouse with a Humanized Liver.International journal of molecular sciences · 2025Article
- Hepatic OATP1B zonal distribution: Implications for rifampicin-mediated drug-drug interactions explored within a PBPK framework.CPT: pharmacometrics & systems pharmacology · 2024Article
- 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
- Inhibition of CYP2C8 by Acyl Glucuronides of Gemfibrozil and Clopidogrel: Pharmacological Significance, Progress and Challenges.Biomolecules · 2022Review
- Structural Analysis of Human Serum Albumin in Complex with the Fibrate Drug Gemfibrozil.International journal of molecular sciences · 2022Article
- In Silico Prediction of Major Clearance Pathways of Drugs among 9 Routes with Two-Step Support Vector Machines.Pharmaceutical research · 2018Article
- Repaglinide-irbesartan drug interaction: effects of SLCO1B1 polymorphism on repaglinide pharmacokinetics and pharmacodynamics in Chinese population.European journal of clinical pharmacology · 2018Article
- Inhibitory Effect of Sauchinone on UDP-Glucuronosyltransferase (UGT) 2B7 Activity.Molecules (Basel, Switzerland) · 2018Article
- Drug interactions of meglitinide antidiabetics involving CYP enzymes and OATP1B1 transporter.Therapeutic advances in endocrinology and metabolism · 2018Review
- Physiologically Based Pharmacokinetic Modeling Suggests Limited Drug-Drug Interaction Between Clopidogrel and Dasabuvir.Clinical pharmacology and therapeutics · 2017Article
- Progress in Prediction and Interpretation of Clinically Relevant Metabolic Drug-Drug Interactions: a Minireview Illustrating Recent Developments and Current Opportunities.Current pharmacology reports · 2017Review
- In Vitro Metabolism of Montelukast by Cytochrome P450s and UDP-Glucuronosyltransferases.Drug metabolism and disposition: the biological fate of chemicals · 2015Article
- Simultaneous assessment of uptake and metabolism in rat hepatocytes: a comprehensive mechanistic model.The Journal of pharmacology and experimental therapeutics · 2012Article
Corrections and comments
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Authors and funding
12 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
aimTo further explore the mechanism underlying the interaction between repaglinide and gemfibrozil, alone or in combination with itraconazole.
methodsRepaglinide metabolism was assessed in vitro (human liver subcellular fractions, fresh human hepatocytes, and recombinant enzymes) and the resulting incubates were analyzed, by liquid chromatography-mass spectrometry (LC-MS) and radioactivity counting, to identify and quantify the different metabolites therein. Chemical inhibitors, in addition to a trapping agent, were also employed to elucidate the importance of each metabolic pathway. Finally, a panel of human liver microsomes (genotyped for UGT1A1*28 allele status) was used to determine the importance of UGT1A1 in the direct glucuronidation of repaglinide.
resultsThe results of the present study demonstrate that repaglinide can undergo direct glucuronidation, a pathway that can possibly contribute to the interaction with gemfibrozil. For example, [³H]-repaglinide formed glucuronide and oxidative metabolites (M2 and M4) when incubated with primary human hepatocytes. Gemfibrozil effectively inhibited (∼78%) both glucuronide and M4 formation, but had a minor effect on M2 formation. Concomitantly, the overall turnover of repaglinide was also inhibited (∼80%), and was completely abolished when gemfibrozil was co-incubated with itraconazole. These observations are in qualitative agreement with the in vivo findings. UGT1A1 plays a significant role in the glucuronidation of repaglinide. In addition, gemfibrozil and its glucuronide inhibit repaglinide glucuronidation and the inhibition by gemfibrozil glucuronide is time-dependent.
conclusionsInhibition of UGT enzymes, especially UGT1A1, by gemfibrozil and its glucuronide is an additional mechanism to consider when rationalizing the interaction between repaglinide and gemfibrozil.
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