A1 Refereed original research article in a scientific journal
The effect of gemfibrozil on repaglinide pharmacokinetics persists for at least 12 h after the dose: Evidence for mechanism-based inhibition of CYP2C8 in vivo
Authors: Tornio A, Niemi M, Neuvonen M, Laitila J, Kalliokoski A, Neuvonen PJ, Backman JT
Publisher: NATURE PUBLISHING GROUP
Publication year: 2008
Journal: Clinical Pharmacology and Therapeutics
Journal name in source: CLINICAL PHARMACOLOGY & THERAPEUTICS
Journal acronym: CLIN PHARMACOL THER
Volume: 84
Issue: 3
First page : 403
Last page: 411
Number of pages: 9
ISSN: 0009-9236
DOI: https://doi.org/10.1038/clpt.2008.34
Abstract
Repaglinide is metabolized by cytochrome P450 (CYP) 2C8 and 3A4. gemfibrozil has the effect of increasing the area under the concentration-time curve (AUC) of repaglinide eightfold. We studied the effect of dosing interval on the extent of the gemfibrozil-repaglinide interaction. in a randomized five-phase crossover study, 10 healthy volunteers ingested 0.25 mg repaglinide, with or without gemfibrozil pretreatment. plasma repaglinide, gemfibrozil, their metabolites, and blood glucose were measured. When the last dose of 600 mg gemfibrozil was ingested simultaneously with repaglinide, or 3, 6, or 12 h before, it increased the AUC(0-infinity) of repaglinide 7.0-, 6.5-, 6.2- and 5.0-fold, respectively (P < 0.001). The peak repaglinide concentration increased approximately twofold (P < 0.001), and the half-life was prolonged from 1.2 h to 2-3 h (P < 0.001) during all the gemfibrozil phases. The drug interaction effects persisted at least 12 h after gemfibrozil was administered, although plasma gemfibrozil and gemfibrozil 1-O-beta-glucuronide concentrations were only 5 and 10% of their peak values, respectively. The long-lasting interaction is likely caused by mechanism-based inhibition of Cyp2C8 by gemfibrozil glucuronide.
Repaglinide is metabolized by cytochrome P450 (CYP) 2C8 and 3A4. gemfibrozil has the effect of increasing the area under the concentration-time curve (AUC) of repaglinide eightfold. We studied the effect of dosing interval on the extent of the gemfibrozil-repaglinide interaction. in a randomized five-phase crossover study, 10 healthy volunteers ingested 0.25 mg repaglinide, with or without gemfibrozil pretreatment. plasma repaglinide, gemfibrozil, their metabolites, and blood glucose were measured. When the last dose of 600 mg gemfibrozil was ingested simultaneously with repaglinide, or 3, 6, or 12 h before, it increased the AUC(0-infinity) of repaglinide 7.0-, 6.5-, 6.2- and 5.0-fold, respectively (P < 0.001). The peak repaglinide concentration increased approximately twofold (P < 0.001), and the half-life was prolonged from 1.2 h to 2-3 h (P < 0.001) during all the gemfibrozil phases. The drug interaction effects persisted at least 12 h after gemfibrozil was administered, although plasma gemfibrozil and gemfibrozil 1-O-beta-glucuronide concentrations were only 5 and 10% of their peak values, respectively. The long-lasting interaction is likely caused by mechanism-based inhibition of Cyp2C8 by gemfibrozil glucuronide.
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