¹Department of Clinical Pharmacology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland

Correspondence: JT Backman, (janne.backman@helsinki.fi)

Received 21 November 2007; Accepted 26 January 2008; Published online 26 March 2008.

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– 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--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.