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

Correspondence: Kari T. Kivistö, MD, Department of Clinical Pharmacology, Helsinki University Central Hospital, PO Box 340, FIN-00029 HUS, Finland E-mail: kari.kivisto@hus.fi

^*Supported by grants from the Helsinki University Central Hospital Research Fund and the National Technology Agency of Finland (TEKES).

Received 25 October 2000; Accepted 9 January 2001.

Abstract

Objective: Our objective was to study the effects of fluconazole and fluvoxamine on the pharmacokinetics and pharmacodynamics of glimepiride, a new sulfonylurea antidiabetic drug. Methods: In this randomized, double-blind, three-phase crossover study, 12 healthy volunteers took 200 mg of fluconazole once daily (400 mg on day 1), 100 mg of fluvoxamine once daily, or placebo once daily for 4 days. On day 4, a single oral dose of 0.5 mg of glimepiride was administered. Plasma glimepiride and blood glucose concentrations were measured up to 12 hours. Results: In the fluconazole phase, the mean total area under the plasma concentration-time curve of glimepiride was 238% (P < .0001) and the peak plasma concentration was 151% (P < .0001) of the respective control value. The mean elimination half-life of glimepiride was prolonged from 2.0 to 3.3 hours (P < .0001) by fluconazole. In the fluvoxamine phase, the mean area under the plasma concentration-time curve of glimepiride was not significantly different from that in the placebo phase. However, the mean peak plasma concentration of glimepiride was 143% (P < .05) of the control and the elimination half-life was prolonged from 2.0 to 2.3 hours (P < .01) by fluvoxamine. Fluconazole and fluvoxamine did not cause statistically significant changes in the effects of glimepiride on blood glucose concentrations. Conclusions: Fluconazole considerably increased the area under the plasma concentration-time curve of glimepiride and prolonged its elimination half-life. This was probably caused by inhibition of the cytochrome P-450 2C9–mediated biotransformation of glimepiride by fluconazole. Concomitant use of fluconazole with glimepiride may increase the risk of hypoglycemia as much as would a 2- to 3-fold increase in the dose of glimepiride. Fluvoxamine moderately increased the plasma concentrations and slightly prolonged the elimination half-life of glimepiride.