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

Correspondence: Mikko Niemi, MD, Department of Clinical Pharmacology, Helsinki University Central Hospital, PO Box 340, FIN-00029 HUS, Finland. E-mail: mikko.niemi@helsinki.fi

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

Received 10 December 2002; Accepted 18 March 2003.

Abstract

Objective: Our aim was to investigate the possible effects of fluconazole on the pharmacokinetics and pharmacodynamics of nateglinide, a new short-acting meglitinide analog antidiabetic drug.

Methods: In a randomized, double-blind, crossover study with 2 phases, 10 healthy volunteers took 200 mg fluconazole (400 mg on day 1) or placebo once daily for 4 days. On day 4, they ingested a single 30-mg dose of nateglinide. Plasma nateglinide and blood glucose concentrations were measured for up to 7 hours.

Results: Fluconazole raised the total area under the plasma concentration–time curve from time 0 to infinity of nateglinide by 48% (range, 20%-73%; P < .00001) and prolonged its half-life from 1.6 to 1.9 hours (P < .05), but the peak plasma nateglinide concentration remained unchanged. The peak plasma concentration of the M7 metabolite of nateglinide was reduced by 34% by fluconazole (P < .001), and its half-life was prolonged from 2.2 to 3.5 hours (P < .05). No significant differences were seen in the blood glucose response to nateglinide between the phases.

Conclusions: Fluconazole raised the plasma concentrations and reduced the systemic elimination of nateglinide probably by inhibiting its cytochrome P4502C9–mediated biotransformation. Concomitant use of fluconazole with nateglinide may prolong its blood glucose–lowering effect.