Effect of fluconazole on the pharmacokinetics and pharmacodynamics of nateglinide.

Author(s): Niemi M, Neuvonen M, Juntti-Patinen L, Backman JT, Neuvonen PJ

Affiliation(s): Department of Clinical Pharmacology, University of helsinki and Helsinki University Central Hospital, Finland. mikko.niemi@helsinki.fi

Publication date & source: 2003-07, Clin Pharmacol Ther., 74(1):25-31.

Publication type: Clinical Trial; Randomized Controlled Trial

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.