Effect of fluconazole on the pharmacokinetics and pharmacodynamics of nateglinide.
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.
Niemi
Mikko
M
Department of Clinical Pharmacology, University of helsinki and Helsinki University Central Hospital, Finland. mikko.niemi@helsinki.fi
Neuvonen
Mikko
M
Juntti-Patinen
Laura
L
Backman
Janne T
JT
Neuvonen
Pertti J
PJ
D000328:Adult; D019540:Area Under Curve; D001786:Blood Glucose / Q000378:metabolism; D018592:Cross-Over Studies; D003510:Cyclohexanes / Q000097:blood / Q000493:pharmacokinetics*; D004311:Double-Blind Method; D005260:Female; D015725:Fluconazole / Q000008:administration & dosage*; D006801:Humans; D008297:Male; D000077715:Nateglinide; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics*; D018709:Statistics, Nonparametric
D001786:Blood Glucose; D003510:Cyclohexanes; D000077715:Nateglinide; D010649:Phenylalanine; D015725:Fluconazole