Effects of fluconazole and fluvoxamine on the pharmacokinetics and pharmacodynamics of glimepiride.
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.
Niemi
M
M
Department of Clinical Pharmacology, University of Helsinki and Helsinki University Central Hospital, Finland.
Backman
J T
JT
Neuvonen
M
M
Laitila
J
J
Neuvonen
P J
PJ
Kivistö
K T
KT
D000328:Adult; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases; D001786:Blood Glucose / Q000032:analysis; D018592:Cross-Over Studies; D065607:Cytochrome P-450 Enzyme Inhibitors; D004311:Double-Blind Method; D004347:Drug Interactions; D005260:Female; D015725:Fluconazole / Q000493:pharmacokinetics / Q000494:pharmacology*; D016666:Fluvoxamine / Q000493:pharmacokinetics / Q000494:pharmacology*; D006207:Half-Life; D006801:Humans; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics* / Q000494:pharmacology*; D008297:Male; D039181:Steroid 16-alpha-Hydroxylase; D013250:Steroid Hydroxylases / Q000037:antagonists & inhibitors; D013453:Sulfonylurea Compounds / Q000493:pharmacokinetics* / Q000494:pharmacology*
D001786:Blood Glucose; D065607:Cytochrome P-450 Enzyme Inhibitors; D007004:Hypoglycemic Agents; D013453:Sulfonylurea Compounds; C057619:glimepiride; D015725:Fluconazole; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; D039181:Steroid 16-alpha-Hydroxylase; D016666:Fluvoxamine