Effects of gemfibrozil, itraconazole, and their combination on the pharmacokinetics and pharmacodynamics of repaglinide: potentially hazardous interaction between gemfibrozil and repaglinide

Diabetologia. 2003 Mar;46(3):347-51. doi: 10.1007/s00125-003-1034-7. Epub 2003 Feb 27.


Aims/hypothesis: Our aim was to investigate possible interactions of gemfibrozil, itraconazole, and their combination with repaglinide.

Methods: In a randomised crossover study, 12 healthy volunteers received twice daily for 3 days either 600 mg gemfibrozil, 100 mg itraconazole (first dose 200 mg), both gemfibrozil and itraconazole, or placebo. On day 3 they ingested a 0.25 mg dose of repaglinide. Plasma drug and blood glucose concentrations were followed for 7 h and serum insulin and C-peptide concentrations for 3 h postdose.

Results: Gemfibrozil raised the area under the plasma concentration-time curve (AUC) of repaglinide 8.1-fold (range 5.5- to 15.0-fold; p<0.001) and prolonged its half-life (t(1/2)) from 1.3 to 3.7 h (p<0.001). Although itraconazole alone raised repaglinide AUC only 1.4-fold (1.1- to 1.9-fold; p<0.001), the gemfibrozil-itraconazole combination raised it 19.4-fold (12.9- to 24.7-fold) and prolonged the t(1/2) of repaglinide to 6.1 h (p<0.001). Plasma repaglinide concentration at 7 h was increased 28.6-fold by gemfibrozil and 70.4-fold by the gemfibrozil-itraconazole combination (p<0.001). Gemfibrozil alone and in combination with itraconazole considerably enhanced and prolonged the blood glucose-lowering effect of repaglinide; i.e., repaglinide became a long-acting and stronger antidiabetic.

Conclusion/interpretation: Clinicians should be aware of this previously unrecognised and potentially hazardous interaction between gemfibrozil and repaglinide. Concomitant use of gemfibrozil and repaglinide is best avoided. If the combination is considered necessary, repaglinide dosage should be greatly reduced and blood glucose concentrations carefully monitored.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antifungal Agents / adverse effects*
  • Area Under Curve
  • Aryl Hydrocarbon Hydroxylases / metabolism
  • Biotransformation
  • Blood Glucose / metabolism
  • C-Peptide / blood
  • Carbamates / adverse effects
  • Carbamates / pharmacokinetics*
  • Carbamates / pharmacology*
  • Cross-Over Studies
  • Cytochrome P-450 CYP2C8
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme System / metabolism
  • Drug Interactions
  • Female
  • Gemfibrozil / adverse effects*
  • Half-Life
  • Humans
  • Hypoglycemic Agents / adverse effects
  • Hypoglycemic Agents / pharmacokinetics*
  • Hypoglycemic Agents / pharmacology*
  • Hypolipidemic Agents / adverse effects*
  • Insulin / blood
  • Itraconazole / adverse effects*
  • Male
  • Piperidines / adverse effects
  • Piperidines / pharmacokinetics*
  • Piperidines / pharmacology*


  • Antifungal Agents
  • Blood Glucose
  • C-Peptide
  • Carbamates
  • Hypoglycemic Agents
  • Hypolipidemic Agents
  • Insulin
  • Piperidines
  • Itraconazole
  • repaglinide
  • Cytochrome P-450 Enzyme System
  • Aryl Hydrocarbon Hydroxylases
  • CYP2C8 protein, human
  • CYP3A protein, human
  • Cytochrome P-450 CYP2C8
  • Cytochrome P-450 CYP3A
  • Gemfibrozil