Coadministration of gemfibrozil and itraconazole has only a minor effect on the pharmacokinetics of the CYP2C9 and CYP3A4 substrate nateglinide

Br J Clin Pharmacol. 2005 Aug;60(2):208-17. doi: 10.1111/j.1365-2125.2005.02385.x.


Background and aims: Gemfibrozil, and particularly its combination with itraconazole, greatly increases the area under the plasma concentration-time curve [AUC(0, infinity)] and response to the cytochrome P450 (CYP) 2C8 and 3A4 substrate repaglinide. In vitro, gemfibrozil is a more potent inhibitor of CYP2C9 than of CYP2C8. Our aim was to investigate the effects of the gemfibrozil-itraconazole combination on the pharmacokinetics and pharmacodynamics of another meglitinide analogue, nateglinide, which is metabolized by CYP2C9 and CYP3A4.

Methods: In a randomized crossover study with two phases, nine healthy subjects took 600 mg gemfibrozil and 100 mg itraconazole (first dose 200 mg) twice daily or placebo for 3 days. On day 3, they ingested a single 30-mg dose of nateglinide. Plasma nateglinide and blood glucose concentrations were measured for up to 12 h.

Results: During the gemfibrozil-itraconazole phase, the AUC(0, infinity) and C(max) of nateglinide were 47% (range 23-74%; P < 0.0001) and 30% (range - 8% to 104%; P = 0.0146) higher than during the placebo phase, respectively, but the t(max) and t1/2 of nateglinide remained unchanged. The combination of gemfibrozil and itraconazole had no effect on the formation of the M7 metabolite of nateglinide but impaired its elimination. The blood glucose response to nateglinide was not significantly changed by coadministration of gemfibrozil and itraconazole.

Conclusions: The combination of gemfibrozil and itraconazole has only a limited influence on the pharmacokinetics of nateglinide. This is in marked contrast to the substantial effect of this combination on the pharmacokinetics of repaglinide. The findings suggest that in vivo gemfibrozil, probably due to its metabolites, is a much more potent inhibitor of CYP2C8 than of CYP2C9.

Publication types

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

MeSH terms

  • Administration, Oral
  • Adult
  • Antifungal Agents / administration & dosage*
  • Area Under Curve
  • Aryl Hydrocarbon Hydroxylases / metabolism
  • Blood Glucose / analysis
  • Cross-Over Studies
  • Cyclohexanes / blood
  • Cyclohexanes / pharmacokinetics*
  • Cytochrome P-450 CYP2C9
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme System / metabolism
  • Drug Interactions
  • Female
  • Gemfibrozil / administration & dosage*
  • Humans
  • Hypoglycemic Agents / blood
  • Hypoglycemic Agents / pharmacokinetics*
  • Hypolipidemic Agents / administration & dosage*
  • Itraconazole / administration & dosage*
  • Male
  • Nateglinide
  • Phenylalanine / analogs & derivatives*
  • Phenylalanine / blood
  • Phenylalanine / pharmacokinetics


  • Antifungal Agents
  • Blood Glucose
  • Cyclohexanes
  • Hypoglycemic Agents
  • Hypolipidemic Agents
  • Itraconazole
  • Nateglinide
  • Phenylalanine
  • Cytochrome P-450 Enzyme System
  • CYP2C9 protein, human
  • Cytochrome P-450 CYP2C9
  • Aryl Hydrocarbon Hydroxylases
  • CYP3A protein, human
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • Gemfibrozil