Telithromycin, but not montelukast, increases the plasma concentrations and effects of the cytochrome P450 3A4 and 2C8 substrate repaglinide

Clin Pharmacol Ther. 2006 Mar;79(3):231-42. doi: 10.1016/j.clpt.2005.11.002. Epub 2006 Feb 7.


Background and objective: The antidiabetic repaglinide is metabolized by cytochrome P450 (CYP) 2C8 and CYP3A4. Telithromycin, an antimicrobial agent, inhibits CYP3A4 in vitro and in vivo. Montelukast, an antiasthmatic drug, is a potent inhibitor of CYP2C8 in vitro. We studied the effects of telithromycin, montelukast, and the combination of telithromycin and montelukast on the pharmacokinetics and pharmacodynamics of repaglinide.

Methods: In a randomized 4-phase crossover study, 12 healthy volunteers received 800 mg telithromycin, 10 mg montelukast, both telithromycin and montelukast, or placebo once daily for 3 days. On day 3, they ingested a single 0.25-mg dose of repaglinide. Plasma and urine concentrations of repaglinide and its metabolites M1, M2, and M4, as well as blood glucose concentrations, were measured for 12 hours.

Results: Telithromycin alone raised the mean peak plasma repaglinide concentration to 138% (range, 91%-209%; P = .006) and the total area under the plasma concentration-time curve from 0 hours to infinity [AUC0-infinity] of repaglinide to 177% (range, 125%-257%; P < .001) of control (placebo). Telithromycin reduced the AUC0-infinity ratio of the metabolite M1 to repaglinide by 68% (P < .001) and the urinary excretion ratio of M1 to repaglinide by 77% (P = .001). In contrast to previous estimates based on in vitro CYP2C8 inhibition data, montelukast had no significant effect on the pharmacokinetics of repaglinide or its metabolites and did not significantly alter the effect of telithromycin on repaglinide pharmacokinetics. Telithromycin, unlike montelukast, lowered the maximum blood glucose concentration (P = .002) and mean blood glucose concentration from 0 to 3 hours (P = .008) after repaglinide intake, as compared with placebo.

Conclusions: Telithromycin increases the plasma concentrations and blood glucose-lowering effect of repaglinide by inhibiting its CYP3A4-catalyzed biotransformation and may increase the risk of hypoglycemia. Unexpectedly, montelukast has no significant effect on repaglinide pharmacokinetics, suggesting that it does not significantly inhibit CYP2C8 in vivo. The low free fraction of montelukast in plasma may explain the lack of effect on CYP2C8 in vivo, despite the low in vitro inhibition constant, highlighting the importance of incorporating plasma protein binding to interaction predictions.

Publication types

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

MeSH terms

  • Acetates / pharmacology*
  • Adolescent
  • Adult
  • Area Under Curve
  • Aryl Hydrocarbon Hydroxylases / metabolism*
  • Biotransformation
  • Blood Glucose / metabolism
  • Carbamates / blood
  • Carbamates / pharmacokinetics*
  • Cross-Over Studies
  • Cyclopropanes
  • Cytochrome P-450 CYP2C8
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme System / metabolism*
  • Drug Interactions
  • Female
  • Humans
  • Hypoglycemic Agents / blood
  • Hypoglycemic Agents / pharmacokinetics*
  • Ketolides / pharmacology*
  • Leukotriene Antagonists / pharmacology*
  • Male
  • Piperidines / blood
  • Piperidines / pharmacokinetics*
  • Quinolines / pharmacology*
  • Sulfides


  • Acetates
  • Blood Glucose
  • Carbamates
  • Cyclopropanes
  • Hypoglycemic Agents
  • Ketolides
  • Leukotriene Antagonists
  • Piperidines
  • Quinolines
  • Sulfides
  • repaglinide
  • Cytochrome P-450 Enzyme System
  • Aryl Hydrocarbon Hydroxylases
  • CYP2C8 protein, human
  • CYP3A protein, human
  • Cytochrome P-450 CYP2C8
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • telithromycin
  • montelukast