The CYP2C8 inhibitor trimethoprim increases the plasma concentrations of repaglinide in healthy subjects

Br J Clin Pharmacol. 2004 Apr;57(4):441-7. doi: 10.1046/j.1365-2125.2003.02027.x.


Aims: Our aim was to investigate the effect of the CYP2C8 inhibitor trimethoprim on the pharmacokinetics and pharmacodynamics of the antidiabetic drug repaglinide, and to examine the influence of the former on the metabolism of the latter in vitro.

Methods: In a randomized, double-blind, crossover study with two phases, nine healthy volunteers took 160 mg trimethoprim or placebo orally twice daily for 3 days. On day 3, 1 h after the last dose of trimethoprim or placebo, they ingested a single 0.25 mg dose of repaglinide. Plasma repaglinide and blood glucose concentrations were measured for up to 7 h post-dose. In addition, the effect of trimethoprim on the metabolism of repaglinide by human liver microsomes was investigated.

Results: Trimethoprim raised the AUC(0, infinity ) and C(max) of repaglinide by 61% (range, 30-117%; P= 0.0008) and 41% (P = 0.005), respectively, and prolonged the t((1/2)) of repaglinide from 0.9 to 1.1 h (P = 0.001). Trimethoprim had no significant effect on the pharmacokinetics of its aromatic amine metabolite (M1), but decreased the M1 : repaglinide AUC(0, infinity ) ratio by 38% (P = 0.0005). No effect of trimethoprim on the blood glucose-lowering effect of repaglinide was detectable. In vitro, trimethoprim inhibited the metabolism of (220 nm) repaglinide in a concentration-dependent manner.

Conclusions: Trimethoprim raised the plasma concentrations of repaglinide probably by inhibiting its CYP2C8-mediated biotransformation. Although the interaction did not significantly enhance the effect of repaglinide on blood glucose concentration at the drug doses used, the possibility of an increased risk of hypoglycaemia should be considered during concomitant use of trimethoprim and repaglinide in patients with diabetes.

Publication types

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

MeSH terms

  • Adult
  • Aryl Hydrocarbon Hydroxylases / antagonists & inhibitors*
  • Biotransformation
  • Carbamates / blood
  • Carbamates / pharmacokinetics*
  • Cross-Over Studies
  • Cytochrome P-450 CYP2C8
  • Diabetes Mellitus / drug therapy*
  • Double-Blind Method
  • Drug Interactions
  • Female
  • Humans
  • Hypoglycemic Agents / blood
  • Hypoglycemic Agents / pharmacokinetics*
  • Male
  • Piperidines / blood
  • Piperidines / pharmacokinetics*
  • Trimethoprim / pharmacology*


  • Carbamates
  • Hypoglycemic Agents
  • Piperidines
  • repaglinide
  • Trimethoprim
  • Aryl Hydrocarbon Hydroxylases
  • CYP2C8 protein, human
  • Cytochrome P-450 CYP2C8