Effects of trimethoprim and rifampin on the pharmacokinetics of the cytochrome P450 2C8 substrate rosiglitazone

Clin Pharmacol Ther. 2004 Sep;76(3):239-49. doi: 10.1016/j.clpt.2004.05.001.


Background: Trimethoprim is a relatively selective inhibitor of the cytochrome P450 (CYP) 2C8 enzyme in vitro. Rifampin (INN, rifampicin) is a potent inducer of several CYP enzymes, and in vitro studies have suggested that it also induces CYP2C8.

Objective: Our aims were to investigate possible effects of trimethoprim and rifampin on CYP2C8 activity by use of rosiglitazone, a thiazolidinedione antidiabetic drug metabolized primarily by CYP2C8, as an in vivo probe.

Methods: Two separate randomized crossover studies with 2 phases were conducted. In study 1, 10 healthy volunteers took 160 mg trimethoprim or placebo orally twice daily for 4 days. On day 3, they ingested a single 4-mg dose of rosiglitazone. In study 2, 10 healthy volunteers took 600 mg rifampin or placebo orally once daily for 5 days. On day 6, they ingested a single 4-mg dose of rosiglitazone. In both studies, plasma rosiglitazone and N -desmethylrosiglitazone concentrations were measured for up to 48 hours. Results In study 1, trimethoprim raised the area under the plasma rosiglitazone concentration-time curve [AUC(0- infinity )] by 37% (range, 16% to 51%; P <.0001) and the peak plasma rosiglitazone concentration (C max ) by 14% (range, -3% to 38%; P =.0014). The elimination half-life (t 1/2 ) of rosiglitazone was prolonged from 3.8 to 4.8 hours ( P =.0013). Trimethoprim reduced the formation of N -desmethylrosiglitazone. In study 2, rifampin reduced the AUC(0- infinity ) and C max of rosiglitazone by 54% (range, 46% to 63%; P <.0001) and 28% (range, 2% to 56%; P =.0003), respectively. The t 1/2 of rosiglitazone was shortened from 3.8 to 1.9 hours ( P <.0001). Rifampin increased the formation of N -desmethylrosiglitazone.

Conclusions: Trimethoprim raises and rifampin reduces the plasma concentrations of rosiglitazone by inhibiting and inducing, respectively, the CYP2C8-catalyzed biotransformation of rosiglitazone.

Publication types

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

MeSH terms

  • Adult
  • Aryl Hydrocarbon Hydroxylases / metabolism*
  • Cross-Over Studies
  • Cytochrome P-450 CYP2C8
  • Drug Interactions
  • Female
  • Humans
  • Male
  • Rifampin / pharmacology*
  • Rosiglitazone
  • Thiazolidinediones / pharmacokinetics*
  • Trimethoprim / pharmacokinetics
  • Trimethoprim / pharmacology*


  • Thiazolidinediones
  • Rosiglitazone
  • Trimethoprim
  • Aryl Hydrocarbon Hydroxylases
  • CYP2C8 protein, human
  • Cytochrome P-450 CYP2C8
  • Rifampin