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Clin Pharmacol Ther. 2004 Sep;76(3):239-49.

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

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Department of Clinical Pharmacology, University of Helsinki and Helsinki University Central Hospital, PO Box 340, FIN-00029 HUS, Helsinki, Finalnd.



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.


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.


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.


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

[Indexed for MEDLINE]

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