Gemfibrozil considerably increases the plasma concentrations of rosiglitazone

Aims/hypothesis. Our aim was to investigate possible interaction between gemfibrozil and rosiglitazone, a thiazolidinedione antidiabetic drug. Methods. In a randomised crossover study with two phases, 10 healthy volunteers took 600 mg gemfibrozil or placebo orally twice daily for 4 days. On day 3, they ingested a single 4 mg dose of rosiglitazone. Plasma rosiglitazone and its N-desmethyl metabolite concentrations were measured for up to 48 h. Results. Gemfibrozil raised the mean area under the plasma rosiglitazone concentration-time curve (AUC) 2.3-fold (range 1.5- to 2.8-fold; p=0.00002) and prolonged the elimination half-life (t(1/2)) of rosiglitazone from 3.6 to 7.6 h (p=0.000002). The peak plasma rosiglitazone concentration (C-max) was increased only 1.2-fold (range 0.9- to 1.6-fold; p=0.01) by gemfibrozil, but gemfibrozil raised the plasma rosiglitazone concentration measured 24 h after dosing (C-24) 9.8-fold (range, 4.5- to 33.6-fold; p=0.00008). In addition, gemfibrozil prolonged the t(max) of N-desmethylrosiglitazone from 7 to 12 h and reduced the N-desmethylrosiglitazone/rosiglitazone AUC(0-48) ratio by 38% (p<0.01). Conclusions/interpretation. Gemfibrozil raises the plasma concentrations of rosiglitazone probably by inhibiting the CYP2C8-mediated biotransformation of rosiglitazone. Co-administration of gemfibrozil, or another potent inhibitor of CYP2C8, and rosiglitazone could increase the efficacy but also the risk of concentration-dependent adverse effects of rosiglitazone.