Background and objective: The thiazolidinedione antidiabetic drug pioglitazone is metabolized mainly by cytochrome P450 (CYP) 2C8 and CYP3A4 in vitro. Our objective was to study the effects of gemfibrozil, itraconazole, and their combination on the pharmacokinetics of pioglitazone to determine the role of these enzymes in the fate of pioglitazone in humans.
Methods: In a randomized, double-blind, 4-phase crossover study, 12 healthy volunteers took either 600 mg gemfibrozil or 100 mg itraconazole (first dose, 200 mg), both gemfibrozil and itraconazole, or placebo twice daily for 4 days. On day 3, they received a single dose of 15 mg pioglitazone. Plasma drug concentrations and the cumulative excretion of pioglitazone and its metabolites into urine were measured for up to 48 hours.
Results: Gemfibrozil alone raised the mean total area under the plasma concentration-time curve from time 0 to infinity [AUC(0-infinity)] of pioglitazone 3.2-fold (range, 2.3-fold to 6.5-fold; P < .001) and prolonged its elimination half-life (t (1/2) ) from 8.3 to 22.7 hours ( P < .001) but had no significant effect on its peak concentration (C max ) compared with placebo (control). Gemfibrozil increased the 48-hour excretion of pioglitazone into urine by 2.5-fold ( P < .001) and reduced the ratios of the active metabolites M-III and M-IV to pioglitazone in plasma and urine. Gemfibrozil decreased the area under the plasma concentration-time curve from time 0 to 48 hours [AUC(0-48)] of the metabolites M-III and M-IV by 42% ( P < .05) and 45% ( P < .001), respectively, but their total AUC(0-infinity) values were reduced by less or not at all. Itraconazole had no significant effect on the pharmacokinetics of pioglitazone and did not alter the effect of gemfibrozil on pioglitazone pharmacokinetics. The mean area under the concentration versus time curve to 49 hours [AUC(0-49)] of itraconazole was 46% lower ( P < .001) during the gemfibrozil-itraconazole phase than during the itraconazole phase.
Conclusions: Gemfibrozil elevates the plasma concentrations of pioglitazone, probably by inhibition of its CYP2C8-mediated metabolism. CYP2C8 appears to be of major importance and CYP3A4 of minor importance in pioglitazone metabolism in vivo in humans. Concomitant use of gemfibrozil with pioglitazone may increase the effects and risk of dose-related adverse effects of pioglitazone. However, studies in diabetic patients are needed to determine the clinical significance of the gemfibrozil-pioglitazone interaction.