Peppermint oil enhances cyclosporine oral bioavailability in rats: comparison with D-alpha-tocopheryl poly(ethylene glycol 1000) succinate (TPGS) and ketoconazole

Abstract

Peppermint oil inhibits cyclosporine metabolism in vitro. The current work compared the effects of peppermint oil, ketoconazole, and D-alpha-tocopheryl poly(ethylene glycol 1000) succinate (TPGS) on cyclosporine oral bioavailability. Male Sprague-Dawley rats were administered cyclosporine (25 mg/kg) as the Sandimmune formulation. Peppermint oil (100 mg/kg) tripled the mean cyclosporine maximum concentration (C(max)) from 0.60 to 1.6 microg/mL and increased the area under the concentration versus time curve (AUC(0-infinity)) from 8.3 to 24.3 microg x h/mL. The median time to reach C(max) (t(max)) was increased from 2 to 6 h. Terminal half-life (10 h) and mean residence time (MRT; 15 h) were unaffected. Coadministration of TPGS (50 mg/kg) with cyclosporine in a saline vehicle doubled cyclosporine C(max) from 1.3 to 2.9 microg/mL and increased AUC(0-infinity) from 28.5 to 59.7 microg x h/mL. The t(max) was unchanged (3 h). Terminal half-life and MRT were increased by 44% (15.4 versus 10.7 h) and 24% (19.9 versus 16.0 h), respectively. Cyclosporine pharmacokinetics were not altered when corn oil was used instead of saline as a gavage vehicle, however the TPGS effect was abolished. Ketoconazole (10 and 20 mg/kg) had no effect on cyclosporine absorption. The lack of a significant ketoconazole effect may reflect poor metabolism of cyclosporine in rat intestinal tissue and suggests that inhibition of cytochrome P450 3A is not the only means by which peppermint oil enhances cyclosporine oral bioavailability.