Evaluation of peppermint oil and ascorbyl palmitate as inhibitors of cytochrome P4503A4 activity in vitro and in vivo.

OBJECTIVES: Our study was designed to determine the effect of peppermint oil and ascorbyl palmitate on cytochrome P4503A4 (CYP3A4) activity in vitro and oral bioavailability of felodipine in humans. METHODS: Reversible and mechanism-based inhibitions of nifedipine oxidation were studied in human liver microsomes. The oral pharmacokinetics of felodipine and its dehydrofelodipine metabolite were determined in 12 healthy volunteers after administration of felodipine, 10-mg extended-release tablet, with grapefruit juice (300 mL), peppermint oil (600 mg), ascorbyl palmitate (500 mg), or water in a randomized 4-way crossover study. RESULTS: Peppermint oil (inhibition constant [K(i)] = 35.9 +/- 3.3 microg/mL, mean +/- SEM) and 2 constituents, menthol (K(i) = 87.0 +/- 7.0 micromol/L), and menthyl acetate (K(i) = 124.0 +/- 7.0 micromol/L), produced reversible inhibition of nifedipine oxidation. Ascorbyl palmitate was more potent (K(i) = 12.3 +/- 0.5 micromol/L). None of these substances were mechanism-based inhibitors. Grapefruit juice and peppermint oil increased the area under the curve (AUC) values of felodipine to 173% (range, 94%-280%; P <.01) and 140% (range, 77%-262%; P <.05), respectively, of those with water. They augmented the peak plasma concentration (C(max)) of felodipine and the AUC and C(max) of dehydrofelodipine but did not alter the half-life (t(1/2)) of either substance. Grapefruit juice decreased the dehydrofelodipine/felodipine AUC ratio, but peppermint oil did not. Ascorbyl palmitate did not change the pharmacokinetics of felodipine or dehydrofelodipine compared with water. CONCLUSIONS: Peppermint oil, menthol, menthyl acetate, and ascorbyl palmitate were moderately potent reversible inhibitors of in vitro CYP3A4 activity. Grapefruit juice increased the oral bioavailability of felodipine by inhibition of CYP3A4-mediated presystemic drug metabolism. Peppermint oil may also have acted by this mechanism. However, this requires further investigation. Ascorbyl palmitate did not inhibit CYP3A4 activity in vivo.

Minimal effect of ketoconazole on cyclosporine (SangCyA) oral absorption and first-pass metabolism in rats: evidence of a significant vehicle effect on SangCyA absorption.

The current work evaluated the effect of the CYP3A inhibitor ketoconazole on the oral absorption and first-pass metabolism of cyclosporine administered as the SangCyA formulation. Groups of 6 male Sprague-Dawley rats were administered SangCyA (5 and 15 mg/kg) by oral gavage alone and with ketoconazole (30 mg/kg). Blood cyclosporine levels were measured over 6 h, encompassing the cyclosporine absorption window. A significant vehicle effect on SangCyA absorption was observed. Comparing a 15 mg/kg dose, cyclosporine C(max) (mean+/-SD 1.12+/-0.16 microg/ml) and AUC(0-6) (5.34+/-0.71 microg h/ml) were 50% lower when propylene glycol was used as gavage vehicle instead of saline (2.19+/-0.94 microg/ml and 9.52+/-2.52 microg h/ml, respectively). Coefficients-of-variation for these parameters were halved in the propylene glycol vehicle however T(max) was unaffected. Ketoconazole increased cyclosporine C(max) and AUC(0-6) by 50-60%, regardless of the vehicle or the cyclosporine dose, without altering T(max) (2-3 h). The small effect of ketoconazole suggests that CYP3A-mediated intestinal and first-pass hepatic metabolism are minor determinants of cyclosporine oral bioavailability in rats.

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

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.