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Evaluation of peppermint oil and ascorbyl palmitate as inhibitors of cytochrome P4503A4 activity in vitro and in vivo
Author(s) -
Dresser George K.,
Wacher Vincent,
Wong Susan,
Wong Harrison T.,
Bailey David G.
Publication year - 2002
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1067/mcp.2002.126409
Subject(s) - felodipine , ascorbyl palmitate , chemistry , bioavailability , grapefruit juice , pharmacokinetics , pharmacology , nifedipine , food science , chromatography , ascorbic acid , calcium , endocrinology , medicine , organic chemistry , blood pressure
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 μg/mL, mean ± SEM) and 2 constituents, menthol (K i = 87.0 ± 7.0 μmol/L), and menthyl acetate (K i = 124.0 ± 7.0 μmol/L), produced reversible inhibition of nifedipine oxidation. Ascorbyl palmitate was more potent (K i = 12.3 ± 0.5 μmol/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 ½ ) 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. Clinical Pharmacology & Therapeutics (2002) 72 , 247–255; doi: 10.1067/mcp.2002.126409