Evaluation of peppermint oil and ascorbyl palmitate as inhibitors of cytochrome P4503A4 activity in vitro and in vivo.
OBJECTIVE
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.
Dresser
George K
GK
Department of Medicine, London Health Sciences Centre, University of Western Ontario, London, Ontario, Canada.
Wacher
Vincent
V
Wong
Susan
S
Wong
Harrison T
HT
Bailey
David G
DG
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D001205:Ascorbic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology*; D001628:Beverages; D001682:Biological Availability; D002957:Citrus / Q000378:metabolism; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D015736:Felodipine / Q000031:analogs & derivatives* / Q000097:blood / Q000494:pharmacology; D005260:Female; D006801:Humans; D008297:Male; D036142:Mentha piperita; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D010938:Plant Oils / Q000008:administration & dosage / Q000494:pharmacology*
D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D010938:Plant Oils; C081790:dehydrofelodipine; D003577:Cytochrome P-450 Enzyme System; C015424:peppermint oil; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D015736:Felodipine; D001205:Ascorbic Acid; C031226:6-O-palmitoylascorbic acid