Fruit juices inhibit organic anion transporting polypeptide-mediated drug uptake to decrease the oral availability of fexofenadine.
OBJECTIVE
Our objective was to examine the effect of different fruits and their constituents on P-glycoprotein and organic anion transporting polypeptide (OATP) activities in vitro and on drug disposition in humans.


METHODS
P-glycoprotein-mediated digoxin or vinblastine efflux was determined in polarized epithelial cell monolayers. OATP-mediated fexofenadine uptake was measured in a transfected cell line. The oral pharmacokinetics of 120 mg fexofenadine was assessed with water, 25%-strength grapefruit juice, or normal-strength grapefruit, orange, or apple juices (1.2 L over 3 hours) in a randomized 5-way crossover study in 10 healthy subjects.


RESULTS
Grapefruit juice and segments and apple juice at 5% of normal strength did not alter P-glycoprotein activity. Grapefruit extract reduced transport. 6',7'-Dihydroxybergamottin had modest inhibitory activity (50% inhibitory concentration [IC(50)], 33 micromol/L). In contrast, grapefruit, orange, and apple juices at 5% of normal strength markedly reduced human OATP and rat oatp activity. 6',7'-Dihydroxybergamottin potently inhibited rat oatp3 and oatp1 (IC(50), 0.28 micromol/L). Other furanocoumarins and bioflavonoids also reduced rat oatp3 activity. Grapefruit, orange, and apple juices decreased the fexofenadine area under the plasma concentration-time curve (AUC), the peak plasma drug concentration (C(max)), and the urinary excretion values to 30% to 40% of those with water, with no change in the time to reach C(max), elimination half-life, renal clearance, or urine volume in humans. Change in fexofenadine AUC with juice was variable among individuals and inversely dependent on value with water.


CONCLUSIONS
Fruit juices and constituents are more potent inhibitors of OATPs than P-glycoprotein activities, which can reduce oral drug bioavailability. Results support a new model of intestinal drug absorption and mechanism of food-drug interaction.
Dresser
George K
GK
Department of Medicine, University of Western Ontario, London, Ontario, Canada.
Bailey
David G
DG
Leake
Brenda F
BF
Schwarz
Ute I
UI
Dawson
Paul A
PA
Freeman
David J
DJ
Kim
Richard B
RB
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D000284:Administration, Oral; D000328:Adult; D019540:Area Under Curve; D001628:Beverages / Q000009:adverse effects*; D001682:Biological Availability; D002352:Carrier Proteins / Q000378:metabolism; D002957:Citrus; D004311:Double-Blind Method; D005260:Female; D005419:Flavonoids / Q000378:metabolism; D018565:Food-Drug Interactions / Q000502:physiology*; D005638:Fruit; D006367:HeLa Cells; D006634:Histamine H1 Antagonists / Q000493:pharmacokinetics*; D006801:Humans; D007408:Intestinal Absorption; D008297:Male; D027845:Malus; D026901:Membrane Transport Proteins; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D029363:Organic Anion Transporters, Sodium-Dependent; D027981:Symporters; D016593:Terfenadine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*
D018435:ATP Binding Cassette Transporter, Subfamily B; D002352:Carrier Proteins; D005419:Flavonoids; D006634:Histamine H1 Antagonists; D026901:Membrane Transport Proteins; D027361:Organic Anion Transporters; D029363:Organic Anion Transporters, Sodium-Dependent; D027981:Symporters; C071908:sodium-bile acid cotransporter; D016593:Terfenadine; C093230:fexofenadine