¹Department of Medicine, University of Western Ontario, London; the Departments of Internal Medicine and Pathology, Wake Forest University School of Medicine, Winston-Salem; and the Division of Clinical Pharmacology, Departments of Medicine and Pharmacology, Vanderbilt University School of Medicine, Nashville.

Correspondence: David G. Bailey, PhD, Department of Medicine, London Health Sciences Centre, Victoria Campus, 375 South St, London, Ontario, Canada N6A 4G5. E-mail: david.bailey@lhsc.on.ca

^*Supported in part by grants GM54724 and GM31304 from the United States Public Health Service and by grant MT-13750 from the Medical Research Council of Canada.

Received 25 July 2001; Accepted 17 October 2001.

Abstract

Objectives: 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 [IC₅₀], 33 mol/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 (IC₅₀, 0.28 mol/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.