Effect of grapefruit juice volume on the reduction of fexofenadine bioavailability: possible role of organic anion transporting polypeptides.
OBJECTIVE
The purpose of this study was to elucidate the potential clinical relevance and mechanism(s) of action of 2 different volumes of grapefruit juice on the reduction of bioavailability of fexofenadine, a substrate of organic anion transporting polypeptides.


METHODS
Grapefruit juice or water at normal (300 mL) or high (1200 mL) volume was ingested concomitantly with 120 mg fexofenadine by 12 healthy volunteers in a randomized 4-way crossover study, and fexofenadine pharmacokinetics were determined over a period of 8 hours.


RESULTS
The 300-mL volume of grapefruit juice decreased the mean area under the plasma drug concentration-time curve (AUC) and the peak plasma drug concentration of fexofenadine to 58% (P < .001) and 53% (P < .001), respectively, of those with the corresponding volume of water, and 1200 mL grapefruit juice reduced these parameters to 36% ( P < .001) and 33% ( P < .001), respectively, of those with the corresponding volume of water. The 300-mL volume of grapefruit juice diminished the AUC of fexofenadine variably among individuals. This decline correlated with baseline AUC of fexofenadine with water at equivalent volume (r(2) = 0.97, P < .0001). The 1200-mL volume of grapefruit juice decreased the AUC of fexofenadine more than the 300-mL volume of grapefruit juice compared with the corresponding volume of water in each subject by a constant amount. Grapefruit juice, 300 mL and 1200 mL, reduced the coefficient of variation of the AUC of fexofenadine by 2-fold compared with that with a matching volume of water.


CONCLUSIONS
Grapefruit juice at a commonly consumed volume diminished the oral bioavailability of fexofenadine sufficiently to be pertinent clinically, likely by direct inhibition of uptake by intestinal organic anion transporting polypeptide A (OATP-A; new nomenclature, OATP1A2). A much higher volume caused an additional modest effect, possibly from reduced intestinal concentration and transit time of fexofenadine. This food-drug interaction appears to be novel and may be relevant to other fruit juices and drugs.
Dresser
George K
GK
Lawson Health Research Institute, London Health Sciences Centre, UK.
Kim
Richard B
RB
Bailey
David G
DG
D000284:Administration, Oral; D000328:Adult; D019540:Area Under Curve; D001682:Biological Availability; D032083:Citrus paradisi / Q000502:physiology*; D018592:Cross-Over Studies; D004326:Drinking; D005260:Female; D018565:Food-Drug Interactions; D006801:Humans; D008297:Male; D008875:Middle Aged; D027361:Organic Anion Transporters / Q000737:chemistry / Q000378:metabolism*; D010455:Peptides / Q000737:chemistry / Q000378:metabolism*; D016593:Terfenadine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics*; D014867:Water / Q000378:metabolism / Q000494:pharmacology
D027361:Organic Anion Transporters; D010455:Peptides; D014867:Water; D016593:Terfenadine; C093230:fexofenadine