Fruit juice inhibition of uptake transport: a new type of food-drug interaction

Abstract

A new type of interaction in which fruit juices diminish oral drug bioavailability through inhibition of uptake transport is the focus of this review. The discovery was based on an opposite to anticipated finding when assessing the possibility of grapefruit juice increasing oral fexofenadine bioavailability in humans through inhibition of intestinal MDR1-mediated efflux transport. In follow-up investigations, grapefruit or orange juice at low concentrations potentially and selectively inhibited in vitro OATP1A2-mediated uptake compared with MDR1-caused efflux substrate transport. These juices at high volume dramatically depressed oral fexofenadine bioavailability. Grapefruit was the representative juice to characterize the interaction subsequently. A volume-effect relationship study using a normal juice amount halved average fexofenadine absorption. Individual variability and reproducibility data indicated the clinical interaction involved direct inhibition of intestinal OATP1A2. Naringin was a major causal component suggesting that other flavonoids in fruits and vegetables might also produce the effect. Duration of juice clinical inhibition of fexofenadine absorption lasted more than 2 h but less than 4 h indicating the interaction was avoidable with appropriate interval of time between juice and drug consumption. Grapefruit juice lowered the oral bioavailability of several medications transported by OATP1A2 (acebutolol, celiprolol, fexofenadine, talinolol, L-thyroxine) while orange juice did the same for others (atenolol, celiprolol, ciprofloxacin, fexofenadine). Juice clinical inhibition of OATP2B1 was unresolved while that of OATP1B1 seemed unlikely. The interaction between grapefruit juice and etoposide also seemed relevant. Knowledge of both affected uptake transporter and drug hydrophilicity assisted prediction of the clinical interaction with grapefruit or orange juice.

Figure 1

Pilot study results of plasma drug concentration–time profiles of fexofenadine 120 mg for two subjects administered water or grapefruit juice (GFJ) 300 ml. 300 ml water (); 300 ml GFJ ()

Figure 2

Area under the plasma drug concentration–time profile from 0 to 8 h (AUC(0,8 h)) of fexofenadine 120 mg with water 300 ml or 1200 ml (300 ml with drug followed by 150 ml every 0.5 h until 3.0 h) plotted against the absolute change in this parameter with the matching volume of grapefruit juice for each individual (n= 12). Horizontal dashed line indicates no change in fexofenadine AUC(0,8 h). The lines of best fit (solid lines) were determined by linear regression analysis. Dashed lines with arrows indicate the variable and constant components of the interaction. GFJ 1200 ml (); GFJ 300 ml (○) Reprinted with permission from Clinical Pharmacology & Therapeutics