In a recent clinical study, it was reported that the ingestion of apple juice (AJ) markedly reduced the plasma concentration of atenolol. However, our in vitro study showed that atenolol may not be a substrate of OATP2B1, so this AJ-atenolol interaction cannot be explained by inhibition of OATP2B1. On the other hand, we more recently showed that the solution osmolality influences gastrointestinal (GI) water volume, and this may indirectly affect intestinal drug absorption. In this study, we examined whether the osmolality-dependence of water dynamics can account for AJ-atenolol interactions by evaluating the GI water volume and the atenolol aborption in the presence of AJ in rats. Water absorption was the highest in purified water, followed by saline and isosmotic mannitol solution, and the lowest in AJ, confirming that water absorption is indeed osmolality-dependent. Interestingly, AJ showed apparent water secretion into the intestinal lumen. The intestinal concentration of FD-4, a non-permeable compound, after administration in AJ was lower than the initial concentration, while that in purified water was greater than the initial concentration. Further, the fraction absorbed of atenolol in intestine was significantly lower in AJ or hyperosmotic mannitol solution (adjusted to the osmolality of AJ) than after administration in purified water. Comparable results were observed in in vivo pharmacokinetic study in rats. Our results indicate that orally administered AJ has a capacity to modulate luminal water volume depending on the osmolality, and this effect may result in significant AJ-atenolol interactions.

It was recently shown that osmolality-dependent fluid movement is a significant factor causing the clinically observed apple juice (AJ)-atenolol interaction. Here we examined whether osmolality-dependent fluid movement may also explain the AJ volume dependence of the AJ-atenolol interaction. In Wistar rats, the luminal fluid volume after administration of different volumes of purified water (0.5 and 1.0 mL) gradually reduced to a similar steady-state level, while that after administration of different volumes of AJ (0.5 and 1.0 mL) increased and attained different apparent steady-state levels. It was hypothesized that osmolality-dependent fluid secretion would account for the volume dependence of the apparent steady-state. Indeed, the luminal concentration of FD-4, a non-permeable compound, after administration in AJ was attenuated depending upon the ingested volume, whereas that after administration in purified water was independent of the ingested fluid volume. An in vivo pharmacokinetic study in rats showed that co-administration of AJ and hyperosmotic solution (adjusted to the osmolality of AJ) with atenolol volume-dependently reduced the AUC and C_max of atenolol significantly. These results show that osmolality-dependent variations in luminal fluid volume may indirectly influence the absorption characteristics of drugs, and can account for the observed volume dependence of beverage-drug interactions.