TY - JOUR T1 - Effect of Osmolality on the Pharmacokinetic Interaction Between Apple Juice and Atenolol in Rats JF - Drug Metabolism and Disposition JO - Drug Metab Dispos DO - 10.1124/dmd.118.084483 SP - dmd.118.084483 AU - Yuta Funai AU - Yoshiyuki Shirasaka AU - Marika Ishihara AU - Miyuki Takemura AU - Kazuki Ichijo AU - Hisanao Kishimoto AU - Katsuhisa Inoue Y1 - 2019/01/01 UR - http://dmd.aspetjournals.org/content/early/2019/01/08/dmd.118.084483.abstract N2 - 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. ER -