Effect of ingested fluid volume and solution osmolality on intestinal drug absorption: Impact on drug interaction with beverages

Abstract

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 Cmax 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.