Influence of osmolality on gastrointestinal fluid volume and drug absorption: potential impact on oral salt supplementation

Abstract

Background The syndrome of inappropriate secretion of antidiuretic hormone (SIADH) is the most frequent cause of hyponatremia in patients with cerebrovascular disease, and is often treated with oral salt tablets. However, we have shown that osmolality-dependent variations in gastrointestinal (GI) fluid volume can alter the concentration of a poorly permeable drug in the GI tract, potentially affecting its absorption. Here, we examined the effect of ingestion of hyperosmotic solution (10% NaCl) on drug concentration and absorption in the GI tract. Methods The effects of osmolality on luminal fluid volume and drug absorption in rat intestine (jejunum, ileum and colon) were examined by means of an in situ closed loop method using fluorescein isothiocyanate-dextran 4000 (FD-4) and atenolol. In vivo absorption in rats was determined by measuring the plasma concentration after oral administration of the test compounds dissolved in purified water or hyperosmotic solution (10% NaCl). Results Administration of hyperosmotic solution directly into the GI tract significantly increased the GI fluid volume, owing to secretion of water into the lumen. After administration in hyperosmotic solution, the luminal concentration of non-permeable FD-4 was significantly lower than the initial dosing concentration, whereas after administration in purified water, the luminal concentration exceeded the initial concentration. The fraction absorbed of atenolol was markedly lower after administration in hyperosmotic solution than after administration in purified water. An in vivo pharmacokinetic study in rats was consistent with these findings. Conclusions Administration of hyperosmotic NaCl solution increased GI fluid volume and reduced the plasma level of orally administered atenolol. This may imply that oral salt tablets used to treat hyponatremia in SIADH patients could decrease the intestinal absorption of concomitantly administered drugs, resulting in lower plasma exposure.

Magnitude of Fruit Juice–Drug Interactions Due to Osmolality-Dependent Fluid Secretion: Differences among Apple, Orange, and Grapefruit Juices

“…In this context, we have proposed that osmolality-dependent changes in GI fluid volume may indirectly affect the drug absorption process by altering the drug concentration in the GI tract. [12][13][14] Indeed, we showed that this effect could account for the AJ-atenolol interaction. Specifically, ingestion of AJ leads to fluid secretion into the GI lumen due to the high osmolality of AJ, resulting in a reduction of GI absorption of atenolol owing to its reduced concentration in the GI fluid.…”

Quantitative analysis of gastrointestinal fluid absorption and secretion to estimate luminal fluid dynamics in rats

“…Indeed, dynamic variations in fluid volumes along the GI tract have been observed by means of fluid-sensitive MRI and PET analyses in healthy volunteers and/or experimental animals 6 , 11 . Furthermore, our recent studies have shown that the solution osmolality influences the GI fluid volume 1 – 5 . We also demonstrated that osmolality-dependent variations in GI fluid volume can alter drug concentration in the GI tract, and consequently change drug absorption characteristics 2 .…”

“…Fluid volume is a major factor directly determining GI drug concentration and the amount of dissolution of poorly soluble drugs in the GI tract. We recently reported that changes in the GI fluid volume may indirectly influence the drug absorption profile by altering the drug concentration and absorption kinetics 1 – 5 . Furthermore, we and other research groups demonstrated that water secretion and drug resultant dilution of drug concentration in the GI tract may contribute to beverage-drug interactions that result in decreased drug absorption 1 , 6 , 7 .…”