The contribution of solvent drag to the intestinal absorption of the acidic drugs benzoic acid and salicylic acid from the jejunum of the rat

Summary

• 1. Jejunal loops of anaesthetized rats were perfused with hypotonic, isotonic and hypertonic buffered solutions containing ¹⁴C-labelled benzoic acid and salicylic acid at pH 6.2 and 2.2. The blood flow of the loop was maintained at an intermediate rate (0.78–0.97 ml min⁻¹ g⁻¹). The water net flux was determined by polyethylene glycol as non-absorbable marker and amounted up to +31 or-27 μl min⁻¹ g⁻¹.

• 2. A positive water net flux (leaving the gut lumen) increased the appearance rate of benzoic acid and salicylic acid in the intestinal venous blood by maximally 47 and 41%, a negative water net flux (entering the gut lumen) diminished the appearance rate by 28 and 37%.

• 3. The experimental data were analysed by means of a kinetic model. The parameters of the model were the epithelial permeability kF _D , the serosal permeability k _S F _S and the sieving coefficient Φ=1−σ. The epithelial permeability was 0.115 and 0.107 for benzoic acid and salicylic acid at pH 6.2 and increased to 0.163 and 0.185 ml min⁻¹ g⁻¹ at pH 2.2. The serosal permeability was assumed to be identical for neutral and acidic pH and amounted to 0.046 and 0.112 ml min⁻¹ g⁻¹ indicating that a certain proportion of the absorbed drugs was transferred to the serosal side. The sieving coefficient was 2.92 and 2.31 at neutral pH and 3.79 and 3.56 at acidic pH.

• 4. The main resistance to the absorption of the two drugs is the epithelial membrane, since the effective blood flow and the unstirred layer are not ratelimiting. The high sieving coefficient for the two drugs is interpreted as indicating an interaction of drug and water molecules inside the lipid part of the cell membrane (which contains at least 30% water). The electric potential across the gut wall may contribute to the size of the sieving coefficient, if the drug molecules permeate also in the ionized form.

• 5. Using acidic perfusion solutions the epithelial permeability and the sieving coefficient were increased by the factor 1.3–1.5. This increase can be explained sufficiently by a facilitated entrance of the unionized drug molecules into the epithelial membrane.