Effect of Bile Salts on Partitioning Behavior and Gi Absorption of a Quaternary Ammonium Compound, Isopropamide Iodide

Abstract

The effect of various bile salts and, in particular, sodium glycocholate upon the partitioning behavior of the quaternary ammonium compound isopropamide iodide was studied in vitro. Absorption of this compound from the rat ileum in situ, in the presence of various concentrations of bile salt, was also studied. The results indicate that sodium glycocholate progressively increases the partitioning of isopropamide from a physiological aqucous buffer into n-octanol below the CMC of the bile salt, but increased partitioning is inhibited above this value. Isopropamide did not partition in the absence of the bile salt counterion. The formation of a lipid-soluble ion-pair between the bile salt anion and the quaternary cation is suggested as the mechanism by which enhanced partitioning occurs, the decrease in maximal transport being related to mixed micelle formation or adsorption of ammonium ions to the outer surface of the bile salt aggregate. Absorption from the rat ileum in situ in the presence of sodium glycocholate below and above its CMC appears not to follow a similar pattern. It is suggested that the GI absorption of the isopropamide cation cannot be increased in the presence of bile salt molecules through ion-pair formation or mixed micelle formation. Above the CMC of bile salt, the absorptive process appears actually to be hindered through a decrease in the availability of the drug to the absorptive surface, either by a physicochemical interaction with the micellar phase or by decreased diffusivity of the drug in the presence of bile salt aggregates.