Mechanistic Studies On The Anatomical Reserve Length For Intestinal Absorption Of Bile Acids.

Abstract

This research is aimed at establishing the basic framework by which relevant physicochemical properties, dosage form properties, gastrointestinal factors and mass transport kinetics are put into quantitative and mechanistic interrelationships. The anatomical reserve length, which is the length of small intestine yet available for absorption provides the foundation on which the facts and relationships of rate-determining steps and factors are accommodated. Chenodeoxycholic (CDCA) and ursodeoxycholic (UDCA) acids were employed as the model drugs and the rat as the animal model for intestinal absorption studies. Using the in situ steady-state, flow-through intestinal perfusion method, absorption studies were carried out in isolated jejunum and ileum segments at buffer pH 6.0 and principally pH 7.5 for various Na CDCA and Na UDCA concentrations. The effective permeability coefficients (P(,e)) of both bile acids were nearly identical. The average fluxes in the intestinal segments were linear with bile salt concentrations below the CMC of 1 mM for Na CDCA and 3 mM for Na UDCA. These findings indicate that the passive absorption in the jejunum of these bile acids were efficient and essentially controlled by the convective-diffusional step across the aqueous boundary layer in front of the membrane. When the bile salt concentrations were increased beyond their CMC, P(,e) decreased monotonically and the average intestinal fluxes increased but at a gradually decreasing rate. Therefore, in dilute micellar solutions, the membrane became a significant transport barrier because only bile acid monomers were absorbed. The results are consistent with the mechanism in which there is penetration of micelles into the aqueous boundary layer, resulting in a micelle concentration gradient with constant monomer activity equal to the CMC, followed by a concentration gradient of monomer species to the membrane surface. The rat intestinal absorption studies were culminated by putting the experimentally determined interrelationships of fluid flow, pH, permeability of the aqueous boundary layer, intestinal membrane permeability and bile acid concentration within the anatomical reserve length model. The predicted intestinal length at which micellar solutions of Na CDCA and Na UDCA and suspensions of CDCA and UDCA are completely absorbed were in remarkable agreement with corresponding clinical data obtained with intubated human subjects. (Abstract shortened with permission of author.)