The effect of inhibitors of folic acid absorption on the transfer rate constants in the rat everted proximal jejunum: a method for their evaluation from a three-compartment model.

When solute transfer through the intestinal in vitro everted sac preparation is described by a three-compartment system, solute transfer rate constants can be derived for the mucosal and serosal permeability barriers. A catenary variant has been presented as well as a mammillary one where paracellular movement of solute is additionally allowed for. The first order differential rate equations governing the change in solute concentration in all three compartments with respect to time have been solved and the explicit analytical solutions provided. Since these solutions are cumbersome to use in the estimation of the required rate constants, a least squares procedure has been applied directly to the differential form of the rate equations in order to derive the rate constants without recourse to the analytical solutions. Verification of the solutions and of the estimated rate constants was by substitution of the latter into the former to test the goodness of fit for folic acid absorption data. Both variants take into account the simultaneous fluid movement which occurs during absorption experiments and which complicates the interpretation of absorption data. The mammillary model showed that only 10% of folic acid movement could pass directly through the paracellular pathways and that the bulk of folate movement is probably through the epithelial cells. However the catenary model without paracellular movement gave just as good fit to the data and was used subsequently. Experiments investigating the effect of substances implicated in folate malabsorption were analyzed in terms of the catenary model for folic acid absorption, in order to investigate their effects on the transfer rate constants free from the complicating effects on fluid movement. When pronounced inhibition took place, as with methotrexate, the mucosal rate constants were reduced, whereas the serosal rate constants were elevated. Also, the forward (k12) mucosal rate constant correlated significantly with the overall folate transfer in contrast to the other rate constants. These observations are consonant with the concept of a mucosally sited entry step exerting a controlling influence over the transfer rate of folic acid rather than a serosally sited exit process and with the conclusion that this may be the site of action of substances causing folate malabsorption.