Evaluation of an Ussing Chamber System Equipped with Rat Intestinal Tissues to Predict Intestinal Absorption and Metabolism in Humans.

BACKGROUND AND OBJECTIVE

Oral bioavailability (F) is one of the key factors that need to be determined in drug discovery. This factor is determined by the permeability and solubility of new molecule entities (NMEs) according to the biopharmaceutics classification system (BCS).

METHODS

In the present study, we evaluated the permeability of 22 drugs in rat intestinal tissues using an Ussing chamber system and correlated the permeability with data on human intestinal absorption (F) and intestinal availability (F × F) reported in the literature.

RESULTS

The rat intestinal permeability data were better correlated with the combined effect of the absorbed fraction (F) and the fraction escaping intestinal metabolism (F) than F itself. Clear regional dependent absorption was observed for most of the test drugs, and ileal P was generally higher than that in other segments. Finally, the function of the efflux transporter P-glycoprotein (P-gp) with regard to oral absorption of substrates was evaluated with an Ussing chamber. We also demonstrated that the rat intestinal stability of the three cytochrome P450 (CYP) substrates was consistent with the human data.

CONCLUSION

An Ussing chamber system incorporating rat intestinal tissue would be a valuable tool to predict human intestinal absorption and metabolism for molecules with various physicochemical properties.