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 (Fa) and intestinal availability (Fa × Fg) reported in the literature. RESULTS: The rat intestinal permeability data were better correlated with the combined effect of the absorbed fraction (Fa) and the fraction escaping intestinal metabolism (Fg) than Fa itself. Clear regional dependent absorption was observed for most of the test drugs, and ileal Papp 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.
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 (Fa) and intestinal availability (Fa × Fg) reported in the literature. RESULTS: The rat intestinal permeability data were better correlated with the combined effect of the absorbed fraction (Fa) and the fraction escaping intestinal metabolism (Fg) than Fa itself. Clear regional dependent absorption was observed for most of the test drugs, and ileal Papp 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.
Authors: Duxin Sun; Hans Lennernas; Lynda S Welage; Jeffery L Barnett; Christopher P Landowski; David Foster; David Fleisher; Kyung-Dall Lee; Gordon L Amidon Journal: Pharm Res Date: 2002-10 Impact factor: 4.200