Physicochemical and biopharmaceutical characterization of BTA-243, a diacidic drug with low oral bioavailability

This investigation has examined possible causes of the poor bioavailability of the beta(3)-adrenoceptor agonist BTA-243. The aqueous solubility of BTA-243 is pH dependent with a solubility minimum at pH 1.5. However, the dissolution rate of the disodium salt of BTA-243 is similar at both pH 2.0 and 7.4 indicating that dissolution rate is unlikely to be the controlling factor in the absorption of BTA-243. The apparent permeability coefficient of BTA-243 across Caco-2 monolayers at pH 6 was lower than that of mannitol and therefore the epithelial permeability of the molecule in vivo is predicted to be very low and potentially bioavailability limiting. Apparent permeability coefficients were not dependent on BTA-243 concentration over the concentration range 0.5 to 12 mM, indicating that epithelial transport is unlikely to occur via a saturable mechanism. They were of similar magnitude in both directions across the monolayers, indicative of no significant effluxing of BTA-243 by components of the cell membrane. Apparent octanol/water distribution coefficients increased with decrease of pH between 2 and 6; the relatively low values at pH 4 and 6 suggest that the limited intestinal absorption predicted in vivo will occur predominantly via paracellular passive diffusion. Everted gut sac experiments performed at pH 2.0 and 6.8 suggest that at pH 2.0 a significant proportion of the BTA-243 transport occurs via the transcellular route confirming that the ionization state of the BTA-243 molecule influences the route and rate of epithelial permeability. (C) 2001 Elsevier Science B.V. All rights reserved.