Biopharmaceutics Classification of Selected β-Blockers:  Solubility and Permeability Class Membership

The purpose of this study was to determine the permeability and solubility of seven β-blockers (acebutolol, atenolol, labetalol, metoprolol, nadolol, sotalol, and timolol) and to classify them according to the Biopharmaceutics Classification System (BCS). Apparent permeability coefficients (P app) were measured using the Caco-2 cell line, and the solubility was determined at 37 °C over a pH range of 1.0−7.5. The permeability coefficients ranged from 1.0 × 10-7 to 4.8 × 10-5 cm/s. On the basis of the in vitro permeability and solubility data observed in the study, labetolol, metoprolol, and timolol can be categorized as BCS Class I drugs, whereas acebutolol, atenolol, and nadolol belong to BCS Class III. The permeability coefficients in Caco-2 cells were consistent with the reported extent of intestinal absorption in humans for all drugs except sotalol. Sotalol displayed low permeability in the Caco-2 cell line, but the extent of intestinal absorption in humans is over 90%. The low permeability through the Caco-2 monolayers might be largely related to its low lipophilicity. In addition, the difference between the tightness of the intercellular junction in vivo and in vitro may partially contribute to this disparity in the sotalol permeability of in vivo and in vitro. Keywords: Biopharmaceutics Classification System; β-blockers; Caco-2; permeability; solubility