IN-VITRO PERMEABILITY SCREENING FOR IDENTIFICATION OF ORALLY BIOAVAILABLE ENDOTHELIN RECEPTOR ANTAGONISTS

In vitro intestinal permeability screening identified a compound, SB 2 17242, in the indane carboxylic acid series of endothelin receptor ant agonists, with greatly improved permeability over the initial lead com pound in this series. Based on mucosal-to-serosal and serosal-to-mucos al permeability studies, and on the fact that SB 217242 transport does not correlate with changes in mannitol permeability, it was concluded that SB 217242 follows a passive transcellular pathway. Permeability studies at different pH values demonstrate that the permeating species is the unionized form of SB 217242. This compound is well absorbed up on intraduodenal dosing in the rat (Ohlstein et al. (1996) J. Pharm. E xp. Ther. 276, 609-615).