THE USE OF RABBIT INTESTINAL PERMEABILITY AS AN IN-VITRO ASSAY IN THESEARCH FOR ORALLY-ACTIVE GPIIB IIIA ANTAGONISTS/

A series of potent, high affinity GPIIb/IIIa antagonists were evaluate d for intestinal permeability in vitro using rabbit intestinal strips mounted in the Ussing Chamber. In this series of compounds, structural modifications were found to impact intestinal permeability. In genera l, modifications that would contribute to lipophilicity (e.g. olefinic replacement for amide, phenethyl or isopropyl for methyl) did not enh ance permeability. When these intestinal permeabilities were compared to mannitol, which displays similar to 20% oral bioavailability in hum ans (Laker et al. (1982) fur. J. Clin. Invest. 12, 485-491), it was po ssible then to select compounds with permeabilities comparable to mann itol for oral (intraduodenal) evaluation in conscious dogs. The influe nce of intestinal permeability on oral efficacy can be observed within a series of compounds with closely related structures, but is less di scernable in across structural series. Intestinal permeability data ca n provide meaningful, reliable data that can help in analog design and in the selection of compounds for oral evaluation.