The use of rabbit intestinal permeability as an in vitro assay in the search for orally active GPIIb/IIIa antagonists

A series of potent, high affinity GPIIb/IIIa antagonists were evaluated 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 general, modifications that would contribute to lipophilicity (e.g. olefinic replacement for amide, phenethyl or isopropyl for methyl) did not enhance permeability. When these intestinal permeabilities were compared to mannitol, which displays similar to 20% oral bioavailability in humans (Laker et al. (1982) fur. J. Clin. Invest. 12, 485-491), it was possible then to select compounds with permeabilities comparable to mannitol for oral (intraduodenal) evaluation in conscious dogs. The influence of intestinal permeability on oral efficacy can be observed within a series of compounds with closely related structures, but is less discernable in across structural series. Intestinal permeability data can provide meaningful, reliable data that can help in analog design and in the selection of compounds for oral evaluation.