Zonula occludens toxin synthetic peptide derivative AT1002 enhances in vitro and in vivo intestinal absorption of low molecular weight heparin.

摘要

Zonula occludens toxin (Zot) is an enterotoxin obtained from the bacterium vibrio cholerae that has been shown to reversibly and safely open the tight junctions and enhance paracellular transport. AT1002 is a novel synthetic hexapeptide derived from Zot. The hypothesis to be tested in this study is that AT1002 enhances the oral absorption of ardeparin, a low molecular weight heparin (LMWH). To test this hypothesis, drug transport through Caco-2 cell monolayers was monitored in the presence and absence of AT1002. Regional permeability studies using rat intestine were performed. Cell viability in the presence of various concentrations of enhancer was determined. The absorption of ardeparin after oral administration in rats was measured by anti-factor Xa assay. Furthermore, the eventual mucosal and epithelial damage was histologically evaluated. Higher ardeparin permeability (approximately 2-fold) compared to control was observed in the presence of 0.025% of AT1002. Regional permeability studies revealed that the permeability of ardeparin across the duodenal membrane was improved by the AT1002. Cell viability studies showed no significant cytotoxicity below 0.0028% of AT1002. In the presence of 100 microg/kg of AT1002, ardeparin oral bioavailability was significantly increased (F(relative/s.c) approximately 20.5%). Furthermore, AT1002 at a dose of 100 microg/kg did not induce any observable morphological damage on gastrointestinal (GI) tissues in vivo. These in vivo and in vitro results suggest that the co-administration of LMWH with AT1002 may be a useful delivery strategy to increase its permeability and hence oral absorption.