Heparin absorption across the intestine:: Effects of sodium N-[8-(2-hydroxybenzoyl)amino]caprylate in rat in situ intestinal instillations and in Caco-2 monolayers

Purpose. The effects of sodium N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAG) on heparin intestinal absorption were studied using rat in situ ileal and colonic instillations and Caco-2 monolayers. Methods. The flux of heparin was tested in the following groups: i) heparin alone, ii) heparin in the presence of SNAG, iii) heparin in the presence of propylene glycol (PG), and iv) heparin in the presence of SNAG and PG. Heparin absorption was measured by the APTT assay in the in situ models and by the anti-Factor Xa assay in Caco-2. SNAG and [H-3]-SNAC fluxes were assessed by HPLC and by scintillation counting respectively. Results. In the rat ileal and colonic in situ instillations SNAG (17-35mg) promoted heparin absorption in the presence and absence of PG without damaging the tissue. PG done did not alter heparin absorption in situ, but it amplified the effect of SNAG. In Caco-2, enhanced heparin fluxes were variable in the presence of non-cytotoxic concentrations of SNAG (<10mg/ml and these effects could not be discriminated from those of PG. Papp values for SNAG alone were 2.2 x 10(-5) cm/s and 2.0 x 10(-5) cm/s in the mucosal-to-serosal and serosal-to-mucosal directions respectively, suggesting a substantial passive transcellular flux. Transport of SNAG was significantly reduced in the presence of heparin and/or PG, perhaps indicating physical association between the agents. Conclusions. SNAG augmented heparin absorption alone and in combination with PG in the rat in situ models without causing toxicity. Caco-2 had limitations for testing increased heparin absorption due to cytotoxic effects of high concentrations of SNAG and PG. However, SNAG itself was well absorbed across Caco-2 and its mechanism of permeation was determined.