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 f lux of heparin was tested in the following groups: i) heparin alone, i i) heparin in the presence of SNAG, iii) heparin in the presence of pr opylene glycol (PG), and iv) heparin in the presence of SNAG and PG. H eparin 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. Res ults. In the rat ileal and colonic in situ instillations SNAG (17-35mg ) promoted heparin absorption in the presence and absence of PG withou t damaging the tissue. PG done did not alter heparin absorption in sit u, but it amplified the effect of SNAG. In Caco-2, enhanced heparin fl uxes 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. Tra nsport of SNAG was significantly reduced in the presence of heparin an d/or PG, perhaps indicating physical association between the agents. C onclusions. SNAG augmented heparin absorption alone and in combination with PG in the rat in situ models without causing toxicity. Caco-2 ha d limitations for testing increased heparin absorption due to cytotoxi c effects of high concentrations of SNAG and PG. However, SNAG itself was well absorbed across Caco-2 and its mechanism of permeation was de termined.