caa a22 4500 477126553 CHVBK 20180405111651.0 cr unu---uuuuu 170330e19971201xx s 000 0 eng 10.1023/A:1012192115828 doi (NATIONALLICENCE)springer-10.1023/A:1012192115828 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 [Elektronische Daten] [David Brayden, Elizabeth Creed, Alan O'Connell, Harry Leipold, Rajesh Agarwal, Andrea Leone-Bay] Purpose. The effects of sodium N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC) 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 SNAC, iii) heparin in the presence of propylene glycol (PG), and iv) heparin in the presence of SNAC 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. SNAC and [3H]-SNAC fluxes were assessed by HPLC and by scintillation counting respectively. Results. In the rat ileal and colonic in situ instillations SNAC (17−35mg) promoted heparin absorption in the presence and absence of PG without damaging the tissue. PG alone did not alter heparin absorption in situ, but it amplified the effect of SNAC. In Caco-2, enhanced heparin fluxes were variable in the presence of non-cytotoxic concentrations of SNAC (< l0mg/ml) and these effects could not be discriminated from those of PG. Papp values for SNAC alone were 2.2 × 10−5 cm/s and 2.0 × 10−5 cm/s in the mucosal-to-serosal and serosal-to-mucosal directions respectively, suggesting a substantial passive transcellular flux. Transport of SNAC was significantly reduced in the presence of heparin and/or PG, perhaps indicating physical association between the agents. Conclusions. SNAC 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 SNAC and PG. However, SNAC itself was well absorbed across Caco-2 and its mechanism of permeation was determined. Plenum Publishing Corporation, 1997 heparin absorption nationallicence amido acid nationallicence rat intestinal instillation nationallicence Caco-2 nationallicence Brayden David Elan Pharmaceutical Technologies, Trinity College, 2, Dublin, Ireland aut Creed Elizabeth Elan Pharmaceutical Technologies, Trinity College, 2, Dublin, Ireland aut O'Connell Alan Elan Pharmaceutical Technologies, Trinity College, 2, Dublin, Ireland aut Leipold Harry Emisphere Technologies, Inc., 15 Skyline Drive, 10532, Hawthorne, New York aut Agarwal Rajesh Emisphere Technologies, Inc., 15 Skyline Drive, 10532, Hawthorne, New York aut Leone-Bay Andrea Emisphere Technologies, Inc., 15 Skyline Drive, 10532, Hawthorne, New York aut Pharmaceutical Research Kluwer Academic Publishers-Plenum Publishers 14/12(1997-12-01), 1772-1779 0724-8741 14:12<1772 1997 14 11095 https://doi.org/10.1023/A:1012192115828 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1023/A:1012192115828 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Brayden David Elan Pharmaceutical Technologies, Trinity College, 2, Dublin, Ireland aut NATIONALLICENCE 700 1- Creed Elizabeth Elan Pharmaceutical Technologies, Trinity College, 2, Dublin, Ireland aut NATIONALLICENCE 700 1- O'Connell Alan Elan Pharmaceutical Technologies, Trinity College, 2, Dublin, Ireland aut NATIONALLICENCE 700 1- Leipold Harry Emisphere Technologies, Inc., 15 Skyline Drive, 10532, Hawthorne, New York aut NATIONALLICENCE 700 1- Agarwal Rajesh Emisphere Technologies, Inc., 15 Skyline Drive, 10532, Hawthorne, New York aut NATIONALLICENCE 700 1- Leone-Bay Andrea Emisphere Technologies, Inc., 15 Skyline Drive, 10532, Hawthorne, New York aut NATIONALLICENCE 773 0- Pharmaceutical Research Kluwer Academic Publishers-Plenum Publishers 14/12(1997-12-01), 1772-1779 0724-8741 14:12<1772 1997 14 11095 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer