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Evaluation of intestinal absorption enhancement and local mucosal toxicity of two promoters. I. Studies in isolated rat and human colonic mucosae.
Eur J Pharm Sci. 2009 Nov 05; 38(4):291-300.EJ

Abstract

The effects of two absorption promoters, (sodium caprate (C(10)) and melittin), on intestinal permeability and viability were measured in intact rat and human colonic epithelia mounted in Ussing chambers. Apical-side addition of C(10) (10 mM) and melittin (10-50 microM) rapidly reduced the transepithelial electrical resistance (TEER) and increased the apparent permeability coefficient (Papp) of [(14)C]-mannitol and FITC-dextran-4 kDa (FD4) across colonic mucosae from both species. Effects of C(10) on flux were greater than those of melittin at the concentrations selected. C(10) irreversibly decreased TEER, but the effects of melittin were partially reversible. Enhanced permeability of polar sugars (0.18-70 kDa) in colonic mucosae with C(10) was accompanied by significant release of lactate dehydrogenase (LDH) from the luminal surface as well as by inhibition of electrogenic chloride secretion induced by the muscarinic agonist, carbachol (0.1-10 microM). Although melittin did not alter electrogenic chloride secretion in rat or human colonic mucosae, it caused leakage of LDH from rat tissue. Gross histology and electron microscopy of rat and human colonic mucosae demonstrated that each permeation enhancer can induce colonic epithelial damage at concentrations required to increase marker fluxes. C(10) led to more significant mucosal damage than melittin, characterised by sloughing and mucosal erosion. Overall, these results indicate that while C(10) and melittin increase transport of paracellular flux markers across isolated human and rat colonic mucosae in vitro, these effects are associated with some cytotoxicity.

Authors+Show Affiliations

UCD School of Agriculture, Food Science and Veterinary Medicine and UCD Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19737613

Citation

Maher, Sam, et al. "Evaluation of Intestinal Absorption Enhancement and Local Mucosal Toxicity of Two Promoters. I. Studies in Isolated Rat and Human Colonic Mucosae." European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences, vol. 38, no. 4, 2009, pp. 291-300.
Maher S, Kennelly R, Bzik VA, et al. Evaluation of intestinal absorption enhancement and local mucosal toxicity of two promoters. I. Studies in isolated rat and human colonic mucosae. Eur J Pharm Sci. 2009;38(4):291-300.
Maher, S., Kennelly, R., Bzik, V. A., Baird, A. W., Wang, X., Winter, D., & Brayden, D. J. (2009). Evaluation of intestinal absorption enhancement and local mucosal toxicity of two promoters. I. Studies in isolated rat and human colonic mucosae. European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences, 38(4), 291-300. https://doi.org/10.1016/j.ejps.2009.09.001
Maher S, et al. Evaluation of Intestinal Absorption Enhancement and Local Mucosal Toxicity of Two Promoters. I. Studies in Isolated Rat and Human Colonic Mucosae. Eur J Pharm Sci. 2009 Nov 5;38(4):291-300. PubMed PMID: 19737613.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Evaluation of intestinal absorption enhancement and local mucosal toxicity of two promoters. I. Studies in isolated rat and human colonic mucosae. AU - Maher,Sam, AU - Kennelly,Rory, AU - Bzik,Victoria A, AU - Baird,Alan W, AU - Wang,Xuexuan, AU - Winter,Desmond, AU - Brayden,David J, Y1 - 2009/09/06/ PY - 2009/03/08/received PY - 2009/08/04/revised PY - 2009/09/01/accepted PY - 2009/9/10/entrez PY - 2009/9/10/pubmed PY - 2010/6/4/medline SP - 291 EP - 300 JF - European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences JO - Eur J Pharm Sci VL - 38 IS - 4 N2 - The effects of two absorption promoters, (sodium caprate (C(10)) and melittin), on intestinal permeability and viability were measured in intact rat and human colonic epithelia mounted in Ussing chambers. Apical-side addition of C(10) (10 mM) and melittin (10-50 microM) rapidly reduced the transepithelial electrical resistance (TEER) and increased the apparent permeability coefficient (Papp) of [(14)C]-mannitol and FITC-dextran-4 kDa (FD4) across colonic mucosae from both species. Effects of C(10) on flux were greater than those of melittin at the concentrations selected. C(10) irreversibly decreased TEER, but the effects of melittin were partially reversible. Enhanced permeability of polar sugars (0.18-70 kDa) in colonic mucosae with C(10) was accompanied by significant release of lactate dehydrogenase (LDH) from the luminal surface as well as by inhibition of electrogenic chloride secretion induced by the muscarinic agonist, carbachol (0.1-10 microM). Although melittin did not alter electrogenic chloride secretion in rat or human colonic mucosae, it caused leakage of LDH from rat tissue. Gross histology and electron microscopy of rat and human colonic mucosae demonstrated that each permeation enhancer can induce colonic epithelial damage at concentrations required to increase marker fluxes. C(10) led to more significant mucosal damage than melittin, characterised by sloughing and mucosal erosion. Overall, these results indicate that while C(10) and melittin increase transport of paracellular flux markers across isolated human and rat colonic mucosae in vitro, these effects are associated with some cytotoxicity. SN - 1879-0720 UR - https://www.unboundmedicine.com/medline/citation/19737613/Evaluation_of_intestinal_absorption_enhancement_and_local_mucosal_toxicity_of_two_promoters__I__Studies_in_isolated_rat_and_human_colonic_mucosae_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0928-0987(09)00245-0 DB - PRIME DP - Unbound Medicine ER -