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Sodium caprate-induced increases in intestinal permeability and epithelial damage are prevented by misoprostol.
Eur J Pharm Biopharm. 2015 Aug; 94:194-206.EJ

Abstract

Epithelial damage caused by intestinal permeation enhancers is a source of debate concerning safety. The medium chain fatty acid, sodium caprate (C10), causes reversible membrane perturbation at high dose levels required for efficacy in vivo, so the aim was to model it in vitro. Exposure of Caco-2 monolayers to 8.5mM C10 for 60min followed by incubation in fresh buffer led to (i) recovery in epithelial permeability (i.e. transepithelial electrical resistance (TEER) and apparent permeability coefficient (Papp) of [(14)C]-mannitol), (ii) recovery of cell viability parameters (monolayer morphology, plasma membrane potential, mitochondrial membrane potential, and intracellular calcium) and (iii) reduction in mRNA expression associated with inflammation (IL-8). Pre-incubation of monolayers with a mucosal prostaglandin cytoprotectant was attempted in order to further decipher the mechanism of C10. Misoprostol (100nM), inhibited C10-induced changes in monolayer parameters, an effect that was partially attenuated by the EP1 receptor antagonist, SC51322. In rat isolated intestinal tissue mucosae and in situ loop instillations, C10-induced respective increases in the [(14)C]-mannitol Papp and the AUC of FITC-dextran 4000 (FD-4) were similarly inhibited by misoprostol, with accompanying morphological damage spared. These data support a temporary membrane perturbation effect of C10, which is linked to its capacity to mainly increase paracellular flux, but which can be prevented by pre-exposure to misoprostol.

Authors+Show Affiliations

School of Veterinary Medicine and Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland. Electronic address: david.brayden@ucd.ie.School of Veterinary Medicine and Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland.School of Veterinary Medicine and Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland.School of Veterinary Medicine and Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland.

Pub Type(s)

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

Language

eng

PubMed ID

26026287

Citation

Brayden, David J., et al. "Sodium Caprate-induced Increases in Intestinal Permeability and Epithelial Damage Are Prevented By Misoprostol." European Journal of Pharmaceutics and Biopharmaceutics : Official Journal of Arbeitsgemeinschaft Fur Pharmazeutische Verfahrenstechnik E.V, vol. 94, 2015, pp. 194-206.
Brayden DJ, Maher S, Bahar B, et al. Sodium caprate-induced increases in intestinal permeability and epithelial damage are prevented by misoprostol. Eur J Pharm Biopharm. 2015;94:194-206.
Brayden, D. J., Maher, S., Bahar, B., & Walsh, E. (2015). Sodium caprate-induced increases in intestinal permeability and epithelial damage are prevented by misoprostol. European Journal of Pharmaceutics and Biopharmaceutics : Official Journal of Arbeitsgemeinschaft Fur Pharmazeutische Verfahrenstechnik E.V, 94, 194-206. https://doi.org/10.1016/j.ejpb.2015.05.013
Brayden DJ, et al. Sodium Caprate-induced Increases in Intestinal Permeability and Epithelial Damage Are Prevented By Misoprostol. Eur J Pharm Biopharm. 2015;94:194-206. PubMed PMID: 26026287.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Sodium caprate-induced increases in intestinal permeability and epithelial damage are prevented by misoprostol. AU - Brayden,David J, AU - Maher,Sam, AU - Bahar,Bojlul, AU - Walsh,Edwin, Y1 - 2015/05/27/ PY - 2015/04/06/received PY - 2015/05/19/revised PY - 2015/05/20/accepted PY - 2015/6/1/entrez PY - 2015/6/1/pubmed PY - 2016/5/18/medline KW - Caco-2 monolayers KW - Cytotoxicity assays KW - Intestinal permeation enhancers KW - Medium chain fatty acids KW - Oral peptide delivery KW - Sodium caprate SP - 194 EP - 206 JF - European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V JO - Eur J Pharm Biopharm VL - 94 N2 - Epithelial damage caused by intestinal permeation enhancers is a source of debate concerning safety. The medium chain fatty acid, sodium caprate (C10), causes reversible membrane perturbation at high dose levels required for efficacy in vivo, so the aim was to model it in vitro. Exposure of Caco-2 monolayers to 8.5mM C10 for 60min followed by incubation in fresh buffer led to (i) recovery in epithelial permeability (i.e. transepithelial electrical resistance (TEER) and apparent permeability coefficient (Papp) of [(14)C]-mannitol), (ii) recovery of cell viability parameters (monolayer morphology, plasma membrane potential, mitochondrial membrane potential, and intracellular calcium) and (iii) reduction in mRNA expression associated with inflammation (IL-8). Pre-incubation of monolayers with a mucosal prostaglandin cytoprotectant was attempted in order to further decipher the mechanism of C10. Misoprostol (100nM), inhibited C10-induced changes in monolayer parameters, an effect that was partially attenuated by the EP1 receptor antagonist, SC51322. In rat isolated intestinal tissue mucosae and in situ loop instillations, C10-induced respective increases in the [(14)C]-mannitol Papp and the AUC of FITC-dextran 4000 (FD-4) were similarly inhibited by misoprostol, with accompanying morphological damage spared. These data support a temporary membrane perturbation effect of C10, which is linked to its capacity to mainly increase paracellular flux, but which can be prevented by pre-exposure to misoprostol. SN - 1873-3441 UR - https://www.unboundmedicine.com/medline/citation/26026287/Sodium_caprate_induced_increases_in_intestinal_permeability_and_epithelial_damage_are_prevented_by_misoprostol_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0939-6411(15)00245-3 DB - PRIME DP - Unbound Medicine ER -