期刊
EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS
卷 94, 期 -, 页码 194-206出版社
ELSEVIER
DOI: 10.1016/j.ejpb.2015.05.013
关键词
Oral peptide delivery; Medium chain fatty acids; Sodium caprate; Caco-2 monolayers; Intestinal permeation enhancers; Cytotoxicity assays
资金
- Science Foundation Ireland (SFI) Strategic Research Cluster Grant (Irish Drug Delivery Network) [07/SRC/B1154]
- Irish Research Council
- Merrion Pharmaceuticals Ireland Ltd
Epithelial damage caused by intestinal permeation enhancers is a source of debate concerning safety. The medium chain fatty acid, sodium caprate (C-10), 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 8.5 mM C-10 for 60 min followed by incubation in fresh buffer led to (i) recovery in epithelial permeability (i.e. transepithelial electrical resistance (TEER) and apparent permeability coefficient (P-app) of [C-14]-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 C-10. Misoprostol (100 nM), inhibited C-10-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, C-10-induced respective increases in the [C-14]-mannitol P-app 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 C-10, which is linked to its capacity to mainly increase paracellular flux, but which can be prevented by pre-exposure to misoprostol. (C) 2015 Elsevier BM. All rights reserved.
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