Effects of surfactant-based permeation enhancers on mannitol permeability, histology, and electrogenic ion transport responses in excised rat colonic mucosae

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dc.contributor.authorMaher, Sam-
dc.contributor.authorHeade, Joanne-
dc.contributor.authorMcCartney, Fiona-
dc.contributor.authorBrayden, David James-
dc.contributor.authoret al.-
dc.date.copyright2018 Elsevieren_US
dc.identifier.citationInternational Journal of Pharmaceuticsen_US
dc.description.abstractSurfactant-based intestinal permeation enhancers (PEs) are constituents of several oral macromolecule formulations in clinical trials. This study examined the interaction of a test panel of surfactant-based-PEs with isolated rat colonic mucosae mounted in Ussing chambers in an attempt to determine if increases in transepithelial permeability can be separated from induction of mucosal perturbation. The aim was to establish assess if increases in permeability (i) intestinal permeability (the apparent permeability coefficient (Papp) of [14C]-mannitol), (ii) epithelial histology, and (iii) short-circuit current (ΔIsc) responses to a cholinomimetic (carbachol, CCh). Enhancement ratio increases for Papp values followed the order: C10 > C9 = C11:1 > a bile salt blend > sodium choleate > sucrose laurate > Labrasol® >C12E8 > C12 > Cremophor® A25 > C7 > sucrose stearate > Kolliphor® HS15 > Kolliphor® TPGS. Exposures that increased the Papp by ≥2-fold over 120 min were accompanied by histological damage in 94% of tissues, and by a decreased ΔIsc response to CCh of 83%. A degree of separation between the increased Papp of [14C]-mannitol, histological damage, and diminution of the ΔIsc response to CCh was observed at selected PE concentrations (e.g. Labrasol® at 2 mg/mL). Overall, this surfactant-based PE selection caused transcellular perturbation at similar concentrations to those that enhanced permeability.en_US
dc.description.sponsorshipEuropean Commission - European Regional Development Funden_US
dc.description.sponsorshipIrish Research Councilen_US
dc.description.sponsorshipScience Foundation Irelanden_US
dc.rightsThis is the author’s version of a work that was accepted for publication in International Journal of Pharmaceuticals. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in International Journal of Pharmaceuticals (VOL 539, ISSUE 1-2, (March 25 2018)) DOI:https://doi.org/10.1016/j.ijpharm.2018.01.008en_US
dc.subjectUssing chamberen_US
dc.subjectIntestinal permeation enhancersen_US
dc.subjectSurfactant toxicityen_US
dc.subjectIntestinal epithelial damageen_US
dc.titleEffects of surfactant-based permeation enhancers on mannitol permeability, histology, and electrogenic ion transport responses in excised rat colonic mucosaeen_US
dc.typeJournal Articleen_US
dc.statusPeer revieweden_US
dc.neeo.contributorMaher S|Heade J, McCartney F, Waters S, Bleiel SB, Brayden DJ|aut|-
dc.description.othersponsorshipAnaBio Technologies Ltden_US
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