Restoration of Rat Colonic Epithelium After
            <i>In Situ</i>
            Intestinal Instillation of the Absorption promoter, Sodium Caprate

Wang, Xuexuan; Maher, Sam; Brayden, David J.

doi:10.4155/tde.10.5

Cited by 47 publications

(32 citation statements)

References 34 publications

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“…Mucosa histology also shows a perturbation of the intestinal and colonic epithelia, comparable to previous studies investigating these MCFA (23). Repair is possible following transient mild damage to the tissue in intact in situ rat intestinal instillations using similar enhancers, which caused similar initial perturbation (38).…”

Section: Discussionsupporting

confidence: 82%

Stability, toxicity and intestinal permeation enhancement of two food-derived antihypertensive tripeptides, Ile-Pro-Pro and Leu-Lys-Pro

et al. 2015

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Publication information Peptides, 71 : 1-7Publisher Elsevier Item record/more information http://hdl.handle.net/10197/8723 Publisher's statementThis is the author's version of a work that was accepted for publication in Peptides. 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 Peptides (VOL 71, ISSUE 2015, (2015 colonic mucosae were low, but were significantly increased in each tissue type by the medium chain fatty acids (MCFA) permeation enhancers, sodium caprate (C 10 ) and the sodium salt of 10-undecylenic acid (uC 11 ). IPP and LKP were therefore stable against intestinal and liver peptidases and were non-cytotoxic; their P app values across rat intestinal mucosae were low, but could be increased by MCFA. There is potential to make on oral dosage form once in vivo pharmacology is confirmed.

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Section: Discussionsupporting

confidence: 82%

Stability, toxicity and intestinal permeation enhancement of two food-derived antihypertensive tripeptides, Ile-Pro-Pro and Leu-Lys-Pro

et al. 2015

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“…39 The peptides may then traverse either paracellularly, and/or transcellularly in mixed micelles with bile salts, although evidence for the latter pathway is yet to be fully deciphered. 40 It is known that the concentration of PE and the time it is in contact with the epithelia plays a role in the extent of the perturbation caused.…”

Section: Damage and Repairmentioning

confidence: 99%

“…In the in situ intestinal instillation rat model, repair occurred within 30-60 min; due to an intact mesenteric blood supply, this was much faster than in the in vitro models. 39 In the in situ study, fluorescein isothiocyanate-labeled dextran (4 kDa) (FD4) was instilled either at the same time or 10, 30 or 60 min following addition of C 10 . The highest absolute bioavailability (33%) and membrane perturbation was seen when C 10 and FD4 were coadministered together, whereas FD4 instilled 60min after C 10 had a bioavailability of just 4% .…”

Section: Pe-induced Intestinal Epithelial Damagementioning

confidence: 99%

Safety concerns over the use of intestinal permeation enhancers: A mini-review

2016

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Intestinal permeation enhancers (PEs) are key components in »12 oral peptide formulations in clinical trials for a range of molecules, primarily insulin and glucagon-like-peptide 1 (GLP-1) analogs. The main PEs comprise medium chain fatty acid-based systems (sodium caprate, sodium caprylate, and N-[8-(2-hydroxybenzoyl) amino] caprylate (SNAC)), bile salts, acyl carnitines, and EDTA. Their mechanism of action is complex with subtle differences between the different molecules. With the exception of SNAC and EDTA, most PEs fluidize the plasma membrane causing plasma membrane perturbation, as well as enzymatic and intracellular mediator changes that lead to alteration of intestinal epithelial tight junction protein expression. The question arises as to whether PEs can cause irreversible epithelial damage and tight junction openings sufficient to permit co-absorption of payloads with bystander pathogens, lipopolysaccharides and its fragment, or exo-and endotoxins that may be associated with sepsis, inflammation and autoimmune conditions. Most PEs seem to cause membrane perturbation to varying extents that is rapidly reversible, and overall evidence of pathogen co-absorption is generally lacking. It is unknown however, whether the intestinal epithelial damage-repair cycle is sustained during repeat-dosing regimens for chronic therapy.

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“…concentrations of the same order as those required to induce permeation enhancement in rat intestinal instillations (9), suggesting relatively narrow safety margins for repeat oral dosing regimens. This would suggest that new enhancers are needed where, if possible, permeation enhancement and mucosal damage can be more clearly dissociated across a wider dose range.…”

Section: Introductionmentioning

confidence: 99%

Efficacious Intestinal Permeation Enhancement Induced by the Sodium Salt of 10-undecylenic Acid, A Medium Chain Fatty Acid Derivative

Brayden

Walsh

2014

AAPS J

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ABSTRACT. 10-undecylenic acid (UA) is an OTC antifungal therapy and a nutritional supplement. It is an unsaturated medium chain fatty acid (MCFA) derivative, so our hypothesis was that its 11-mer sodium salt, uC 11 , would improve intestinal permeation similar to the established enhancer, sodium caprate (C 10 ), but without the toxicity of the parent saturated MCFA, decylenic acid (C 11 ). MTT assay and high-content screening (HCS) confirmed a cytotoxicity ranking in Caco-2 cells: C 11 >C 10 =uC 11 . Five to ten millimolars of the three agents reduced TEER and increased the Papp of [ 14 C]-mannitol across Caco-2 monolayers and rat intestinal mucosae, a concentration that matched increases in plasma membrane permeability seen in HCS. Although C 11 was the most efficacious enhancer in vitro, it damaged monolayers and tissue mucosae more than the other two agents at similar concentrations and exposure times and was therefore not pursued further. Rat jejunal and colonic in situ intestinal instillations of 100 mM C 10 or uC 11 with FITC-dextran 4000 (FD4) solutions yielded comparable regional enhancement ratios of~10 and 30%, respectively, for each agent with acceptable tissue histology. Mini-tablets of uC 11 and FD4 however delivered more FD4 compared to C 10 -FD-4 mini-tablets in both regions, as reflected by a statistically higher AUC, and with no evidence of membrane perturbation. The unsaturated bond in uC 11 therefore confers a reduction in lipophilicity and cytotoxicity compared to C 11 , and the resulting permeation enhancement is on a par with or superior to that of C 10 , a key component of formulations in current phase II oral peptide clinical trials.

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Restoration of Rat Colonic Epithelium After In Situ Intestinal Instillation of the Absorption promoter, Sodium Caprate

Abstract: Publication informationTherapeutic Delivery, 1 (

Cited by 47 publications

References 34 publications

Stability, toxicity and intestinal permeation enhancement of two food-derived antihypertensive tripeptides, Ile-Pro-Pro and Leu-Lys-Pro

Stability, toxicity and intestinal permeation enhancement of two food-derived antihypertensive tripeptides, Ile-Pro-Pro and Leu-Lys-Pro

Safety concerns over the use of intestinal permeation enhancers: A mini-review

Efficacious Intestinal Permeation Enhancement Induced by the Sodium Salt of 10-undecylenic Acid, A Medium Chain Fatty Acid Derivative

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