Dataset Information

Altered Intestinal Permeability and Drug Repositioning in a Post-operative Ileus Guinea Pig Model.

ABSTRACT:

Background/aims

The aim of this study is to identify the alteration in intestinal permeability with regard to the development of post-operative ileus (POI). Moreover, we investigated drug repositioning in the treatment of POI.

Methods

An experimental POI model was developed using guinea pigs. To measure intestinal permeability, harvested intestinal membranes of the ileum and proximal colon was used in an Ussing chamber. To identify the mechanisms associated with altered permeability, we measured leukocyte count and expression of calprotectin, claudin-1, claudin-2, and mast cell tryptase. We compared control, POI, and drug groups (mosapride [0.3 mg/kg and 1 mg/kg, orally], glutamine [500 mg/kg, orally], or ketotifen [1 mg/kg, orally] with regard to these parameters.

Results

Increased permeability after surgery significantly decreased after administration of mosapride, glutamine, or ketotifen. Leukocyte counts increased in the POI group and decreased significantly after administration of mosapride (0.3 mg/kg) in the ileum, and mosapride (0.3 mg/kg and 1 mg/kg), glutamine, or ketotifen in the proximal colon. Increased expression of calprotectin after surgery decreased after administration of mosapride (0.3 mg/kg), glutamine, or ketotifen in the ileum and proximal colon, and mosapride (1 mg/kg) in the ileum. The expression of claudin-1 decreased significantly and that of claudin-2 increased after operation. After administration of glutamine, the expression of both proteins was restored. Finally, mast cell tryptase levels increased in the POI group and decreased significantly after administration of ketotifen.

Conclusions

The alteration in intestinal permeability is one of the factors involved in the pathogenesis of POI. We repositioned 3 drugs (mosapride, glutamine, and ketotifen) as novel therapeutic agents for POI.

SUBMITTER: Kim YM

PROVIDER: S-EPMC8521477 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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Publications

Altered Intestinal Permeability and Drug Repositioning in a Post-operative Ileus Guinea Pig Model.

Kim Young Min YM Hussain Zahid Z Lee Young Ju YJ Park Hyojin H

Journal of neurogastroenterology and motility 20211001 4

<h4>Background/aims</h4>The aim of this study is to identify the alteration in intestinal permeability with regard to the development of post-operative ileus (POI). Moreover, we investigated drug repositioning in the treatment of POI.<h4>Methods</h4>An experimental POI model was developed using guinea pigs. To measure intestinal permeability, harvested intestinal membranes of the ileum and proximal colon was used in an Ussing chamber. To identify the mechanisms associated with altered permeabili ...[more]

PMID: 34642285

Similar Datasets

Project description:BackgroundUnderstanding the quantitative relationship between a drug's physical chemical properties and its rate of intestinal absorption (QSAR) is critical for selecting candidate drugs. Because of limited experimental human small intestinal permeability data, approximate surrogates such as the fraction absorbed or Caco-2 permeability are used, both of which have limitations.MethodsGiven the blood concentration following an oral and intravenous dose, the time course of intestinal absorption in humans was determined by deconvolution and related to the intestinal permeability by the use of a new 3 parameter model function ("Averaged Model" (AM)). The theoretical validity of this AM model was evaluated by comparing it to the standard diffusion-convection model (DC). This analysis was applied to 90 drugs using previously published data. Only drugs that were administered in oral solution form to fasting subjects were considered so that the rate of gastric emptying was approximately known. All the calculations are carried out using the freely available routine PKQuest Java (http://www.pkquest.com) which has an easy to use, simple interface.ResultsTheoretically, the AM permeability provides an accurate estimate of the intestinal DC permeability for solutes whose absorption ranges from 1% to 99%. The experimental human AM permeabilities determined by deconvolution are similar to those determined by direct human jejunal perfusion. The small intestinal pH varies with position and the results are interpreted in terms of the pH dependent octanol partition. The permeability versus partition relations are presented separately for the uncharged, basic, acidic and charged solutes. The small uncharged solutes caffeine, acetaminophen and antipyrine have very high permeabilities (about 20 x 10-4 cm/sec) corresponding to an unstirred layer of only 45 μm. The weak acid aspirin also has a large AM permeability despite its low octanol partition at pH 7.4, suggesting that it is nearly completely absorbed in the first part of the intestine where the pH is about 5.4.ConclusionsThe AM deconvolution method provides an accurate estimate of the human intestinal permeability. The results for these 90 drugs should provide a useful benchmark for evaluating QSAR models.

Dataset Information

Altered Intestinal Permeability and Drug Repositioning in a Post-operative Ileus Guinea Pig Model.

Background/aims

Methods

Results

Conclusions

Publications

Altered Intestinal Permeability and Drug Repositioning in a Post-operative Ileus Guinea Pig Model.

Similar Datasets

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