The effect of ΔG on the transport and oral absorption of macromolecules

Salama, Noha N.; Fasano, Alessio; Thakar, Manjusha; Eddington, Natalie D.

doi:10.1002/jps.20052

Cited by 37 publications

(28 citation statements)

References 37 publications

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“…36 In vitro studies showed that ⌬G is capable of significantly increasing the apparent permeability coefficients for a wide variety of therapeutic agents and markers across the Caco-2 cell model. [72][73][74] In addition, ⌬G improved the bioavailability of paracellular markers, mannitol, inulin, and PEG4000 after intraduodenal administration to rats. 72,73 The transport/absorption of different therapeutic agents exhibiting different physicochemical properties (lipophilicity/hydrophilicity, molecular weights, efflux properties, structural differences) and belonging to a wide range of drug classes was tested with ⌬G.…”

Section: Therapeutic Use Of the Zonulin Systemmentioning

confidence: 99%

“…[72][73][74] In addition, ⌬G improved the bioavailability of paracellular markers, mannitol, inulin, and PEG4000 after intraduodenal administration to rats. 72,73 The transport/absorption of different therapeutic agents exhibiting different physicochemical properties (lipophilicity/hydrophilicity, molecular weights, efflux properties, structural differences) and belonging to a wide range of drug classes was tested with ⌬G. For example, when the anti-HIV protease inhibitors were administered orally to Sprague Dawley rats with ⌬G, the rate and/or extent of drug absorption were significantly ameliorated, with the exception of drugs such as saquinavir, whose low oral bioavailability is mainly attributable to extensive first pass metabolism.…”

Section: Therapeutic Use Of the Zonulin Systemmentioning

confidence: 99%

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Physiological, Pathological, and Therapeutic Implications of Zonulin-Mediated Intestinal Barrier Modulation

Fasano

2008

The American Journal of Pathology

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The anatomical and functional arrangement of the gastrointestinal tract suggests that this organ, beside its digestive and absorptive functions, regulates the trafficking of macromolecules between the environment and the host through a barrier mechanism. Under physiological circumstances, this trafficking is safeguarded by the competency of intercellular tight junctions, structures whose physiological modulation is mediated by, among others, the recently described protein zonulin. To prevent harm and minimize inflammation, the same paracellular pathway, in concert with the gut-associated lymphoid tissue and the neuroendocrine network, controls the equilibrium between tolerance and immunity to nonself antigens. The zonulin pathway has been exploited to deliver drugs, macromolecules, or vaccines that normally would not be absorbed through the gastrointestinal mucosal barrier. However, if the tightly regulated trafficking of macromolecules is jeopardized secondary to prolonged zonulin up-regulation, the excessive flow of nonself antigens in the intestinal submucosa can cause both intestinal and extraintestinal autoimmune disorders in genetically susceptible individuals. This new paradigm subverts traditional theories underlying the development of autoimmunity, which are based on molecular mimicry and/or the bystander effect, and suggests that the autoimmune process can be arrested if the interplay between genes and environmental triggers is prevented by reestablishing intestinal barrier competency. Understanding the role of zonulin-dependent intestinal barrier dysfunction in the pathogenesis of autoimmune diseases is an area of translational research that encompasses many fields. The intestinal epithelium is the largest mucosal surface, providing an interface between the external environment and the mammalian host. Its exquisite anatomical and functional arrangements and the finely-tuned coordination of digestive, absorptive, motility, neuroendocrine, and immunological functions are testimonial of the complexity of the gastrointestinal (GI) system. Also pivotal is the regulation of molecular trafficking between the intestinal lumen and the submucosa via the paracellular space. The dimensions of the paracellular space are estimated to be between 10 and 15 Å, suggesting that under physiological circumstances, solutes with a molecular radius exceeding 15 Å (ϳ3.5 kDa) will be excluded from this uptake route. Macromolecule trafficking is dictated mainly by intestinal paracellular permeability, the regulation of which depends on the modulation of intercellular tight junctions (TJs). A century ago, TJs were conceptualized as a secreted extracellular cement forming an absolute and unregulated barrier within the paracellular space. The contribution of the paracellular pathway of the GI tract to the general economy of molecule trafficking between environment and host, therefore, was judged to be negligible. It is now apparent that TJs are extremely dynamic structures involved in several key functions of the intestinal epithe...

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Section: Therapeutic Use Of the Zonulin Systemmentioning

confidence: 99%

Section: Therapeutic Use Of the Zonulin Systemmentioning

confidence: 99%

Physiological, Pathological, and Therapeutic Implications of Zonulin-Mediated Intestinal Barrier Modulation

Fasano

2008

The American Journal of Pathology

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“…TEER measurement is a method used frequently to assess the integrity of Caco-2 cell monolayers (Hidalgo et al, 1989;Swaan et al, 1997;Cox et al, 2002;Salama et al, 2003Salama et al, , 2004. TEER was measured each hour over the course of the experiment (5 h).…”

Section: Reversibility Of Transepithelial Electrical Resistance Upon mentioning

confidence: 99%

The Ethanol Metabolite Acetaldehyde Increases Paracellular Drug Permeability In Vitro and Oral Bioavailability In Vivo

Fisher¹,

Swaan²,

Eddington³

2009

J Pharmacol Exp Ther

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Alcohol consumption leads to the production of the highly reactive ethanol metabolite, acetaldehyde, which may affect intestinal tight junctions and increase paracellular permeability. We examined the effects of elevated acetaldehyde within the gastrointestinal tract on the permeability and bioavailability of hydrophilic markers and drug molecules of variable molecular weight and geometry. In vitro permeability was measured unidirectionally in Caco-2 and MDCKII cell models in the presence of acetaldehyde, ethanol, or disulfiram, an aldehyde dehydrogenase inhibitor, which causes acetaldehyde formation when coadministered with ethanol in vivo. Acetaldehyde significantly lowered transepithelial resistance in cell monolayers and increased permeability of the low-molecular-weight markers, mannitol and sucrose; however, permeability of high-molecular-weight markers, polyethylene glycol and inulin, was not affected. In vivo permeability was assessed in male SpragueDawley rats treated for 6 days with ethanol, disulfiram, or saline alone or in combination. Bioavailability of naproxen was not affected by any treatment, whereas that of paclitaxel was increased upon acetaldehyde exposure. Although disulfiram has been shown to inhibit multidrug resistance-1 P-glycoprotein (P-gp) in vitro, our data demonstrate that the known P-gp substrate paclitaxel is not affected by coadministration of disulfiram. In conclusion, we demonstrate that acetaldehyde significantly modulates tight junctions and paracellular permeability in vitro as well as the oral bioavailability of low-molecular-weight hydrophilic probes and therapeutic molecules in vivo even when these molecules are substrates for efflux transporters. These studies emphasize the significance of ethanol metabolism and drug interactions outside of the liver.

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“…However, there are differences in the Zot fragment used, type of cells, protocol for cell studies and the concentrations used which are responsible for the discrepancies observed. Another Zot-derived synthetic peptide has been shown to significantly increase the in vitro transport of paracellular markers in a non-toxic manner (Salama et al 2003(Salama et al ,2004.…”

Section: Transport Of Ardeparin Across Caco-2 Cell Monolayersmentioning

confidence: 99%

“…It is capable of reversibly opening the tight junctions as seen for hydrophilic markers and hydrophobic drugs across the small intestine. Previously, a Zot-derived peptide improved the AUC and Cmax for inulin up to 6.6-and 13-fold, respectively (Salama et al 2004) and the C max and AUC for inulin and PEG up to 57-and 50-fold, respectively (Salama et al 2004). AT1002 also has the potential to act as an absorption enhancer for drugs susceptible to efflux transporters such as cyclosporin A by modification of their transport route.…”

Section: Effects Of At1002 On the Intestinal Absorption Of Ardeparin mentioning

confidence: 99%

RETRACTED: Zonula occludens toxin synthetic peptide derivative AT1002 enhancesin vitroandin vivointestinal absorption of low molecular weight heparin

Motlekar

Fasano

Wachtel

et al. 2006

Journal of Drug Targeting

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Zonula occludens toxin (Zot) is an enterotoxin obtained from the bacterium vibrio cholerae that has been shown to reversibly and safely open the tight junctions and enhance paracellular transport. AT1002 is a novel synthetic hexapeptide derived from Zot. The hypothesis to be tested in this study is that AT1002 enhances the oral absorption of ardeparin, a low molecular weight heparin (LMWH). To test this hypothesis, drug transport through Caco-2 cell monolayers was monitored in the presence and absence of AT1002. Regional permeability studies using rat intestine were performed. Cell viability in the presence of various concentrations of enhancer was determined. The absorption of ardeparin after oral administration in rats was measured by anti-factor Xa assay. Furthermore, the eventual mucosal and epithelial damage was histologically evaluated. Higher ardeparin permeability (~2-fold) compared to control was observed in the presence of 0.025% of AT1002. Regional permeability studies revealed that the permeability of ardeparin across the duodenal membrane was improved by the AT1002. Cell viability studies showed no significant cytotoxicity below 0.0028% of AT1002. In the presence of 100 μg/kg of AT1002, ardeparin oral bioavailability was significantly increased (F relative/s.c ~ 20.5%). Furthermore, AT1002 at a dose of 100 μg/kg did not induce any observable morphological damage on gastrointestinal (GI) tissues in vivo. These in vivo and in vitro results suggest that the co-administration of LMWH with AT1002 may be a useful delivery strategy to increase its permeability and hence oral absorption.

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The effect of ΔG on the transport and oral absorption of macromolecules

Cited by 37 publications

References 37 publications

Physiological, Pathological, and Therapeutic Implications of Zonulin-Mediated Intestinal Barrier Modulation

Physiological, Pathological, and Therapeutic Implications of Zonulin-Mediated Intestinal Barrier Modulation

The Ethanol Metabolite Acetaldehyde Increases Paracellular Drug Permeability In Vitro and Oral Bioavailability In Vivo

RETRACTED: Zonula occludens toxin synthetic peptide derivative AT1002 enhancesin vitroandin vivointestinal absorption of low molecular weight heparin

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