An overview of in vitro, ex vivo and in vivo models for studying the transport of drugs across intestinal barriers

Xu, Yining; Shrestha, Neha; Préat, Véronique; Beloqui, Ana

doi:10.1016/j.addr.2021.05.005

Cited by 101 publications

(48 citation statements)

References 323 publications

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“…Designers usually need to consider permeability since drugs must pass through cell membranes in order to be orally absorbed 91 (at least by the transcellular route) and to engage intracellular targets. 24 Bacterial cell envelopes, biofilms and intracellular pathogens present additional permeability challenges.…”

Section: ■ Permeabilitymentioning

confidence: 99%

Hydrogen-Bond Donors in Drug Design

Kenny¹

2022

J. Med. Chem.

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Hydrogen-bond donors are seen to cause more problems for drug designers than hydrogen-bond acceptors. Most of the polarity in drug-like compounds comes from hydrogen-bond acceptors since they typically exceed the hydrogen-bond donors in number and are more heavily solvated on an individual basis. The implications of this polarity imbalance for optimization of permeability and aqueous solubility are discussed. A factor that should be considered in optimization of ligand recognition by targets is that the presence of a hydrogen-bond donor generally implies that a hydrogen-bond acceptor is also present (but not vice versa). Frustrated solvation and secondary electrostatic interactions result from aligned hydrogen-bond donors and acceptors, and the design opportunities presented by these phenomena are discussed. Hydrogen-bond donors based on oxygen, nitrogen and carbon are compared as target recognition elements, and halogen- and chalcogen-bond donors are discussed as hydrogen-bond donor equivalents.

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Section: ■ Permeabilitymentioning

confidence: 99%

Hydrogen-Bond Donors in Drug Design

Kenny¹

2022

J. Med. Chem.

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“…In addition, LPS is also intercepted by the defense formed by intestinal epithelial cells (IECs) binding closely ( 15 ). Most exogenous macromolecules cannot be absorbed by cells and therefore cross the intestinal epithelial barrier via the paracellular space ( 16 ). “Non-canonical inflammasome” was reported that LPS directly interact with cytoplasmic caspase 11 to activate intracellular pathways independent on an extracellular receptor, which hint metastasis of LPS into the cytosol and a novel mechanism facilitating LPS to escape the intestinal barrier via transcellular pathway ( 17 ).…”

Section: Introductionmentioning

confidence: 99%

The Mechanism of Lipopolysaccharide Escaping the Intestinal Barrier in Megalobrama amblycephala Fed a High-Fat Diet

et al. 2022

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With the popularity of western food characterized by excessive fat and sugars, obesity has currently been a public health issue. Low-grade chronic inflammation accompanied by obesity increases the risk of multiple epidemics such as diabetes, cancer and cardiovascular diseases. Here, we show that feeding Megalobrama amblycephala with a high-fat diet (HFD) drives obesity-related chronic inflammation and the penetration of lipopolysaccharide (LPS). Interference with antibiotics inhibits the produce of LPS and this alleviates the sustained release of pro-inflammatory factors induced by HFD. LPS penetration is attributed to weakened intestinal mucus barrier after high-fat exposure. Mechanically, the consumption of HFD inhibits the secretion of mucin 2 (MUC2) due to the induction of endoplasmic reticulum stress mediated by the inositol-requiring enzyme 1 (IRE1) /X box-binding protein 1 (XBP1) pathway in goblet cells. Furthermore, excessive lipid exacerbates the leakage of LPS across the intestinal epithelial cell barrier via the transcellular pathway. Mechanically, lipid increases the internalization of LPS in intestinal epithelial cells depending on the activation of fatty acid translocase (FAT/CD36). These results demonstrate that HFD causes the penetration of LPS due to the weakened intestinal mucosal barrier and the assistance of CD36.

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“…Designers usually need to consider permeability since drugs must pass through cell membranes in order to be orally absorbed [86] (at least by the transcellular route) and to engage intracellular targets [24]. Bacterial cell envelopes, biofilms and intracellular pathogens present additional permeability challenges.…”

Section: Permeabilitymentioning

confidence: 99%

Hydrogen bond donors in drug design

Kenny¹

2022

Preprint

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In medicinal chemistry, hydrogen bond donors are seen to cause more problems than hydrogen bond acceptors and this study examines hydrogen bond donor-acceptor asymmetries in the context of drug design. Hydrogen bond acidity is reviewed and it is shown how polarity can be estimated for individual hydrogen bond donors and acceptors from alkane/water partition coefficient measurements. Hydrogen bond donors are generally less polar than hydrogen bond acceptors and desolvation penalty is therefore an implausible explanation for deleterious effects of hydrogen bond donors. Generally, the number of hydrogen bond acceptors in organic compounds exceeds the number of hydrogen bond donors and the apparently greater restrictiveness of the Rule of 5 for hydrogen bond donors may simply be a reflection of this imbalance. The weaker hydration of hydrogen bond donors implies that attempts to address polarity surfeit in optimization of permeability should be focused on hydrogen bond acceptors. Elimination of redundant hydrogen bond donors can potentially reduce active efflux and destabilize the solid state without resulting in unacceptable increases in lipophilicity. The key hydrogen bond donor-acceptor asymmetry in the context of target recognition is that the presence of a hydrogen bond donor usually implies that a hydrogen bond acceptor is also present. Target-ligand hydrogen bonds form in aqueous media and design opportunities presented by frustrated hydration and secondary interactions are discussed. Hydrogen bond donors based on oxygen, nitrogen and carbon are compared as target recognition elements and potential benefits of halogen and chalcogen bond donors as replacements for hydrogen bond donors are discussed.

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An overview of in vitro, ex vivo and in vivo models for studying the transport of drugs across intestinal barriers

Cited by 101 publications

References 323 publications

Hydrogen-Bond Donors in Drug Design

Hydrogen-Bond Donors in Drug Design

The Mechanism of Lipopolysaccharide Escaping the Intestinal Barrier in Megalobrama amblycephala Fed a High-Fat Diet

Hydrogen bond donors in drug design

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