A head-to-head Caco-2 assay comparison of the mechanisms of action of the intestinal permeation enhancers: SNAC and sodium caprate (C10)

Twarog, Caroline; Liu, Kai; O’Brien, Peter J.; Dawson, Kenneth A.; Fattal, Elias; Illel, Brigitte; Brayden, David J.

doi:10.1016/j.ejpb.2020.04.023

Cited by 41 publications

(41 citation statements)

References 61 publications

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“…They suggested that SNAC was less potent than caprate at inducing plasma membrane perturbation associated with membrane permeabilization. 67 Indeed, this was observed in our simulations, where SNAC were randomly adsorbed onto the surface rather than being inserted into the phospholipid bilayer.…”

Section: Resultsmentioning

confidence: 51%

Influence of Bile Composition on Membrane Incorporation of Transient Permeability Enhancers

et al. 2020

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Transient permeability enhancers (PEs), such as caprylate, caprate, and salcaprozate sodium (SNAC), improve the bioavailability of poorly permeable macromolecular drugs. However, the effects are variable across individuals and classes of macromolecular drugs and biologics. Here, we examined the influence of bile compositions on the ability of membrane incorporation of three transient PEs—caprylate, caprate, and SNAC—using coarse-grained molecular dynamics (CG-MD). The availability of free PE monomers, which are important near the absorption site, to become incorporated into the membrane was higher in fasted-state fluids than that in fed-state fluids. The simulations also showed that transmembrane perturbation, i.e ., insertion of PEs into the membrane, is a key mechanism by which caprylate and caprate increase permeability. In contrast, SNAC was mainly adsorbed onto the membrane surface, indicating a different mode of action. Membrane incorporation of caprylate and caprate was also influenced by bile composition, with more incorporation into fasted- than fed-state fluids. The simulations of transient PE interaction with membranes were further evaluated using two experimental techniques: the quartz crystal microbalance with dissipation technique and total internal reflection fluorescence microscopy. The experimental results were in good agreement with the computational simulations. Finally, the kinetics of membrane insertion was studied with CG-MD. Variation in micelle composition affected the insertion rates of caprate monomer insertion and expulsion from the micelle surface. In conclusion, this study suggests that the bile composition and the luminal composition of the intestinal fluid are important factors contributing to the interindividual variability in the absorption of macromolecular drugs administered with transient PEs.

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Section: Resultsmentioning

confidence: 51%

Influence of Bile Composition on Membrane Incorporation of Transient Permeability Enhancers

et al. 2020

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“…Inspired by Lindmark's study, PhD students Ed Walsh and Caroline Twarog from my own lab filled in some of the gaps around C 10 's mechanism in Caco-2 using HCA to show that membrane perturbation was an overarching event and that the actions of the enhancer were multi-modal and not exclusive to the TJ route. 24,25 Limitations in using filter-grown Caco-2 monolayers in PE studies have been confirmed by Hans Lenernas's group who showed that the static bioassay poorly mimics the dynamic intestinal environment where dilution and absorption of such excipients cannot be modelled well and, moreover, that the concentrations that induce permeability increases in vitro are very close to those that damage the monolayers, which do not repair as well as in vivo. 26 Per's work with PEs in Caco-2 monolayers revealed important clues on mechanisms of action for selected agents and provided an opportunity to rank order candidates, but given the constraints, once an agent shows efficacy in Caco-2, work needs to move to in vivo models of intestinal absorption.…”

Section: Caco-2 and Intestinal Permeation Enhancersmentioning

confidence: 99%

Per Artursson’s Major Contributions to the Caco-2 Cell Literature in Pharmaceutical Sciences

Brayden

2021

Journal of Pharmaceutical Sciences

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This edition of the Journal of Pharmaceutical Sciences is dedicated to the wonderful career of Per Artursson from the Uppsala University. My Commentary focusses on Per's major contributions to the Caco-2 cell literature over the past 30 years. Two especially influential papers have been cited more than 1000 times out of a total citation count of almost 30,000 and a h-index of 93 (Google Scholar), making Per one of the most cited and influential Pharmaceutical scientists of his generation. The Caco-2 field to which Per contributed so many advances has informed the community on key areas including predictive drug fluxes across the intestine, metabolism by intestinal epithelia, the role of transporters during flux, enantiomer-selective flux, excipient interaction with tight junctions, and nanoparticle uptake by enterocytes. In this pioneering work, Per has been careful to emphasise that Caco-2 monolayers have limitations and are a model of the human small intestine where observations must be backed up with in vitro tissue and in vivo work. Throughout, he has paid great attention to detail in methodology, as reflected by co-authorship of two Nature Protocols on Caco-2 assays. The article briefly assesses some of the most important milestones in Per's published Caco-2 research.

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“…All evidence suggested that C 10 increased paracellular permeability via a membrane-perturbation induced alteration in intracellular calcium levels, which leads to TJ opening through a MLC regulated mechanism. 30,40 Additionally C 10 has been shown to have a direct effect on membrane fluidity above its critical micelle concentration 41 , illustrating how PEs, like C 10 , can affect numerous different pathways simultaneously. 21 The perceived mechanism of the main member of the acetylated amino acid class, SNAC, has also recently been updated.…”

Section: Elucidating Permeation Enhancers' Modes Of Action Using Fluorescence Imagingmentioning

confidence: 99%

“…This mode of transport concurs with the known function of SNAC as a modulator of the transcellular pathway. 30 …”

Section: Oral Peptide Drugs For Systemic Applications Used In the Clinicmentioning

confidence: 99%

“… 33 Also, a thorough description of the mode of action of C 10 was recently performed to resolve previous ambiguity of C 10 function. 30 The study included in vitro cell monolayer imaging of various TJ proteins, showing a clear C 10 concentration-dependent loss in claudin-5 and occludin localization. Additionally, the authors performed a fluorescence imaging-based high-content analysis, where simultaneous multiplexed detection of fluorescent reporters for nuclear intensity, mitochondrial membrane potential, plasma membrane permeability, and intracellular calcium was achieved at the single-cell level.…”

Section: Elucidating Permeation Enhancers’ Modes Of Action Using Fluorescence Imagingmentioning

confidence: 99%

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Imaging therapeutic peptide transport across intestinal barriers

et al. 2021

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A head-to-head Caco-2 assay comparison of the mechanisms of action of the intestinal permeation enhancers: SNAC and sodium caprate (C10)

Cited by 41 publications

References 61 publications

Influence of Bile Composition on Membrane Incorporation of Transient Permeability Enhancers

Influence of Bile Composition on Membrane Incorporation of Transient Permeability Enhancers

Per Artursson’s Major Contributions to the Caco-2 Cell Literature in Pharmaceutical Sciences

Imaging therapeutic peptide transport across intestinal barriers

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