Excised segments of rat small intestine in Ussing chamber studies: A comparison of native and stripped tissue viability and permeability to drugs

Sjögren, Erik; Eriksson, Johanna; Vedin, Charlotta; Breitholtz, Katarina; Hilgendorf, Constanze

doi:10.1016/j.ijpharm.2016.03.063

Cited by 27 publications

(16 citation statements)

References 33 publications

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“…The basal TEER for isolated jejunal tissue mounted in Ussing chambers was 46 ± 9 Ω.cm 2 (n=48), within the range of TEER values typically reported for this tissue in vitro [40].…”

Section: C10 Enhances Flux Of [ 3 H]-ipp and [ 3 H]-lkp Across Isolatsupporting

confidence: 76%

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Sodium caprate enables the blood pressure-lowering effect of Ile-Pro-Pro and Leu-Lys-Pro in spontaneously hypertensive rats by indirectly overcoming PepT1 inhibition

Gleeson

Frias²,

Ryan

et al. 2018

European Journal of Pharmaceutics and Biopharmaceutics

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The tripeptides, Ile-Pro-Pro (IPP) and Leu-Lys-Pro (LKP), inhibit angiotensin-converting enzyme (ACE) resulting in lowered blood pressure. Our hypothesis was that the medium chain fatty acid permeation enhancer, sodium caprate (C), may prevent the decrease in permeability of the tripeptides when PepT1 is inhibited by glycyl-sarcosine (Gly-Sar), a situation that may occur in the presence of food hydrolysates. Using Caco-2 monolayers and isolated rat jejunal tissue, the apparent permeability coefficients (P) of [H]-IPP and [H]-LKP were assessed in the presence of Gly-Sar with and without C. Gly-Sar decreased the P of both tripeptides across monolayers and isolated jejunal tissue, but C restored it. C likely increased the paracellular permeability of the tripeptides, as indicated by immunofluorescence changes in tight junction proteins in Caco-2 monolayers accompanied by a concentration-dependent decrease in transepithelial electrical resistance (TEER). [H]-IPP and [H]-LKP were orally-gavaged to normal rats with Gly-Sar, C, or with a mixture. Plasma levels of both peptides were reduced by Gly-Sar to less than half that of the levels detected in its absence, but were restored when C was co-administered. In spontaneously hypertensive rats (SHRs), unlabelled IPP and LKP lowered blood pressure when delivered either by i.v. or oral routes. Oral gavage of Gly-Sar reduced the hypotensive action of peptides in SHRs, but the effect was restored in the presence of C. In conclusion, there was a reduction in the hypotensive effects of IPP and LKP in SHRs when intestinal PepT1 was inhibited by Gly-Sar, but C may circumvent this by enhancing paracellular permeability.

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“…The basal TEER for isolated jejunal tissue mounted in Ussing chambers was 46 ± 9 Ω.cm 2 (n=48), within the range of TEER values typically reported for this tissue in vitro [40].…”

Section: C10 Enhances Flux Of [ 3 H]-ipp and [ 3 H]-lkp Across Isolatsupporting

confidence: 76%

“…Male Wistar rats (250-350 g; Charles River Labs, UK, and the UCD Biomedical Facility) were euthanized by stunning and cervical dislocation. Jejunal mucosae with intact underlying circular and longitudinal muscle were mounted in Ussing chambers with a circular window areas of 0.63 cm 2 [40].…”

Section: Isolated Rat Jejunal Mucosae Transport Studies In Ussing Chamentioning

confidence: 99%

Sodium caprate enables the blood pressure-lowering effect of Ile-Pro-Pro and Leu-Lys-Pro in spontaneously hypertensive rats by indirectly overcoming PepT1 inhibition

Gleeson

Frias²,

Ryan

et al. 2018

European Journal of Pharmaceutics and Biopharmaceutics

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“…The intestinal tissues are likely to express all the transporters and the enzymes at the same “physiological” level of expression. Moreover, the data obtained through rat intestine can be directly correlated to in vivo experiments that will be conducted in the same animal model ( Mazzaferro et al, 2012 ; Sjögren et al, 2016 ). However, samples withdrawn from the receiver compartment often at very low concentration.…”

Section: Discussionmentioning

confidence: 99%

“…In this system, the drugs can be exposed at either mucosal or serosal levels, and therefore the absorption direction (M-S) and secretion direction (S-M) characteristics both can be detected. Furthermore, the usefulness of Ussing chambers for intestinal transport studies has long been recognized, and many researchers regard it as gold standards ( Erik et al, 2016 ). Up to now, studies of P-gp influences in drug intestinal absorption by using this technique have been reported ( Ballent et al, 2014 ; Xiao et al, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

Interactions Between Emodin and Efflux Transporters on Rat Enterocyte by a Validated Ussing Chamber Technique

et al. 2018

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Emodin, a major active anthraquinone, frequently interacts with other drugs. As changes of efflux transporters on intestine are one of the essential reasons why the drugs interact with each other, a validated Ussing chamber technique was established to detect the interactions between emodin and efflux transporters, including P-glycoprotein (P-gp), multidrug-resistant associated protein 2 (MRP2), and multidrug-resistant associated protein 3 (MRP3). Digoxin, pravastatin, and teniposide were selected as the test substrates of P-gp, MRP2, and MRP3. Verapamil, MK571, and benzbromarone were their special inhibitors. The results showed that verapamil, MK571, and benzbromarone could increase digoxin, pravastatin, and teniposide absorption, and decrease their Er values, respectively. Verapamil (220 μM) could significantly increase emodin absorption at 9.25 μM. In the presence of MK571 (186 μM), the Papp values of emodin from M-S were significantly increased and the efflux ratio decreased. With the treatment of emodin (185, 370, and 740 μM), digoxin absorption was significantly decreased while teniposide increased. These results indicated that emodin might be the substrate of P-gp and MRP2. Besides, it might be a P-gp inducer and MRP3 inhibitor on enterocyte, which are reported for the first time. These results will be helpful to explain the drug–drug interaction mechanisms between emodin and other drugs and provide basic data for clinical combination therapy.

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“…Currently, important tools based on physicochemical properties and in vitro assays are used to predict in vivo gastrointestinal absorption [ 10 ]. In vitro methodologies include animal [ 11 , 12 ] or human tissues [ 13 ], cultured cells [ 14 , 15 ] and artificial membranes [ 16 , 17 , 18 ]. The Caco-2 cell monolayers in vitro model is thoroughly studied and generally mimics major transport pathways in the gastrointestinal tract [ 19 ].…”

Section: Introductionmentioning

confidence: 99%

Biomimetic Artificial Membrane Permeability Assay over Franz Cell Apparatus Using BCS Model Drugs

et al. 2020

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A major parameter controlling the extent and rate of oral drug absorption is permeability through the lipid bilayer of intestinal epithelial cells. Here, a biomimetic artificial membrane permeability assay (Franz–PAMPA Pampa) was validated using a Franz cells apparatus. Both high and low permeability drugs (metoprolol and mannitol, respectively) were used as external standards. Biomimetic properties of Franz–PAMPA were also characterized by electron paramagnetic resonance spectroscopy (EPR). Moreover, the permeation profile for eight Biopharmaceutic Classification System (BCS) model drugs cited in the FDA guidance and another six drugs (acyclovir, cimetidine, diclofenac, ibuprofen, piroxicam, and trimethoprim) were measured across Franz–PAMPA. Apparent permeability (Papp) Franz–PAMPA values were correlated with fraction of dose absorbed in humans (Fa%) from the literature. Papp in Caco-2 cells and Corti artificial membrane were likewise compared to Fa% to assess Franz–PAMPA performance. Mannitol and metoprolol Papp values across Franz–PAMPA were lower (3.20 × 10−7 and 1.61 × 10−5 cm/s, respectively) than those obtained across non-impregnated membrane (2.27 × 10−5 and 2.55 × 10−5 cm/s, respectively), confirming lipidic barrier resistivity. Performance of the Franz cell permeation apparatus using an artificial membrane showed acceptable log-linear correlation (R2 = 0.664) with Fa%, as seen for Papp in Caco-2 cells (R2 = 0.805). Data support the validation of the Franz–PAMPA method for use during the drug discovery process.

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Excised segments of rat small intestine in Ussing chamber studies: A comparison of native and stripped tissue viability and permeability to drugs

Cited by 27 publications

References 33 publications

Sodium caprate enables the blood pressure-lowering effect of Ile-Pro-Pro and Leu-Lys-Pro in spontaneously hypertensive rats by indirectly overcoming PepT1 inhibition

Sodium caprate enables the blood pressure-lowering effect of Ile-Pro-Pro and Leu-Lys-Pro in spontaneously hypertensive rats by indirectly overcoming PepT1 inhibition

Interactions Between Emodin and Efflux Transporters on Rat Enterocyte by a Validated Ussing Chamber Technique

Biomimetic Artificial Membrane Permeability Assay over Franz Cell Apparatus Using BCS Model Drugs

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