Human and simulated intestinal fluids as solvent systems to explore food effects on intestinal solubility and permeability

Stappaerts, Jef; Wuyts, Benjamin; Tack, Jan; Annaert, Pieter; Augustijns, Patrick

doi:10.1016/j.ejps.2014.07.009

Cited by 44 publications

(26 citation statements)

References 34 publications

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“…pH values were of 6.5 and 5.8 in FaSSIF and FeSSIF, respectively and 7.4 in TB. Because the pK a of propranolol was 9.5, significant changes in the ionization degree of basic compound could reduce the intestinal transport in biorelevant fluids (Lee et al, 2005;Stappaerts et al, 2014). Moreover, intestinal absorption of propranolol in TB was similar between co-culture and HT29-MTX single culture whereas the apparent permeability across the Caco-2 monolayer was significantly higher.…”

Section: Discussionmentioning

confidence: 91%

“…Whereas a high absorption was observed in TB with a P app coefficient close to 28 Â 10 À6 cm/s, a tremendous decrease of the permeability was observed with both FaSSIF and FeSSIF. This effect could be due to the sequestration of propranolol within NaTC/lecithin mixed micelles, reducing the concentration of free compounds (Ingels et al, 2004;Stappaerts et al, 2014). An additional explanation may be the differences of pH in transport media.…”

Section: Discussionmentioning

confidence: 97%

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Biorelevant media resistant co-culture model mimicking permeability of human intestine

Antoine

Pellequer

Tempesta

et al. 2015

International Journal of Pharmaceutics

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Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 97%

Biorelevant media resistant co-culture model mimicking permeability of human intestine

Antoine

Pellequer

Tempesta

et al. 2015

International Journal of Pharmaceutics

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“…Despite 998 attempts to generate simulated media that mimic the fed state and 999 retain compatibility with Caco-2 cells, it remains challenging to 1000 avoid the trade-off between compatibility and biorelevance. (Stappaerts et al, 2014b). 1019 The solubility-permeability reciprocity is not limited to 1020 micellar media and was also observed for cyclodextrin-based 1021 formulations.…”

mentioning

confidence: 74%

In situ perfusion in rodents to explore intestinal drug absorption: Challenges and opportunities

Stappaerts

Brouwers

Annaert

et al. 2015

International Journal of Pharmaceutics

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The in situ intestinal perfusion technique in rodents is a very important absorption model, not only because of its predictive value, but it is also very suitable to unravel the mechanisms underlying intestinal drug absorption. This literature overview covers a number of specific applications for which the in situ intestinal perfusion set-up can be applied in favor of established in vitro absorption tools, such as the Caco-2 cell model. Qualities including the expression of drug transporters and metabolizing enzymes relevant for human intestinal absorption and compatibility with complex solvent systems render the in situ technique the most designated absorption model to perform transporter-metabolism studies or to evaluate the intestinal absorption from biorelevant media. Over the years, the in situ intestinal perfusion model has exhibited an exceptional ability to adapt to the latest challenges in drug absorption profiling. For instance, the introduction of the mesenteric vein cannulation allows determining the appearance of compounds in the blood and is of great use, especially when evaluating the absorption of compounds undergoing intestinal metabolism. Moreover, the use of the closed loop intestinal perfusion set-up is interesting when compounds or perfusion media are scarce. Compatibility with emerging trends in pharmaceutical profiling, such as the use of knockout or transgenic animals, generates unparalleled possibilities to gain mechanistic insight into specific absorption processes. Notwithstanding the fact that the in situ experiments are technically challenging and relatively time-consuming, the model offers great opportunities to gain insight into the processes determining intestinal drug absorption.

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“…An important factor, not required for the performance assessment herein, is consideration of the impact of binding of drug to bile salt/phospholipid micelles which in the normal healthy intestine are usually present in the fasted and, at elevated levels, in the fed state. Micelle binding has been shown to impact upon the free fraction driving permeation in the in vivo intestine and therefore upon the calculation of permeability and its application in PBPK models; as discussed in the Methods section the calculation of P UBL (Eq. ) includes consideration of the differential diffusion of free drug monomer and drug‐loaded micelles.…”

Section: Discussionmentioning

confidence: 99%

Application of the MechPeff model to predict passive effective intestinal permeability in the different regions of the rodent small intestine and colon

Pade

Jamei

Rostami‐Hodjegan

et al. 2017

Biopharm & Drug Disp

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A major component of physiologically based pharmacokinetic (PBPK) models is the prediction of the rate and extent of absorption of orally dosed drugs for which knowledge of effective passive intestinal permeability (P ) is essential. Single-pass intestinal perfusion (SPIP) studies are used to establish effective permeability in vivo but are difficult to perform in rodents, while mechanistic models to predict drug P in rat and mouse have not been published. This work evaluates the predictive performance of the 'MechPeff' model to predict P in the rodent intestine based upon knowledge of regional gut physiology and drug-specific physicochemical parameters. The 'MechPeff' model, built-in to the Simcyp Rat and Mouse Simulators, predicts transcellular, paracellular and mucus layer permeabilities and combines these to give the overall P . The jejunal and/or ileal P was predicted for 12 (4) acidic, 13 (12) basic, 10 (8) neutral and 2 (0) ampholytic drugs in the rat (mouse), spanning a wide range of MW and logP , and compared with experimental P obtained using SPIP. A key input is the intrinsic transcellular permeability (P ) which can be derived from modelling of appropriate in vitro permeability experiments or predicted from physicochemical properties. The P predictions were reasonably good when experimentally derived P was used; from 42 P values, 24 (57%) were within 3-fold, and of 19 P values, 12 (63%) were within 3-fold, of observed P . Considering the lack of alternative models to predict P in preclinical species, and the minimal drug-specific inputs required, this model provides a valuable tool within drug discovery and development programmes. Copyright © 2017 John Wiley & Sons, Ltd.

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Human and simulated intestinal fluids as solvent systems to explore food effects on intestinal solubility and permeability

Cited by 44 publications

References 34 publications

Biorelevant media resistant co-culture model mimicking permeability of human intestine

Biorelevant media resistant co-culture model mimicking permeability of human intestine

In situ perfusion in rodents to explore intestinal drug absorption: Challenges and opportunities

Application of the MechPeff model to predict passive effective intestinal permeability in the different regions of the rodent small intestine and colon

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