Evaluation of fasted and fed state simulated and human intestinal fluids as solvent system in the Ussing chambers model to explore food effects on intestinal permeability

Abstract

The Ussing chambers model is almost exclusively used in the presence of plain aqueous phosphate buffers as solvent system. In an attempt to further elucidate the effect of luminal ingredients and postprandial conditions on intestinal permeability, pooled fasted and fed state human intestinal fluids (FaHIFpool, FeHIFpool) were used. In addition, simulated intestinal fluids of both nutritional states (FaSSIF, FeSSIF) were evaluated as possible surrogate media for HIF. The use of FaHIFpool generated a broad range of Papp values for a series of 16 model drugs, ranging from 0.03×10(-6)cm/s (carvedilol) to 33.8×10(-6)cm/s (naproxen). A linear correlation was observed between Papp values using FaSSIF and FaHIFpool as solvent system (R=0.990), justifying the use of FaSSIF as surrogate medium for FaHIF in the Ussing chambers. In exclusion of the outlier carvedilol, a strong sigmoidal relationship was found between Papp and fahuman of 15 model drugs, illustrated by correlation coefficients of 0.961 and 0.936 for FaHIFpool and FaSSIF, respectively. When addressing food effects on intestinal permeability, the use of FeHIFpool resulted in a significantly lower Papp value for nine out of sixteen compounds compared to fasting conditions. FeSSIF as solvent system significantly overestimated Papp values in FeHIFpool. To conclude, the optimized Ussing chambers model using biorelevant media as apical solvent system holds great potential to investigate food effects in a more integrative approach, taking into account drug solubilisation, supersaturation and formulation effects.

Altered duodenal bile salt concentration and receptor expression in functional dyspepsia

“…In line with our results in HVs, Wuyts et al reported a pH of duodenal aspirates from HVs in fasted and fed states of 7.5 and 6.3, respectively. 15 The higher postprandial pH in patients with FD is in apparent conflict with the results from a previous study by Lee et al, in which reduced duodenal acid clearance and increased late postprandial duodenal acid exposure was reported in a selected group of dyspeptic patients with prominent nausea. 16 The different results may be related to differences in patient selection, meal choice, method of pH measurement and especially study design, with a shorter postprandial measurement time in the present study compared to the 24-hour duodenal pH recording in the study by Lee and colleagues in which differences occurred mainly after the second postprandial hour.…”

Assessment of Passive Intestinal Permeability Using an Artificial Membrane Insert System

“…[32][33][34][35][36] Because these media are supplemented with biorelevant substances like taurocholate and lecithin, they are preferred over simple aqueous buffers. Wuyts et al 37,38 previously validated the use of FaSSIF as biorelevant apical substitute medium for FaHIF in the Caco-2 cell assay and the Ussing chambers setup. 33 To verify whether FaSSIF can be considered as a valuable substitute for FaHIF in the AMIsystem, both human and simulated intestinal media were explored as donor solvent system.…”

“…40 In this study, FaSSIF-v1 was used as donor medium because of (i) its simplicity and (ii) the strong correlation observed with FaHIF using other permeation tools (Caco-2 system and Ussing chambers model). 37,38 Nevertheless, it may be worthwhile to explore the passive permeability using FaSSIF-v2 and FaSSIF-v3 as donor medium in the AMI-system. 41…”

Physiologically Relevant, Humanized Intestinal Systems to Study Metabolism and Transport of Small Molecule Therapeutics

“…Early attempts to study disposition of small molecules, in vitro, leveraged Ussing chambers (Wallon et al, 2005;Wuyts et al, 2015) with isolated human (endoscopic biopsied) tissue, followed by migration to gut tissue-derived subcellular fractions, and finally, the deployment of human gut "surrogate" reagents such as LS180 and Caco-2 cells (Rogers et al, 1987;Yamaura et al, 2016). Only recently has it been possible to consider using physiologically relevant human intestinal models by analogy with human primary hepatocytes [see Khetani et al (2018) and Bale et al (2018) in this special issue on novel models of drug metabolism, disposition, and toxicity].…”