title: 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.
authors.affiliation: Drug Delivery and Disposition, KU Leuven Department of Pharmaceutical and Pharmacological Sciences, Belgium.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Wuyts
authors.affiliation: Drug Delivery and Disposition, KU Leuven Department of Pharmaceutical and Pharmacological Sciences, Belgium.
authors.forename: Danny
authors.initials: D
authors.lastname: Riethorst
authors.affiliation: Drug Delivery and Disposition, KU Leuven Department of Pharmaceutical and Pharmacological Sciences, Belgium.
authors.forename: Joachim
authors.initials: J
authors.lastname: Brouwers
authors.affiliation: University Hospitals Leuven, Department of Gastroenterology, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: Tack
authors.affiliation: Drug Delivery and Disposition, KU Leuven Department of Pharmaceutical and Pharmacological Sciences, Belgium.
authors.forename: Pieter
authors.initials: P
authors.lastname: Annaert
authors.affiliation: Drug Delivery and Disposition, KU Leuven Department of Pharmaceutical and Pharmacological Sciences, Belgium. Electronic address: Patrick.augustijns@pharm.kuleuven.be.
authors.forename: Patrick
authors.initials: P
authors.lastname: Augustijns
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000032:analysis; D005215:Fasting / Q000378:metabolism; D018565:Food-Drug Interactions; D006801:Humans; D007082:Ileum / Q000378:metabolism; D066298:In Vitro Techniques; D007408:Intestinal Absorption; D007419:Intestinal Secretions / Q000378:metabolism*; D008297:Male; D010539:Permeability; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D010743:Phospholipids / Q000032:analysis; D019518:Postprandial Period / Q000502:physiology; D017208:Rats, Wistar; D012997:Solvents
chemical_list: D001647:Bile Acids and Salts; D004364:Pharmaceutical Preparations; D010743:Phospholipids; D012997:Solvents
keywords: Food effect; Human intestinal fluid; Permeability; Rat intestine; Ussing chambers