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Intestinal permeability assessment is an important aspect of drug development, which strongly depends on the solvent system used in the intestinal donor compartment. For this purpose, human intestinal fluids (HIF) can be considered as the golden standard. A recent study demonstrated a reduced apparent permeation across rat intestinal tissue from fed versus fasted state HIF for 9 out of 16 compounds tested. Commercially available fed and fasted state simulated fluids (FeSSIF and FaSSIF) reproduced this food effect for only 3 out of 16 compounds. To elucidate this observed difference, the current study assessed the impact of relevant intestinal fluid factors (bile salt, phospholipids, cholesterol, free fatty acids (FFA), monoacylglycerides (MAG)) and 2-factor interactions at a fixed pH of 6.5 on drug permeation across both rat tissue (Ussing chambers setup) and an artificial membrane (dialysis setup). Four representative compounds were selected for the permeation experiments: for propranolol and indomethacin, a food-induced permeation reduction was previously seen in both HIF and SIF; for metoprolol and darunavir, a reduction was only seen in HIF. Using a fractional 25–1 design of experiments (DoE) approach, 16 SIF combinations were defined as donor media for permeation studies.In the Ussing chambers (rat tissue), FFA and MAG reduced the permeation for all 4 compounds. Only for propranolol and indomethacin, permeation was further reduced by bile salts and phospholipids. This explains why the use of FeSSIF vs FaSSIF, lacking FFA and MAG, predicted a negative food effect for propranolol and indomethacin but not for metoprolol and darunavir. In the dialysis set-up using an artificial membrane, significantly higher permeation rates compared to the Ussing chambers were observed. Under those conditions, FFA and MAG no longer reduced permeation, while bile salts and phospholipids still did. This may indicate that lipidic structures can provide depot release in the case of a dynamic equilibrium between free and entrapped drug.