A drug is defined as exhibiting negative food effects, if the co-administration of food statistically decreases its area under the curve, AUC, when compared with its administration on a fasted stomach. In this study, the role of biopharmaceutical factors that contribute to negative food effects was studied using furosemide, nadolol, tacrine and atenolol (as model compounds exhibiting negative food effects), and prednisolone, hydrochlorothiazide and ibuprofen (as model compounds that do not show any food effects). The physiological pH of the upper intestinal tract is lower, at pH 5, in the postprandial state when compared with the preprandial state, pH 6.5. Drugs that exhibited negative food effects had low apical to basolateral Caco-2 permeabilities, low pKa/pKb and Log P values of less than 1. The drugs exhibiting negative food effects had low distribution coefficients at the pH conditions of the fed and fasted states. Furosemide, being a hydrophilic, poorly soluble acidic drug showed lower solubility in the fed state when compared with the fasted state. Basic drugs, atenolol, nadolol and tacrine, are ionized to a higher extent in the fed state and exhibit lower permeability and lower absorption when compared with the fasted state. Thus, drugs were found to exhibit negative food effects owing to their decrease in solubility or permeability in the upper intestinal tract of the fed state when compared with the fasted state.

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The model indicated that high-solubility and high-permeability drugs undergoing Cl of more than 27 L/h may exhibit statistically significant positive food effects.

Anticancer drugs have to cross many layers of cells and the extracellular matrix to reach the tumor cells and elicit their pharmacological action. The three dimensional structure (micro-environment) of tumors poses a penetration barrier to antitumor drugs resulting in poor response. Two in vitro model barriers representing the extracellular matrix and multilayered structure of tumors were used in this study to evaluate the permeability of four structurally related antitumor compounds, thioxanthones. Matrigel was used to represent the tumor extracellular matrix and multilayered Caco-2 cells were used to represent the multilayered confluence of solid tumor. The in vitro permeability characteristics of the thioxanthones across the model barriers were correlated to their in vivo distribution. The apparent permeability coefficients of thioxanthone analogs are in the range of 2.9 x 10(-6) to 11.8 x 10(-6) cm/s across matrigel and 12.6 x 10(-6) to 24.5 x 10(-6) cm/s across Caco-2 multilayers. This high in vitro permeability of thioxanthones across the model barriers suggested their good tissue distribution in vivo. Therefore, the use of in vitro model barriers was found to predict in vivo tissue distribution for thioxanthones.

A predictive model for negative food effects based on the correlation of food effects with dissociation constant and Caco-2 permeability was established and simulations of food effects using rat intestinal permeability supported the drugs? published negative food effects. Thus, an empirical and a mechanistic model as potential tools for predicting negative food effects are reported.