Drugs exhibiting decreased extent of absorption in the fed state administration when compared to the fasted state administration are termed to exhibit a negative food effect. The known causes for negative food effects are luminal degradation and complexation to metal ions/Ca 2+ . For the drugs that do not undergo GI degradation and metal ion complexation, different factors were attributed to cause negative food effects, which are inconclusive. The objectives of this investigation were; to identify the physicochemical and physiological changes between fasted and fed states and their role in causing negative food effects; to develop an empirical model that correlates the biopharmaceutical properties of molecules to negative food effects; and translate the empirical model to a mechanistic model and explain the mechanisms of negative food effects for drugs that do not have clearly defined mechanisms of negative food effects. The important physicochemical change in the upper intestine was identified to be pH. The pH of the upper intestine in the fasted state is typically 6.5, whereas, the overall post-prandial pH after a standard meal in the duodenum is 5.4 (5.0 − 5.7) and the jejunal pH is 4.7 owing to the emptying of acidic chyme. Negative food effect drugs exhibited incomplete GI absorption, low Log P values and low apical to basolateral Caco-2 permeabilities. Acidic/basic drugs exhibiting either negative food effects or no food effects with a molecular size range of 200–450 Da and no physiological effects (such as secretions and motility) were selected from the literature. Multiple linear regression analysis using five drugs exhibiting negative food effects and seven drugs exhibiting no food effects indicated that, percent food effects correlated to acidic/basic dissociation constants (Ka/Kb) and to Caco-2 permeability (R 2 = 0.9114, Power ≈ 1 and p < 0.00002). A mathematical model, adopted to understand the mechanisms of negative food effects suggested that, lowering of permeability or solubility of the model compounds at the lower pH of the postprandial upper intestinal state may contribute to their negative food effects. Finally, this model was found to be useful in predicting negative food effects using in situ rat permeability values.

published_or_final_version / Mechanical Engineering / Master / Master of Philosophy

<p>The general aim of the present project was to increase the understanding of the in vivo dissolution of poorly soluble drugs and thereby improve possibility to predict in vivo solubility from substance properties. Increased understanding of the in vivo limitations of drug solubility could potentially also generate ideas for improved formulation principles for poorly soluble compounds and more relevant in vitro dissolution test methods used in formulation development.</p><p>The dynamic gastrointestinal secretory and enzymatic responses to a liquid meal were studied in human intestinal fluid (HIF) by in vivo perfusion of a nutritional drink. The main diversity found compared to simulated intestinal fluids was the presence of dietary lipids in fed human intestinal fluid. This difference was showed to be of importance in the solubility of low soluble drugs, since this parameter was underestimated in the simulated fluid. Thus suggesting that simulated intestinal fluids should be prepared with the addition of dietary lipids for better in vitro in vivo predictions. </p><p>Solubility and dissolution determinations in fasted and fed HIF showed that the solubility was higher in fed state fluid, probably owing to the higher concentration of lipids in this media. The higher solubility was correlated to both the lipophilicity and aqueous solubility of the drug. The dissolution rate also increased, but not to the same extent as the solubility. These findings need to be considered in the design of in vitro models and in the prediction of food effects on oral bioavailability of poorly soluble drugs.</p><p>In addition, an in vivo porcine perfusion study was performed to investigate importance of different mechanisms in food-drug interactions. The results showed that solubilisation might be a more important factor than P-gp inhibition for food-related effects on the intestinal absorption kinetics of Class II drugs. </p>

The general aim of the present project was to increase the understanding of the in vivo dissolution of poorly soluble drugs and thereby improve possibility to predict in vivo solubility from substance properties. Increased understanding of the in vivo limitations of drug solubility could potentially also generate ideas for improved formulation principles for poorly soluble compounds and more relevant in vitro dissolution test methods used in formulation development. The dynamic gastrointestinal secretory and enzymatic responses to a liquid meal were studied in human intestinal fluid (HIF) by in vivo perfusion of a nutritional drink. The main diversity found compared to simulated intestinal fluids was the presence of dietary lipids in fed human intestinal fluid. This difference was showed to be of importance in the solubility of low soluble drugs, since this parameter was underestimated in the simulated fluid. Thus suggesting that simulated intestinal fluids should be prepared with the addition of dietary lipids for better in vitro in vivo predictions. Solubility and dissolution determinations in fasted and fed HIF showed that the solubility was higher in fed state fluid, probably owing to the higher concentration of lipids in this media. The higher solubility was correlated to both the lipophilicity and aqueous solubility of the drug. The dissolution rate also increased, but not to the same extent as the solubility. These findings need to be considered in the design of in vitro models and in the prediction of food effects on oral bioavailability of poorly soluble drugs. In addition, an in vivo porcine perfusion study was performed to investigate importance of different mechanisms in food-drug interactions. The results showed that solubilisation might be a more important factor than P-gp inhibition for food-related effects on the intestinal absorption kinetics of Class II drugs.