Mechanistic studies and modeling of effects of ingested lipids on oral drug absorption

Ingested lipids, typically originating from food and potentially used as delivery agents, can enhance absorption of compounds by several hundred percent, but they can also decrease absorption or have no effect. The influence of lipids on compound absorption originates from colloidal structures they form, compound trafficking between these colloidal structures and aqueous medium, and affects on transport through the intestinal mucosa. However, these effects are typically documented as empirical, compound-specific observations and not predictable a priori. The overall goal of this project was to gain quantitative mechanistic insight into and to predict the influence of lipids, mainly triglycerides, in the gastrointestinal (GI) tract on compound absorption. Previously, the impact of lipid ingestion on coadministered compound absorption (compound solubility enhancement, change in intestinal permeability) has been studied in isolation. The proposed research aimed to thoroughly characterize and model kinetics of parallel processes occurring in the GI tract upon co-dosing a compound with lipids and to relate the kinetics to chemical composition and colloidal structure of intestinal contents. The study included experimental characterization and computational modelling of kinetics of parallel processes occurring in the GI tract after lipid ingestion – namely, compound dissolution, lipid digestion, compound partitioning into colloidal phases, absorption. The specific four aims of the proposed experimental approach were the followings. (1) Design and characterize biorelevant in vitro lipid digestion models able to simulate fundamental features of human intestinal contents in post-prandial conditions. Basic back-titration has been used to establish associated chemical composition characterizing products of the lipolysis process. (2) Investigate the ultra-structure and composition of colloidal species existing in the GI tract upon ingestion of lipids and their dynamic behavior. Dynamic light scattering (DLS), and small angle neutron scattering (SANS) have been employed to characterize the colloidal structures (emulsion droplets, vesicles, micelles) present throughout digestion. (3) Establish kinetics and thermodynamics of drug transport into and out of colloidal structures in the GI tract, based on a model drug that was selected to represent poorly water-soluble drug compounds. High-pressure liquid chromatography (HPLC) has been used in solubility/dissolution experiments, while electron paramagnetic resonance (EPR) has been employed to track the model drug in different phases formed during the digestion process (oil droplets, vesicles, micelles, free in aqueous solution, etc.). (4) Examine kinetics of compound transport across the intestinal membrane in the presence of food-associated lipids. The Caco-2 and HT29-MTX cell culture models were employed to investigate drug permeability proprieties in post-prandial conditions. The outcome was a mechanistic and kinetic model of intestinal absorption in the presence of ingested lipids. Developed kinetic expressions were integrated into a systems-based model that simulated the influence of ingested lipids on oral compound absorption. Mechanistic understanding of how ingested food lipids altered effectiveness of orally delivered compounds was also gained. The final outcome was an experimental and theoretical framework able to quantitatively describe and predict the effects of ingested food lipids on the overall oral drug absorption.