Understanding pharmacokinetic food effects using molecular dynamics simulation coupled with physiologically based...

In this study, a molecular dynamics (MD) method is assessed as a new front-end tool for deriving relevant drug-micelle partitioning rates for use in conjunction with a compartmental-style gastrointestinal absorption model. A refined mechanistic approach for handling micelle-associated vs unbound drug is presented and examined in terms of its utility for projecting human oral pharmacokinetic food/formulation effects. Similar to predecessor oral absorption models, the intestinal drug absorption rate is formulated as a function of the combined permeability through the unstirred water layer and the epithelial membrane, however, an additional diffusion coefficient adjustment is applied to account for the viscosity changes of the postprandial small intestine. Bulk passage of drug particles through the GI tract is simulated by compartmental transit through a network of nine compartments comprising the stomach, small intestine and colon. The tandem MD simulation/compartmental absorption algorithm is applied to identify factors influencing the fed vs fasted absorption ratios of a structurally diverse set of orally administered drugs. The data illustrate the interplay and apparent compromise between micelle solubilization and permeability.