Computational Models of the Gastrointestinal Environment. 1. The Effect of Digestion on the Phase Behavior of Intestinal Fluids

Improved
models of the gastrointestinal environment have great
potential to assist the complex process of drug formulation. Molecular
dynamics (MD) is a powerful method for investigating phase behavior
at a molecular level. In this study we use multiple MD simulations
to calculate phase diagrams for bile before and after digestion. In
these computational models, undigested bile is represented by mixtures
of palmitoyl-oleoylphosphatidylcholine (POPC), sodium glycodeoxycholate
(GDX), and water. Digested bile is modeled using a 1:1 mixture of
oleic acid and palmitoylphosphatidylcholine (lysophosphatidylcholine,
LPC), GDX, and water. The computational phase diagrams of undigested
and digested bile are compared, and we describe the typical intermolecular
interactions that occur between phospholipids and bile salts. The
diffusion coefficients measured from MD simulation are compared to
experimental diffusion data measured by DOSY-NMR, where we observe
good qualitative agreement. In an additional set of simulations, the
effect of different ionization states of oleic acid on micelle formation
is investigated.