title: Computational Models of the Gastrointestinal Environment. 1. The Effect of Digestion on the Phase Behavior of Intestinal Fluids.
abstract: 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.
authors.forename: Woldeamanuel A
authors.initials: WA
authors.lastname: Birru
authors.forename: Dallas B
authors.initials: DB
authors.lastname: Warren
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Headey
authors.affiliation: Capsugel Research and Development , Strasbourg, France.
authors.forename: Hassan
authors.initials: H
authors.lastname: Benameur
authors.forename: Christopher J H
authors.identifier: 0000-0003-3474-7551
authors.initials: CJ
authors.lastname: Porter
authors.forename: Colin W
authors.identifier: 0000-0003-0224-3308
authors.initials: CW
authors.lastname: Pouton
authors.forename: David K
authors.identifier: 0000-0003-2366-569X
authors.initials: DK
authors.lastname: Chalmers
mesh_terms: D001646:Bile / Q000737:chemistry; D001647:Bile Acids and Salts / Q000737:chemistry; D001826:Body Fluids / Q000737:chemistry*; D002626:Chemistry, Pharmaceutical / Q000379:methods; D003198:Computer Simulation; D004063:Digestion / Q000502:physiology*; D041981:Gastrointestinal Tract / Q000737:chemistry*; D006002:Glycodeoxycholic Acid / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008823:Micelles; D056004:Molecular Dynamics Simulation; D019301:Oleic Acid / Q000737:chemistry; D010713:Phosphatidylcholines / Q000737:chemistry; D010743:Phospholipids / Q000737:chemistry; D014867:Water / Q000737:chemistry
chemical_list: D001647:Bile Acids and Salts; D008823:Micelles; D010713:Phosphatidylcholines; D010743:Phospholipids; D014867:Water; D019301:Oleic Acid; D006002:Glycodeoxycholic Acid; C028694:1-palmitoyl-2-oleoylphosphatidylcholine
keywords: DOSY-NMR; bile; bile salts; digested phospholipids; gastrointestinal tract; molecular dynamics; oleic acid; phase behavior; phase diagram; phospholipids