title: Digestion of phospholipids after secretion of bile into the duodenum changes the phase behavior of bile components.
abstract: Bile components play a significant role in the absorption of dietary fat, by solubilizing the products of fat digestion. The absorption of poorly water-soluble drugs from the gastrointestinal tract is often enhanced by interaction with the pathways of fat digestion and absorption. These processes can enhance drug absorption. Thus, the phase behavior of bile components and digested lipids is of great interest to pharmaceutical scientists who seek to optimize drug solubilization in the gut lumen. This can be achieved by dosing drugs after food or preferably by formulating the drug in a lipid-based delivery system. Phase diagrams of bile salts, lecithin, and water have been available for many years, but here we investigate the association structures that occur in dilute aqueous solution, in concentrations that are present in the gut lumen. More importantly, we have compared these structures with those that would be expected to be present in the intestine soon after secretion of bile. Phosphatidylcholines are rapidly hydrolyzed by pancreatic enzymes to yield equimolar mixtures of their monoacyl equivalents and fatty acids. We constructed phase diagrams that model the association structures formed by the products of digestion of biliary phospholipids. The micelle-vesicle phase boundary was clearly identifiable by dynamic light scattering and nephelometry. These data indicate that a significantly higher molar ratio of lipid to bile salt is required to cause a transition to lamellar phase (i.e., liposomes in dilute solution). Mixed micelles of digested bile have a higher capacity for solubilization of lipids and fat digestion products and can be expected to have a different capacity to solubilize lipophilic drugs. We suggest that mixtures of lysolecithin, fatty acid, and bile salts are a better model of molecular associations in the gut lumen, and such mixtures could be used to better understand the interaction of drugs with the fat digestion and absorption pathway.
authors.affiliation: Medicinal Chemistry, ‡Drug Discovery Biology, and §Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University , 381 Royal Parade, Parkville, Victoria 3052, Australia.
authors.forename: Woldeamanuel A
authors.initials: WA
authors.lastname: Birru
authors.forename: Dallas B
authors.initials: DB
authors.lastname: Warren
authors.forename: Ahmed
authors.initials: A
authors.lastname: Ibrahim
authors.forename: Hywel D
authors.initials: HD
authors.lastname: Williams
authors.forename: Hassan
authors.initials: H
authors.lastname: Benameur
authors.forename: Christopher J H
authors.initials: CJ
authors.lastname: Porter
authors.forename: David K
authors.initials: DK
authors.lastname: Chalmers
authors.forename: Colin W
authors.initials: CW
authors.lastname: Pouton
mesh_terms: D001646:Bile / Q000378:metabolism*; D001647:Bile Acids and Salts / Q000737:chemistry; D004041:Dietary Fats; D004386:Duodenum / Q000378:metabolism*; D005227:Fatty Acids / Q000737:chemistry; D041981:Gastrointestinal Tract / Q000187:drug effects; D006801:Humans; D054709:Lecithins / Q000737:chemistry; D008027:Light; D008055:Lipids / Q000737:chemistry; D008823:Micelles; D056004:Molecular Dynamics Simulation; D010713:Phosphatidylcholines / Q000737:chemistry; D010743:Phospholipids / Q000737:chemistry*; D012542:Scattering, Radiation
chemical_list: D001647:Bile Acids and Salts; D004041:Dietary Fats; D005227:Fatty Acids; D054709:Lecithins; D008055:Lipids; D008823:Micelles; D010713:Phosphatidylcholines; D010743:Phospholipids; C028694:1-palmitoyl-2-oleoylphosphatidylcholine