Birru Woldeamanuel A, Warren Dallas B, Ibrahim Ahmed, Williams Hywel D, Benameur Hassan, Porter Christopher J H, Chalmers David K, Pouton Colin W
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.
Mol Pharm. 2014 Aug 4;11(8):2825-34. doi: 10.1021/mp500193g. Epub 2014 Jul 16.
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.
胆汁成分通过溶解脂肪消化产物，在膳食脂肪的吸收过程中发挥着重要作用。胃肠道中水溶性差的药物吸收通常会因与脂肪消化吸收途径相互作用而增强。这些过程能够促进药物吸收。因此，对于致力于优化药物在肠腔中溶解的制药科学家而言，胆汁成分和消化脂质的相行为极具研究价值。这可以通过餐后给药来实现，或者更理想的是将药物制成基于脂质的递送系统。胆汁盐、卵磷脂和水的相图已存在多年，但在此我们研究了在肠腔中存在的稀水溶液浓度下所形成的缔合结构。更重要的是，我们将这些结构与胆汁分泌后不久肠道中预期存在的结构进行了比较。磷脂酰胆碱会被胰酶迅速水解，生成其单酰基等效物和脂肪酸的等摩尔混合物。我们构建了相图，以模拟胆汁磷脂消化产物形成的缔合结构。通过动态光散射和比浊法能够清晰识别胶束 - 囊泡相边界。这些数据表明，要使相转变为层状相（即稀溶液中的脂质体），需要显著更高的脂质与胆汁盐摩尔比。消化胆汁的混合胶束对脂质和脂肪消化产物具有更高溶解能力，并且预计对溶解亲脂性药物具有不同的能力。我们认为溶血卵磷脂、脂肪酸和胆汁盐的混合物是肠腔中分子缔合的更好模型，此类混合物可用于更好地理解药物与脂肪消化吸收途径之间的相互作用。
