PURPOSE: To mechanistically study and model the effect of lipids, either from food or self-emulsifying drug delivery systems (SEDDS), on drug transport in the intestinal lumen. METHODS: Simultaneous lipid digestion, dissolution/release, and drug partitioning were experimentally studied and modeled for two dosing scenarios: solid drug with a food-associated lipid (soybean oil) and drug solubilized in amodel SEDDS (soybean oil and Tween 80 at 1:1 ratio). Rate constants for digestion, permeability of emulsion droplets, and partition coefficients in micellar and oil phases were measured, and used to numerically solve the developed model. RESULTS: Strong influence of lipid digestion on drug release from SEDDS and solid drug dissolution into food-associated lipid emulsion was observed and predicted by the developed model. Ninety minutes after introduction of SEDDS, there was 9% and 70% drug release in the absence and presence of digestion, respectively. However, overall drug dissolution in the presence of food-associated lipids occurred over a longer period than without digestion. CONCLUSION: A systems-based mechanistic model incorporating simultaneous dynamic processes occurring upon dosing of drug with lipids enabled prediction of aqueous drug concentration profile. This model, once incorporated with a pharmacokinetic model considering processes of drug absorption and drug lymphatic transport in the presence of lipids, could be highly useful for quantitative prediction of impact of lipids on bioavailability of drugs.
PURPOSE: To mechanistically study and model the effect of lipids, either from food or self-emulsifying drug delivery systems (SEDDS), on drug transport in the intestinal lumen. METHODS: Simultaneous lipid digestion, dissolution/release, and drug partitioning were experimentally studied and modeled for two dosing scenarios: solid drug with a food-associated lipid (soybeanoil) and drug solubilized in amodel SEDDS (soybeanoil and Tween 80 at 1:1 ratio). Rate constants for digestion, permeability of emulsion droplets, and partition coefficients in micellar and oil phases were measured, and used to numerically solve the developed model. RESULTS: Strong influence of lipid digestion on drug release from SEDDS and solid drug dissolution into food-associated lipid emulsion was observed and predicted by the developed model. Ninety minutes after introduction of SEDDS, there was 9% and 70% drug release in the absence and presence of digestion, respectively. However, overall drug dissolution in the presence of food-associated lipids occurred over a longer period than without digestion. CONCLUSION: A systems-based mechanistic model incorporating simultaneous dynamic processes occurring upon dosing of drug with lipids enabled prediction of aqueous drug concentration profile. This model, once incorporated with a pharmacokinetic model considering processes of drug absorption and drug lymphatic transport in the presence of lipids, could be highly useful for quantitative prediction of impact of lipids on bioavailability of drugs.
Authors: Hywel D Williams; Philip Sassene; Karen Kleberg; Jean-Claude Bakala-N'Goma; Marilyn Calderone; Vincent Jannin; Annabel Igonin; Anette Partheil; Delphine Marchaud; Eduardo Jule; Jan Vertommen; Mario Maio; Ross Blundell; Hassan Benameur; Frédéric Carrière; Anette Müllertz; Christopher J H Porter; Colin W Pouton Journal: J Pharm Sci Date: 2012-05-29 Impact factor: 3.534
Authors: F Carrière; C Renou; V Lopez; J De Caro; F Ferrato; H Lengsfeld; A De Caro; R Laugier; R Verger Journal: Gastroenterology Date: 2000-10 Impact factor: 22.682
Authors: Mette U Anby; Hywel D Williams; Michelle McIntosh; Hassan Benameur; Glenn A Edwards; Colin W Pouton; Christopher J H Porter Journal: Mol Pharm Date: 2012-06-15 Impact factor: 4.939