title: Estimation of intragastric drug solubility in the fed state: comparison of various media with data in aspirates.
abstract: The suitability of various media to forecast the solubility of ketoconazole and dipyridamole in the fed stomach at various periods after meal administration was evaluated. Solubilities were measured with the shake-flask method in gastric fluids aspirated 30, 60 and 120 min after administration of 500 ml Ensure plus to healthy fasted adults, in three sets of simulated gastric fluids based on milk, and in simple aqueous buffered media. Simple aqueous buffered media vastly underestimated the intragastric solubility of model compounds in the fed state. When using undigested milk-based media, the solubilities of model compounds in aspirates were also underestimated by a factor of 2.5-27. Solubility in milk digested with pepsin was useful for estimating the intragastric solubility of ketoconazole (within 20%) but overestimated the intragastric values of dipyridamole by a factor of 2-19. For both drugs, the solubility in milk digested with pepsin and lipase predicted the solubility in aspirates collected 60 min after meal administration, whereas at other times it overestimated the intragastric solubility (by a factor of <5). Both the use of biorelevant media and simulation of intragastric digestion are necessary for the prediction of drug solubility in the fed stomach. Milk digested with pepsin and lipase enabled the estimation of the intragastric solubility of dipyridamole and ketoconazole at 1 h after meal intake. Simulation of vesicle/micellar structures seems to be key for the prediction of intragastric solubility in the fed stomach.
authors: Laboratory of Biopharmaceutics and Pharmacokinetics, National and Kapodistrian University of Athens, Athens, Greece.
authors: A
authors: A
authors: Diakidou
authors: M
authors: M
authors: Vertzoni
authors: J
authors: J
authors: Dressman
authors: C
authors: C
authors: Reppas
mesh_terms: D000328:Adult; D005260:Female; D005502:Food; D018565:Food-Drug Interactions / Q000502:physiology; D005750:Gastric Juice / Q000378:metabolism*; D005753:Gastric Mucosa / Q000378:metabolism*; D006801:Humans; D008297:Male; D004364:Pharmaceutical Preparations / Q000737:chemistry / Q000378:metabolism*; D012527:Satiation / Q000502:physiology*; D012995:Solubility
chemical_list: D004364:Pharmaceutical Preparations