Luminal Lipid Phases after Administration of a Triglyceride Solution of Danazol in the Fed State and Their Contribution to the Flux of Danazol Across Caco-2 Cell Monolayers

Abstract

The first aim of this study was to characterize the luminal contents and their micellar phase after the administration of a heterogeneous liquid meal to healthy adults. The second aim was to evaluate the impact of micellar lipids and coarse lipid particles on danazol flux through intestinal monolayers. A third aim was to compare the micellar composition in the upper small intestine with the composition of fed state simulating intestinal fluid (FeSSIF-V2), a medium that has been proposed for investigating dissolution of poorly soluble drugs in the fed state. Danazol (150 mg), predissolved in the olive oil portion of the meal, was administered via the gastric port of a two-lumen tube to the antrum of eight adults. Aspirates from the ligament of Treitz [collected up to 4 h postdosing (~15 mL every 30 min)] were characterized physicochemically. Comparison of these characteristics with FeSSIF-V2 indicates that FeSSIF-V2 is an appropriate medium for evaluating drug solubilization in the luminal micellar phase in the fed state. Individual aspirates and their corresponding micellar phases were also diluted with aqueous transport medium and subjected to Caco-2 cell permeation experiments. Permeability coefficients for danazol in the diluted aspirates were smaller than those for the diluted micellar phases, which in turn were similar to those for aqueous transport medium. The high danazol concentrations overcompensated the reduced permeability coefficient values in the diluted aspirates in terms of total drug flux. We conclude that drug dissolved in the coarse lipid particles formed after administration of a triglyceride solution can directly contribute to the flux of lipophilic drugs across the intestinal mucosa.

Effect of Ingested Lipids on Drug Dissolution and Release with Concurrent Digestion: A Modeling Approach

“…The significance of predicting drug transport between different colloidal phases present during lipid digestion lies in the assumption that simultaneous absorption occurs in vivo , and that this absorption process is driven by aqueous drug concentration. Although overall drug absorptive flux has been related to total drug concentration (35), multiple literature reports indicate that drug absorption is driven by the concentration of drug in the aqueous phase (33, 35, 36). …”

Increasing the biorelevance of simulated intestinal fluids for better predictions of drug equilibrium solubility in the fasted upper small intestine

“…Vials were then sealed with polypropylene caps, and put in an oscillating water bath (37 °C). Equilibration times were experimentally determined or had already been determined previously using similar media volumes (1-5 ml) and the same in vitro setup [3,10,14,15]. Equilibration times were 2 h (cinnarizine), 8 h (ketoconazole), 2 h (indomethacin) and 4 h (danazol).…”

Supersaturation of zafirlukast in fasted and fed state intestinal media with and without precipitation inhibitors

“…Only a few studies, determining the amount and ratio between fatty acids (FA) and monoglycerides (MG) in the human postprandial intestine are available (Kalantzi et al 2006;Persson et al 2005;Vertzoni et al 2012). These show that the in vivo FA and MG composition is very variable and also very dependent on the administered meal.…”