An in vitro methodology for predicting concentrations and potential precipitation in fasted upper small intestine, after administration of highly permeable, lipophilic weak bases in fasted upper small intestine was developed and evaluated for its predictability in regard to luminal precipitation.

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.

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Although prediction of the plasma profile of lipophilic drugs solely on the basis of in vitro data remains an ambitious target, this study shows that the plasma profile of a lipophilic drug can be predicted with appropriate in vitro dissolution data, provided that the absolute bioavailability of the drug is known and the drug has dissolution limited absorption.