Laboratory of Biopharmaceutics and Pharmacokinetics, National & Kapodistrian University of Athens, Zografou, Greece.
Mol Pharm. 2012 May 7;9(5):1189-98. doi: 10.1021/mp200479f. Epub 2012 Apr 24.
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.
本研究的首要目的是对健康成年人给予非均相液餐后管腔内容物及其胶束相进行特征描述。次要目的是评估胶束脂质和粗脂质颗粒对丹那唑通过肠单层通透性的影响。第三个目的是比较上小肠中的胶束组成与 fed 状态模拟肠液（FeSSIF-V2）的组成，后者被提议用于研究在 fed 状态下难溶性药物的溶解情况。丹那唑（150mg）预先溶解于餐食的橄榄油部分，通过双腔管的胃腔端口给药至 8 位成年人的胃窦。在给药后 4 小时内（约每 30 分钟采集 15 毫升）从 Treitz 韧带抽吸物进行物理化学特性分析。将这些特性与 FeSSIF-V2 进行比较表明，FeSSIF-V2 是一种适用于评价在 fed 状态下管腔胶束相中药物溶解情况的介质。还将单独的抽吸物及其相应的胶束相用水性转运介质稀释，并进行 Caco-2 细胞渗透实验。在稀释的抽吸物中丹那唑的渗透系数小于稀释的胶束相的渗透系数，而后者又与水性转运介质的渗透系数相似。高浓度的丹那唑补偿了稀释抽吸物中药物总通量的渗透系数值降低。我们得出结论，在给予甘油三酯溶液后形成的粗脂质颗粒中溶解的药物可以直接有助于亲脂性药物跨肠黏膜的通量。
