Transient permeability enhancers (PEs), such as caprylate, caprate, and salcaprozate sodium (SNAC), improve the bioavailability of poorly permeable macromolecular drugs. However, the effects are variable across individuals and classes of macromolecular drugs and biologics. Here, we examined the influence of bile compositions on the ability of membrane incorporation of three transient PEs—caprylate, caprate, and SNAC—using coarse-grained molecular dynamics (CG-MD). The availability of free PE monomers, which are important near the absorption site, to become incorporated into the membrane was higher in fasted-state fluids than that in fed-state fluids. The simulations also showed that transmembrane perturbation, i.e., insertion of PEs into the membrane, is a key mechanism by which caprylate and caprate increase permeability. In contrast, SNAC was mainly adsorbed onto the membrane surface, indicating a different mode of action. Membrane incorporation of caprylate and caprate was also influenced by bile composition, with more incorporation into fasted- than fed-state fluids. The simulations of transient PE interaction with membranes were further evaluated using two experimental techniques: the quartz crystal microbalance with dissipation technique and total internal reflection fluorescence microscopy. The experimental results were in good agreement with the computational simulations. Finally, the kinetics of membrane insertion was studied with CG-MD. Variation in micelle composition affected the insertion rates of caprate monomer insertion and expulsion from the micelle surface. In conclusion, this study suggests that the bile composition and the luminal composition of the intestinal fluid are important factors contributing to the interindividual variability in the absorption of macromolecular drugs administered with transient PEs.

中文翻译：

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胆汁成分对瞬时通透性增强剂的膜结合的影响。

瞬时通透性增强剂 (PE)，例如辛酸盐、癸酸盐和硫己酸钠 (SNAC)，可提高渗透性差的大分子药物的生物利用度。然而，效果因个体和大分子药物和生物制剂的类别而异。在这里，我们使用粗粒度分子动力学 (CG-MD) 检查了胆汁成分对三种瞬态 PE（辛酸盐、癸酸盐和 SNAC）的膜结合能力的影响。游离 PE 单体（在吸收位点附近很重要）的可用性在禁食状态流体中比在供给状态流体中更高。模拟还表明，跨膜扰动，即.，将 PE 插入膜中，是辛酸盐和癸酸盐增加渗透性的关键机制。相比之下，SNAC 主要吸附在膜表面，表明其作用方式不同。辛酸盐和癸酸盐的膜掺入也受胆汁成分的影响，与进食状态相比，更多地掺入禁食状态的液体中。使用两种实验技术进一步评估了瞬态 PE 与膜相互作用的模拟：具有耗散技术的石英晶体微量天平和全内反射荧光显微镜。实验结果与计算模拟非常吻合。最后，用 CG-MD 研究了膜插入的动力学。胶束组成的变化影响癸酸单体从胶束表面插入和排出的插入速率。总之，这项研究表明，胆汁成分和肠液的管腔成分是导致大分子药物吸收的个体差异的重要因素。