Department of Pharmacy, Uppsala University, Box 580, 751 23 Uppsala, Sweden.
Department of Neuroscience, Division of Physiology, Uppsala University, 752 36 Uppsala, Sweden.
Eur J Pharm Biopharm. 2019 Sep;142:387-395. doi: 10.1016/j.ejpb.2019.07.012. Epub 2019 Jul 12.
Oral administration of drug products is the preferred administration route. In recent decades there has been an increase in drug candidates with low solubility and/or low permeability. To increase the possibility of oral administration for the poorly permeating drugs, the use of absorption modifying excipients (AMEs) has been proposed. These types of AMEs may also affect the regulatory assessment of a novel drug delivery system if they affect the absorption of a drug from any of the four BCS classes. The effects of AMEs have previously been investigated in various animal models, including the single-pass intestinal perfusion (SPIP) in rats. To further improve the biorelevance and the in vivo predictiveness of the SPIP model, four compounds (atenolol, enalaprilat, ketoprofen, metoprolol) were perfused in fasted or fed state simulated intestinal fluid (FaSSIF or FeSSIF) together with the AMEs N-acetyl-cysteine, caprate, or sodium dodecyl sulfate. For the highly soluble and poorly permeating compounds enalaprilat and atenolol (BCS class III), the flux was increased the most by the addition of SDS in both FaSSIF and FeSSIF. For ketoprofen (BCS class II), the flux decreased in the presence of all AMEs in at least one of the perfusion media. The flux of metoprolol (BCS class I) was not affected by any of the excipients in none of simulated prandial states. The changes in magnitude in the absorption of the compounds were in general smaller in FeSSIF than in FaSSIF. This may be explained by a reduced free concentration AMEs in FeSSIF. Further, the results in FeSSIF were similar to those from intrajejunal bolus administration in rat in a previous study. This suggests that the biorelevance of the SPIP method may be increased when investigating the effects of AMEs, by the addition of intraluminal constituents representative to fasted and/or fed state to the inlet perfusate.
口服给药是首选的给药途径。在最近几十年，具有低溶解度和/或低渗透性的药物候选物有所增加。为了增加渗透性差的药物口服给药的可能性，使用了吸收改性赋形剂（AME）。如果这些类型的 AME 影响任何一种 BCS 分类药物的吸收，则它们也可能影响新型药物输送系统的监管评估。以前已经在各种动物模型中研究了 AME 的作用，包括在大鼠中的单次肠灌注（SPIP）。为了进一步提高 SPIP 模型的生物相关性和体内预测性，在禁食或进食状态模拟肠液（FaSSIF 或 FeSSIF）中灌注了四种化合物（阿替洛尔、依那普利拉、酮洛芬、美托洛尔），并添加了 N-乙酰半胱氨酸、癸酸、或十二烷基硫酸钠。对于高度可溶性和渗透性差的化合物依那普利拉和阿替洛尔（BCS 分类 III），在 FaSSIF 和 FeSSIF 中添加 SDS 可最大程度地增加通量。对于酮洛芬（BCS 分类 II），在至少一种灌注介质中，所有 AME 的存在都会降低通量。在任何模拟进食状态下，美托洛尔（BCS 分类 I）的通量都不受任何赋形剂的影响。在一般情况下，在 FeSSIF 中化合物吸收的变化幅度比在 FaSSIF 中要小。这可能是由于 FeSSIF 中 AME 的游离浓度降低所致。此外，在之前的一项研究中，FeSSIF 中的结果与大鼠空肠内推注给药的结果相似。这表明，当研究 AME 的作用时，通过向入口灌注液中添加代表禁食和/或进食状态的腔内成分，可以提高 SPIP 方法的生物相关性。
