School of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL, UK.
Eur J Pharm Sci. 2011 Oct 9;44(3):299-309. doi: 10.1016/j.ejps.2011.08.007. Epub 2011 Aug 16.
The purpose of this study was to develop an in vitro permeation model that will predict the fraction of drugs absorbed in humans. A rotating-diffusion cell with two aqueous compartments, separated by a lipid-impregnated artificial membrane, was used to determine the permeability of drugs under conditions of controlled hydrodynamics. The measured effective permeability coefficient was modified to include the paracellular transport derived from a previously reported colorectal adenocarcinoma epithelial cell line (Caco-2) permeability study and the effects of unstirred water layer anticipated in vivo. Permeability data were collected for 31 different marketed drugs with known absolute oral bioavailability and human hepatic clearance data. Literature bioavailability values were corrected for the first pass hepatic clearance thus obtaining the fraction absorbed from intestinal lumen (fraction absorbed), F(a), while assuming that the fraction escaping intestinal extraction, F(g), was approximately ~1. Permeability obtained under conditions of controlled hydrodynamics was compared with the permeability measured under unstirred conditions. It is shown that the optimized effective permeability correlates with the fraction absorbed. In contrast, permeability data obtained under unstirred conditions does not show a good correlation. The in vitro permeation model developed in this study predicts the fraction absorbed of the selected drugs in humans within experimental uncertainty. It has been demonstrated that the correlation with the fraction absorbed is greatly improved using the permeability data obtained under controlled hydrodynamics with paracellular transport included in the model.
本研究旨在开发一种体外渗透模型，以预测药物在人体中的吸收分数。使用具有两个水性隔室的旋转扩散细胞，通过脂质浸渍的人工膜将其隔开，以在受控流体动力学条件下确定药物的渗透性。所测量的有效渗透系数经过修正，包括来自先前报道的结直肠腺癌上皮细胞系（Caco-2）渗透性研究的细胞旁转运以及体内预期的未搅动水层的影响。收集了 31 种具有已知绝对口服生物利用度和人体肝清除率数据的市售药物的渗透数据。文献生物利用度值已针对首过肝清除率进行了校正，从而获得了从肠腔吸收的分数（吸收分数），F(a)，同时假设肠提取的逃逸分数，F(g)，约为~1。在受控流体动力学条件下获得的渗透性与在未搅动条件下测量的渗透性进行了比较。结果表明，优化后的有效渗透性与吸收分数相关。相比之下，在未搅动条件下获得的渗透性数据没有显示出很好的相关性。本研究中开发的体外渗透模型在实验不确定性范围内预测了选定药物在人体中的吸收分数。已经证明，通过在模型中包含细胞旁转运，使用在受控流体动力学下获得的渗透性数据，与吸收分数的相关性得到了极大改善。
