In vitro permeability through Caco-2 cells is not quantitatively predictive of in vivo absorption for peptide-like drugs absorbed via the dipeptide transporter system
In vitro permeability through Caco-2 cells is not quantitatively predictive of in vivo absorption for peptide-like drugs absorbed via the dipeptide transporter system
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DOI：
10.1023/a:1016045820933
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发表时间：
1996-01-01
影响因子：
3.7
通讯作者：
Morrison, RA
中科院分区：
文献类型：
--
作者：
Chong, SH;Dando, SA;Morrison, RA
在许多药物发现项目中，具有药理活性的候选药物的肠道通透性差是导致口腔fi疗效不佳的最常见原因之一。因此，同时评估结构-渗透性关系以及结构-活性关系可以加快选择具有良好口服吸收的候选药物。在这方面，Caco-2细胞系统作为体外模型似乎很有希望。Caco-2细胞在培养过程中经历了自发的肠细胞分化，类似于小肠上皮细胞(1)。当它们生长到在半透膜上时，细胞的极性和紧密连接就建立起来了(2)。作为体外吸收模型的Caco-2细胞的形态和细胞特性已在前面描述过(2)。此外，二肽和三肽转运体(3，4)的存在也得到了证实，但我们实验室的初步研究表明，被二肽转运体系统吸收的化合物比通过被动扩散在体内吸收同样好的化合物具有相对较低的渗透率。本研究的目的是评估14种异源药物的渗透性，并研究主要通过二肽转运体系统吸收的药物与被动扩散的药物之间是否存在定量差异。
In many drug discovery programs, poor intestinal permeability of pharmacologically active drug candidates is one of the most common reasons for poor oral efficacy. As such, simultaneous assessment of the structure-permeability relationship as well as the structure-activity relationship can expedite the selection of a drug candidate with good oral ab-sorption. In this regard, the caco-2 cell system as an in vitro model appears promising. Caco-2 cells undergo spontaneous enterocytic differentiation in culture and resemble small intestinal epithelial cells (1). When they grow to confluency on a semi-permeable membrane, the cell polarity and tight junctions are established (2). The morphology and cellular prop-erties of the caco-2 cells as an in vitro absorption model have been described previously (2). In addition, the presence of di-and tri-peptide transporters (3, 4) has also been docu-mented.However, preliminary studies in our laboratory suggested that compounds that are absorbed by the dipeptide transporter system had relatively low permeability values compared to compounds that were equally well absorbed in vivo by passive diffusion. The objectives of the present study were to evaluate the permeability of a heterologous series of fourteen drugs and to investigate whether there is a quantitative difference between drugs that are absorbed primarily via the dipeptide transporter system and passive diffusion.