Intestinal absorption of drugs mediated by transporters in intestinal epithelial cells

本研究对肠道转运蛋白的鉴定及其在药物吸收中的作用进行了研究。主要研究结果如下：1.根据pH分配理论，一元羧酸被认为通过被动扩散机制吸收。然而，在本研究中，两种转运蛋白，存在于肠上皮细胞，并接受作为底物的一元羧酸被确定。MCT 1是一元羧酸（如乳酸和乳酸）的质子共转运蛋白。然而，当MCT 1稳定转染到MDA-MB 231细胞时，它对酸性药物如苯甲酸和水杨酸表现出转运活性。此外，阴离子反向转运体AE 2也转运这些单羧酸。此外，免疫组织化学分析表明，在刷状缘膜以及基底外侧膜的MCT 1的存在。这些结果表明，单羧酸类药物通过特定的反式吸收， 关于我们 这些转运蛋白将有助于促进酸性药物的肠道吸收.肽转运蛋白PepT 1存在于肠上皮细胞的刷状缘膜上，并以pH依赖性方式介导各种二肽和三肽的吸收。将生物利用度低的左旋多巴衍生为二肽，并对其肠吸收机制进行了研究。L-dopa-L-phe是L-dopa的肽衍生物，其跨肠上皮单层的渗透性显著高于L-dopa，并且在高浓度天然二肽的存在下，其渗透性显著降低。因此，肽衍生化有望通过肽转运蛋白PepT 1来促进药物在肠道的吸收。这些研究为进一步认识膜转运蛋白的重要性以及利用肠上皮细胞中的转运蛋白来调控药物在肠道的吸收提供了新的思路。少

In the present study, identification and functional significance of intestinal transporters in the drug absorption were studied. The obtained results are as follows :1. Monocarboxylic acids have been thought to be absorbed by passive diffusion mechanism according to pH-partition theory. However, in the present study, two transporters that are present at the intestinal epithelial cells and accept monocarboxylic acids as the substrates were identified. MCT1 is a proton-cotransporter for monocarboxylic acids such as lactic acid and pyruvic acid. However, when MCT1 was stably transfected to MDA-MB231 cells, it exhibited transport activity for acidic drugs such as benzoic acid and salicylic acid In addition, anion antiporter AE2 also transported such monocarboxylic acids. Furthermore, immunohistochemical analysis demonstrated the presence of MCT1 at the brush-border membrane as well as basolateral membrane. These results suggest that monocarboxylic acid drugs are absorbed via specific trans … More porters and will be useful for the enhancement of intestinal absorption of acidic drugs by utilization of these transporters.2. Peptide transporter, PepT1 is present at the brush-border membrane of intestinal epithelial cells and mediates absorption of various di- and tri-peptides in a pH-dependent manner. L-dopa, which has low bioavailability, was derivated to dipeptide and the mechanism of intestinal absorption was examined. L-dopa-L-phe, a peptide-derivative of L-dopa, showed significantly higher permeability than that of L-dopa across the intestinal epithelial monolayers and the permeability was significantly decreased in the presence of high concentration of native dipeptides. So, peptide-derivation is expected to be useful for the increased intestinal absorption by utilizing peptide transporter PepT1.These lines of studies provide new insight of the significance of membrane transporters and new strategy to control intestinal absorption of drugs by utilizing the transporters in the intestinal epithelial cells. Less