Intestinal absorption of drugs mediated by transporters in intestinal epithelial cells

本研究对肠道转运体在药物吸收中的识别及其功能意义进行了研究。主要研究结果如下：1.根据pH分配理论，认为单元酸是通过被动扩散机制吸附的。然而，在目前的研究中，发现了两种存在于肠上皮细胞并接受单羧酸作为底物的转运体。MCT1是乳酸和丙酮酸等一元羧酸的质子共转运体。然而，当MCT1被稳定地转染到MDA-MB231细胞中时，它对苯甲酸和水杨酸等酸性药物具有转运活性，此外，阴离子逆向转运体AE2也运输这些一元羧酸。此外，免疫组织化学分析显示，MCT1存在于刷状缘膜和基底外侧膜上。这些结果表明，单羧酸类药物是通过特异性反式…吸收的。更多的转运蛋白，将有助于利用这些转运蛋白来促进酸性药物的肠道吸收。多肽转运体PepT1存在于肠上皮细胞刷状缘膜上，以pH依赖的方式调节各种二肽和三肽的吸收。将生物利用度较低的L多巴衍生为二肽，并对其肠道吸收机制进行了研究。L-多巴-L-Phe是L-多巴的多肽衍生物，其对肠上皮单层的通透性明显高于L-多巴，且在高浓度天然二肽存在下，通透性显著降低。这些研究为进一步认识膜转运蛋白的意义和利用肠上皮细胞转运蛋白来控制药物的肠道吸收提供了新的策略。较少

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