Intestinal absorption of drugs mediated by transporters in intestinal epithelial cells

肠上皮细胞转运蛋白介导的药物肠道吸收

• 批准号: 10557214
• 负责人: TSUJI Akira
• 金额: $ 2.69万
• 依托单位: KANAZAWA UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10557214/
• 关键词: transporter; intestinal absorption; peptide; monocarboxylic acid; gene expression; drug delivery endocytosis; エンドサイトーシス; オリゴペプチド; H^+輸送担体; HCO3^-交換輸送担体; valacyclovir; L-dopa-L-phenylalanine; ペプチド化プロドラッグ

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

在本研究中，研究了肠道转运蛋白在药物吸收中的鉴定及其功能意义。所得结果如下： 1．根据 pH 分配理论，单羧酸被认为是通过被动扩散机制吸收的。然而，在本研究中，鉴定了存在于肠上皮细胞并接受单羧酸作为底物的两种转运蛋白。 MCT1 是一元羧酸（例如乳酸和丙酮酸）的质子协同转运蛋白。然而，当MCT1稳定转染MDA-MB231细胞时，它表现出对酸性药物如苯甲酸和水杨酸的转运活性。此外，阴离子反向转运蛋白AE2也转运此类单羧酸。此外，免疫组织化学分析表明 MCT1 在刷状缘膜和基底外侧膜上存在。这些结果表明，单羧酸药物通过特定的转运蛋白被吸收，并且通过利用这些转运蛋白将有助于增强酸性药物的肠道吸收。 2．肽转运蛋白 PepT1 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研究其肠道吸收机制。 L-dopa-L-phe 是 L-dopa 的肽衍生物，其穿过肠上皮单层的渗透性显着高于 L-dopa，并且在高浓度天然二肽存在下，渗透性显着降低。因此，肽衍生有望通过利用肽转运蛋白 PepT1 来增加肠道吸收。这些研究为膜转运蛋白的重要性提供了新的见解，并提供了利用肠上皮细胞中的转运蛋白控制肠道药物吸收的新策略。较少的

项目成果

H. Yabuuchi, I. Tamai, Y. Sai and A. Tsuji.: "Possible role of anion exchanger AE2 as the intestinal monocarboxylic acid/anion antiporter."Pharm. Res.. 15. 411-416 (1998)

H. Yabuuchi、I. Tamai、Y. Sai 和 A. Tsuji.：“阴离子交换剂 AE2 作为肠道单羧酸/阴离子逆向转运蛋白的可能作用。”

Y. Sai, M. Kajita, I. Tamai, J. Wakama, T. Wakamiya and A. Tsuji.: "Adsorptive-mediated transcytosis of a synthetic basic peptide, 001-C8 in Caco-2 cells."Pharm. Res.. 15. 1305-1309 (1998)

Y. Sai、M. Kajita、I. Tamai、J. Wakama、T. Wakamiya 和 A. Tsuji.：“Caco-2 细胞中合成碱性肽 001-C8 的吸附介导转胞吞作用”。

I. Tamai: "Immunohistochemical and functional characterization of pH dependent intestinal absorption of weak organic acids by monocarbosylic acid transporter MCT1."J. Pharm. Pharmcol.. 51. 1113-1121 (1999)

I. Tamai：“单碳基酸转运蛋白 MCT1 对弱有机酸的 pH 依赖性肠道吸收的免疫组织化学和功能表征。”J.

P. V. Balimanen, I. Tamai, A. Guo, T. Nakanishi, H. Kitada, F. H. Leibach, A. Tsuji and P. J. Sinko.: "Direct evidence for peptide transporter (PepT1)-mediated uptake of a nonpeptide prodrug, valacyclovir."Biochem. Biophys. Res. Commun.. 250. 246-251 (199

P. V. Balimanen、I. Tamai、A.Guo、T. Nakanishi、H. Kitada、F. H. Leibach、A. Tsuji 和 P. J. Sinko.：“肽转运蛋白 (PepT1) 介导的非肽前药伐昔洛韦摄取的直接证据。”

H.Yabuuchi: "Possible role of anion exchanger AE2 as the intestinal monocarboxylic acid/anion antiporter." Pharm.Res.15・3. 411-416 (1998)

H. Yabuuchi：“阴离子交换剂 AE2 作为肠道单羧酸/阴离子反向转运蛋白的可能作用。”Pharm.Res.15・3（1998）。