1999 Fiscal Year Final Research Report Summary
Intestinal absorption of drugs mediated by transporters in intestinal epithelial cells
| Project/Area Number |
10557214
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 展開研究 |
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| Research Field |
Physical pharmacy
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| Research Institution | KANAZAWA UNIVERSITY |
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Principal Investigator |
TSUJI Akira Kanazawa University, Pharmacy, Professor, 薬学部, 教授 (10019664)
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| Co-Investigator(Kenkyū-buntansha) |
TAMAI Ikumi Kanazawa University, Graduate School, Associate Professor, 自然科学研究所, 助教授 (20155237)
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| Project Period (FY) |
1998 – 1999
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| Keywords | transporter / intestinal absorption / peptide / monocarboxylic acid / gene expression / drug delivery endocytosis / エンドサイトーシス |
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| Research Abstract |
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
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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
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