QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: mol.104.008375v1 67/3/749    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kondoh, M. Articles by Watanbe, Y. Search for Related Content PubMed PubMed Citation Articles by Kondoh, M. Articles by Watanbe, Y.

ORIGINAL ARTICLE

A Novel Strategy for the Enhancement of Drug Absorption Using a Claudin Modulator

Department of Biopharmaceutics and Pharmaceutics, Showa Pharmaceutical University, Tokyo, Japan (M.K., A.M., A.T., N.A., N.K., M.F., Y.W.); Project III, National Institute of Health Sciences, Osaka Branch, Fundamental Research Laboratories for Development of Medicine, Osaka, Japan (H.M.); National Institute of Health Sciences, Tokyo, Japan (T.H.); and Department of Bacterial Toxicology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan (Y.H.)

Abstract

Claudin, a tight junction integral membrane protein and a family of proteins, forms the actual sealing element of the tight junction. There are more than 20 members of the claudin family with different tissue-specific expression and barrier functions. Thus, a family of claudin may be a target for modifying the absorption of drugs. Here, we examined whether modulation of claudin could be used to enhance drug absorption. In the current studies, we used a C-terminal fragment of Clostridium perfringens enterotoxin (C-CPE) as a modulator of claudin-4. The absorption of dextran was assessed in an in situ loop assay in rats to evaluate the absorption-enhancing effects of C-CPE. Treatment with C-CPE dose-dependently enhanced the absorption of dextran (mol. wt. 4000). These effects were not accompanied by injury of the intestinal mucosa as assessed by leakage of lactose dehydrogenase and histological observation. C-CPE was over 400-fold more potent at enhancing dextran absorption than capric acid, a clinically used enhancer of absorption. C-CPE interacted directly with claudin-4, and C-CPE lacking a part the C terminus neither bound claudin-4 nor enhanced absorption in the rat jejunum. These results suggest that C-CPE enhances the absorption of dextran in rat jejunum, apparently through interactions with claudin-4, and this effect may represent an effective novel strategy for enhancing the absorption of drugs.

Address correspondence to: Dr. Masuo Kondoh, Department of Pharmaceutics and Biopharmaceutics, Showa Pharmaceutical University, Machida, Tokyo, 194-8543, Japan. E-mail: masuo{at}ac.shoyaku.ac.jp

This article has been cited by other articles:

				R. J. Mrsny, G. T. Brown, K. Gerner-Smidt, A. G. Buret, J. B. Meddings, C. Quan, M. Koval, and A. Nusrat A Key Claudin Extracellular Loop Domain is Critical for Epithelial Barrier Integrity Am. J. Pathol., April 1, 2008; 172(4): 905 - 915. [Abstract] [Full Text] [PDF]

				C. M. Van Itallie, L. Betts, J. G. Smedley III, B. A. McClane, and J. M. Anderson Structure of the Claudin-binding Domain of Clostridium perfringens Enterotoxin J. Biol. Chem., January 4, 2008; 283(1): 268 - 274. [Abstract] [Full Text] [PDF]

				C.-H. Wong, D. D. Mruk, W. M. Lee, and C. Y. Cheng Targeted and reversible disruption of the blood-testis barrier by an FSH mutant-occludin peptide conjugate FASEB J, February 1, 2007; 21(2): 438 - 448. [Abstract] [Full Text] [PDF]

				C. Ebihara, M. Kondoh, N. Hasuike, M. Harada, H. Mizuguchi, Y. Horiguchi, M. Fujii, and Y. Watanabe Preparation of a Claudin-Targeting Molecule Using a C-Terminal Fragment of Clostridium perfringens Enterotoxin J. Pharmacol. Exp. Ther., January 1, 2006; 316(1): 255 - 260. [Abstract] [Full Text] [PDF]

				A. Masuyama, M. Kondoh, H. Seguchi, A. Takahashi, M. Harada, M. Fujii, H. Mizuguchi, Y. Horiguchi, and Y. Watanabe Role of N-Terminal Amino Acids in the Absorption-Enhancing Effects of the C-Terminal Fragment of Clostridium perfringens Enterotoxin J. Pharmacol. Exp. Ther., August 1, 2005; 314(2): 789 - 795. [Abstract] [Full Text] [PDF]