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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

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