PT  - JOURNAL ARTICLE
AU  - Masuo Kondoh
AU  - Akane Masuyama
AU  - Azusa Takahashi
AU  - Nagayoshi Asano
AU  - Hiroyuki Mizuguchi
AU  - Naoya Koizumi
AU  - Makiko Fujii
AU  - Takao Hayakawa
AU  - Yasuhiko Horiguchi
AU  - Yoshiteru Watanbe
TI  - A Novel Strategy for the Enhancement of Drug Absorption Using a Claudin Modulator
AID  - 10.1124/mol.104.008375
DP  - 2005 Mar 01
TA  - Molecular Pharmacology
PG  - 749--756
VI  - 67
IP  - 3
4099  - http://molpharm.aspetjournals.org/content/67/3/749.short
4100  - http://molpharm.aspetjournals.org/content/67/3/749.full
SO  - Mol Pharmacol2005 Mar 01; 67
AB  - 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.