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Kondoh, M. et al.

Kondoh, Masuyama, Takahashi, Asano, Mizuguchi, Koizumi, Fujii, Hayakawa, Horiguchi, Watanbe,

A novel strategy for the enhancement of drug absorption using a claudin modulator.

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.[1]

References

A novel strategy for the enhancement of drug absorption using a claudin modulator. Kondoh, M., Masuyama, A., Takahashi, A., Asano, N., Mizuguchi, H., Koizumi, N., Fujii, M., Hayakawa, T., Horiguchi, Y., Watanbe, Y. Mol. Pharmacol. (2005) [Pubmed]

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