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.
Kondoh
Masuo
M
Department of Pharmaceutics and Biopharmaceutics, Showa Pharmaceutical University, Machida, Tokyo, 194-8543, Japan. masuo@ac.shoyaku.ac.jp
Masuyama
Akane
A
Takahashi
Azusa
A
Asano
Nagayoshi
N
Mizuguchi
Hiroyuki
H
Koizumi
Naoya
N
Fujii
Makiko
M
Hayakawa
Takao
T
Horiguchi
Yasuhiko
Y
Watanbe
Yoshiteru
Y
D000818:Animals; D062506:Claudin-4; D003911:Dextrans / Q000378:metabolism; D004768:Enterotoxins / Q000494:pharmacology*; D007408:Intestinal Absorption / Q000187:drug effects / Q000502:physiology*; D007413:Intestinal Mucosa / Q000187:drug effects / Q000502:physiology*; D007583:Jejunum; D007700:Kinetics; D007770:L-Lactate Dehydrogenase / Q000032:analysis; D008297:Male; D008565:Membrane Proteins / Q000187:drug effects / Q000502:physiology*; D010446:Peptide Fragments / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar
D062506:Claudin-4; D003911:Dextrans; D004768:Enterotoxins; D008565:Membrane Proteins; D010446:Peptide Fragments; C035598:enterotoxin, Clostridium; D007770:L-Lactate Dehydrogenase