A novel strategy for the enhancement of drug absorption using a claudin modulator
A novel strategy for the enhancement of drug absorption using a claudin modulator
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DOI：
10.1124/mol.104.008375
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发表时间：
2005-03-01
影响因子：
3.6
通讯作者：
Watanbe, Y
中科院分区：
文献类型：
--
作者：
Kondoh, M;Masuyama, A;Watanbe, Y
Claudin是一种紧密连接的整体膜蛋白和一个蛋白质家族，形成了紧密连接的实际密封元件。claudin家族有20多个成员，具有不同的组织特异性表达和屏障功能。因此，一个克劳丁家族可能是改变药物吸收的靶标。在这里，我们研究了克劳丁的调节是否可以用来增强药物吸收。在目前的研究中，我们使用了产气荚膜梭菌肠毒素（C-CPE）的c端片段作为claudin-4的调节剂。采用原位环法测定大鼠对葡聚糖的吸收，评价C-CPE对葡聚糖的吸收增强作用。C-CPE剂量依赖性地增强了葡聚糖的吸收（mol. wt. 4000）。通过乳糖脱氢酶的渗漏和组织学观察，这些作用没有伴随着肠黏膜的损伤。C- CPE在促进葡聚糖吸收方面比临床使用的吸收促进剂癸酸强400倍以上。C-CPE直接与cludin -4相互作用，C-CPE缺乏C端部分，既不能结合cludin -4，也不能促进大鼠空肠的吸收。这些结果表明，C- CPE明显通过与cludin -4的相互作用增强了大鼠空肠对葡聚糖的吸收，这种作用可能是一种有效的增强药物吸收的新策略。
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.