In vitro evaluation of dexamethasone-beta-D-glucuronide for colon-specific drug delivery.
In vitro evaluation of dexamethasone-beta-D-glucuronide for colon-specific drug delivery.
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地塞米松-β-D-葡萄糖苷酸结肠特异性药物递送的体外评价。
DOI：
10.1023/a:1018956232628
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发表时间：
1993
影响因子：
3.7
通讯作者：
Friend,DR
中科院分区：
文献类型：
--
作者：
Haeberlin,B;Rubas,W;Nolen3rd,HW;Friend,DR
地塞米松-β- d -葡糖苷是抗炎皮质类固醇地塞米松结肠递送的潜在前药。以前的研究[j]。R. Tozeret al.，药学。Res. 8:45 - 454(1991)]表明地塞米松的一种糖苷前药在上胃肠道容易水解。因此，我们评估了地塞米松-β- d -葡糖苷对上消化道水解的耐药性。采用常规大鼠、无菌大鼠和结肠炎大鼠检测胃肠道酶水平，比较两种模型底物（对硝基苯-β- d -葡萄糖苷和-β- d -葡糖苷）的稳定性，并评价前药地塞米松-β- d -葡糖苷。在所有三种类型的大鼠中检测了腔内内容物、粘膜和下层肌肉/结缔组织的水解活性。酶活性（β- d -葡萄糖苷酶和β- d -葡萄糖醛酸酶）在常规大鼠盲肠和结肠管腔中最高。相比之下，无菌大鼠在近端小肠（PSI）和远端小肠（DSI）中表现出相对较高的β- d -葡萄糖苷酶活性（约占常规大鼠总活性的80%）。大鼠诱导结肠炎（醋酸）显示大肠内腔β- d -葡萄糖醛酸酶活性水平降低；而β- d -葡萄糖苷酶活性相对于常规大鼠没有变化。结肠炎大鼠粘膜β- d -葡萄糖醛酸酶活性明显低于常规动物。尽管结肠大鼠腹腔内β- d -葡萄糖醛酸酶活性水平降低，但小肠和大肠之间的活性仍有明显的梯度。与地塞米松相比，地塞米松葡糖苷和葡糖苷前药通过Caco-2细胞单层的通透性相对较低。结果表明，地塞米松-β- d -葡糖苷在上消化道应是相对稳定且吸收不良的。一旦化合物到达大肠，它应该被水解成地塞米松和葡萄糖醛酸。由于人类小肠中β- d -葡萄糖醛酸酶活性水平较实验室大鼠低，因此人类结肠递送的特异性应该更大。
Dexamethasone-β-D-glucuronide is a potential prodrug for colonic delivery of the antiinflammatory corticosteroid dexamethasone. Previous studies [T. R. Tozeret al., Pharm. Res. 8:445–454 (1991)] indicated that a glucoside prodrug of dexamethasone was susceptible to hydrolysis in the upper gastrointestinal tract. Resistance of dexamethasone-β-D-glucuronide to hydrolysis in the upper gastrointestinal tract was therefore assessed. Conventional, germfree, and colitic rats were used to examine enzyme levels along the gastrointestinal tract to compare the stability of two model substrates (p-nitrophenyl-β-D-glucoside and -β-D-glucuronide) and to evaluate the prodrug dexamethasone-β-D-glucuronide. Hydrolytic activity was examined in the luminal contents, mucosa, and underlying muscle/connective tissues in all three types of rats. Enzymatic activity (β-D-glucosidase and β-D-glucuronidase) was greatest in the lumen of cecum and colon of conventional rats. In contrast, germ-free rats exhibited relatively high levels of β-D-glucosidase activity (about 80% of total activity in the conventional rats) in the proximal small intestine (PSI) and the distal small intestine (DSI). Rats with induced colitis (acetic acid) showed reduced levels of luminal β-D-glucuronidase activity in the large intestine; however, β-D-glucosidase activity was relatively unchanged relative to that of the conventional rat. Mucosal β-D-glucuronidase activity was significantly lower in the colitic rats compared with that in the conventional animals. Despite reduced luminal levels of β-D-glucuronidase activity in the colitic rats, there was still a sharp gradient of activity between the small and the large intestines. Permeability of the glucoside and glucuronide prodrugs of dexamethasone through a monolayer of Caco-2 cells was relatively low compared to that of dexamethasone. The results indicate that dexamethasone-β-D-glucuronide should be relatively stable and poorly absorbed in the upper gastrointestinal tract. Once the compound reaches the large intestine, it should be hydrolyzed to dexamethasone and glucuronic acid. Specificity of colonic delivery in humans should be even greater due to lower levels of β-D-glucuronidase activity in the small intestine compared with that in the laboratory rat.