Colon-specific delivery of dexamethasone from a glucoside prodrug in the guinea pig.
Colon-specific delivery of dexamethasone from a glucoside prodrug in the guinea pig.
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豚鼠体内葡萄糖苷前药的地塞米松结肠特异性递送。
DOI：
10.1023/a:1015838825437
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发表时间：
1991
影响因子：
3.7
通讯作者：
Friend,DR
中科院分区：
文献类型：
--
作者：
Tozer,TN;Rigod,J;McLeod,AD;Gungon,R;Hoag,MK;Friend,DR
地塞米松-β-D-葡萄糖苷是一种潜在的结肠给药药物地塞米松的前体药物。该前药选择性地将地塞米松递送至结肠的能力不仅取决于其从消化道缓慢吸收，还取决于其在胃和小肠中具有化学和酶稳定性。一旦到达大肠，它应该被定量水解以释放活性剂。通过测定地塞米松-β-D-葡萄糖苷在豚鼠消化道中的水解速率来评估地塞米松-β-D-葡萄糖苷用于地塞米松结肠特异性递送的潜力，豚鼠是一种已经开发了炎性肠病模型的动物。在胃、小肠近端和远端、盲肠和结肠的组织和管腔内容物中检查水解活性。对于组织，最大的水解活性在近端小肠中，而胃、盲肠和结肠仅具有中等活性。相反，盲肠和结肠的内容物显示出比小肠和胃的内容物更大的活性。即使在反复离心并重悬于缓冲液中后，管腔内容物仍保留β-葡糖苷酶活性。活性不受均质化的影响。这些观察结果表明，水解活性与位于腔细胞表面的酶有关。本文还研究了地塞米松-β-D-葡萄糖苷在豚鼠胃肠道中的运动和水解。大约20 - 30%的口服剂量似乎到达盲肠。在此，前药迅速水解为活性药物。从前体药物和药物的静脉内给药来看，地塞米松-β-D-葡萄糖苷在胃肠道中的吸收很差（生物利用度<1%）。在本实验条件下，地塞米松在豚鼠盲肠组织中的递送具有九倍的选择性优势。因此，有可能降低常规剂量，同时降低地塞米松的全身暴露量。由于人类在小肠中具有少得多的葡糖苷酶活性，预期甚至更大的位点选择性递送至盲肠和结肠。
Dexamethasone-β-D-glucoside is a potential prodrug for colonic delivery of the antiinflammatory agent, dexamethasone. The ability of this prodrug to deliver dexamethasone selectively to the colon depends not only on its being slowly absorbed from the alimentary canal, but also on its having chemical and enzymatic stability in the stomach and small intestine. Once reaching the large bowel, it should be quantitatively hydrolyzed to release the active agent. The potential of dexamethasone-β-D-glucoside for colon-specific delivery of dexamethasone is assessed by determining the rates of its hydrolysis down the alimentary canal of the guinea pig, an animal in which an inflammatory bowel disease model has been developed. The hydrolytic activity is examined in tissues and luminal contents of the stomach, proximal and distal segments of the small intestine, cecum, and colon. For the tissues, the greatest hydrolytic activity is in the proximal small intestine, while the stomach, cecum, and colon have only moderate activity. In contrast, the contents of the cecum and colon show greater activity than the contents of the small intestine and stomach. The luminal contents retained β-glucosidase activity even after repeated centrifugation and resuspension in a buffer. The activity was unaffected by homogenization. These observations suggest that hydrolytic activity is associated with enzymes located on the surface of luminal cells. The movement and hydrolysis of dexamethasone-β-D-glucoside down the gastrointestinal tract of the guinea pig are also examined. About 20 to 30% of an oral dose appears to reach the cecum. Here the prodrug is rapidly hydrolyzed to the active drug. From intravenous administration of the prodrug and drug, it is apparent that dexamethasone-β-D-glucoside is poorly absorbed in the gastrointestinal tract (bioavailability, <1%). There is a ninefold selective advantage for delivery of dexamethasone in cecal tissues in the guinea pig under the conditions of this experiment. Thus, there is a potential for a decrease in the usual dose and a concomitant reduction in the systemic exposure to dexamethasone. Because humans have much less glucosidase activity in the small intestine, even greater site-selective delivery to the cecum and colon is expected.