GLUCOCORTICOID-DEXTRAN CONJUGATES AS POTENTIAL PRODRUGS FOR COLON-SPECIFIC DELIVERY - HYDROLYSIS IN RAT GASTROINTESTINAL-TRACT CONTENTS
GLUCOCORTICOID-DEXTRAN CONJUGATES AS POTENTIAL PRODRUGS FOR COLON-SPECIFIC DELIVERY - HYDROLYSIS IN RAT GASTROINTESTINAL-TRACT CONTENTS
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DOI：
10.1002/jps.2600830919
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发表时间：
1994-09-01
影响因子：
3.8
通讯作者：
TOZER, TN
中科院分区：
文献类型：
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作者：
MCLEOD, AD;FRIEND, DR;TOZER, TN
慢性结肠炎，例如，溃疡性结肠炎和克罗恩氏病目前用糖皮质激素和其它抗炎剂治疗。副作用限制了长期糖皮质激素治疗。通过使用选择性地将药物递送至结肠的前药，可以减少剂量，并因此减少副作用。我们以前合成糖皮质激素-葡聚糖缀合物，其中地塞米松和甲基强的松龙连接到葡聚糖（重均分子量72 600）使用二羧酸接头（琥珀酸和戊二酸）。在本研究中，半酯（半酯糖皮质激素+接头）和葡聚糖缀合物的水解动力学在37 ℃下在雄性Sprague-Dawley大鼠胃肠道（GI）迹线的稀释管腔内容物中孵育后测定。半酯在近端小肠中迅速水解（例如，地塞米松-半戊二酸盐t（1/2）= 0.5 h）该速率沿胃肠道向下逐渐降低（在远端小肠、盲肠和结肠中t（1/2）分别= 4.8、54和68 h）。负责半酯水解的酶，显然是A型碱性羧酸酯酶，可能是宿主来源的，因为其活性在细菌计数低的小肠中最高。葡聚糖缀合物在上胃肠道内容物中抵抗水解，但在细菌计数高的盲肠和结肠内容物中快速降解。所测试的葡聚糖缀合物，甲基强的松龙-琥珀酸酯-葡聚糖，容易被内切葡聚糖酶水解，表明底物特异性在糖皮质激素附着后不会丧失。这项研究的结果表明，葡聚糖缀合物可能是有用的选择性地提供糖皮质激素到大肠治疗结肠炎。
Chronic colitis, e.g., ulcerative colitis and Crohn's disease, is presently treated with glucocorticoids and other antiinflammatory agents. Side effects limit chronic glucocorticoid therapy. The dose, and consequently the side effects, may be reduced by using prodrugs that selectively deliver drug to the colon. We previously synthesized glucocorticoid-dextran conjugates in which dexamethasone and methylprednisolone were attached to dextran (weight-average molecular weight 72 600) using dicarboxylic acid linkers (succinate and glutarate). In the present study, the hydrolysis kinetics of the hemiesters (hemiester glucocorticoid + linker) and dextran conjugates were determined after incubation at 37 degrees C in diluted luminal contents of the gastrointestinal (GI) trace of male Sprague-Dawley rats. The hemiesters were rapidly hydrolyzed in the proximal small intestine (e.g., dexamethasone-hemiglutarate t(1/2) = 0.5 h) This rate decreased progressively down the GI tract (t(1/2) = 4.8, 54, and 68 h in distal small intestine, cecum, and colon, respectively). The enzyme responsible for hemiester hydrolysis, apparently a type-A alkaline carboxylesterase, is probably of host origin because its activity is highest in the small intestine where bacterial count is low. The dextran conjugates resisted hydrolysis in upper GI tract contents but were rapidly degraded in cecal and colonic contents where the bacterial count is high. The dextran conjugate tested, methylprednisolone-succinate-dextran, was easily hydrolyzed by an endodextranase, indicating that substrate specificity is not lost upon the attachment of glucocorticoid. The results of this study indicate that dextran conjugates may be useful in selectively delivering glucocorticoids to the large intestine for the treatment of colitis.