Pang Yi-Nuo, Zhang Yan, Zhang Zhi-Rong
West China School of Pharmacy, Sichuan University, Chengdu, 610041, Sichuan Province, China.
World J Gastroenterol. 2002 Oct;8(5):913-7. doi: 10.3748/wjg.v8.i5.913.
To synthesize dexamethasone-succinate-dextran (DSD) conjugate and to evaluate the potentiality of DSD for the treatment of inflammatory bowel diseases.
Dexamethasone was attached to dextran (average molecular weight=70,400 Dalton) using succinate anhydride in an anhydrous environment catalyzed by 4-dimethylaminopyridine and 1, 1'-carbonyldiimidazole. The chemical structure of DSD was identified by UV, IR and NMR, and the in vivo drug release behavior of this prodrug was investigated after oral administration of DSD suspension.
The DSD conjugate was obtained in two steps and the content of dexamethasone in DSD was 11.28 %. The dextran prodrug was stable in rat stomach and small intestine and negligibly absorbed from these tracts. Four to nine hours after the oral administration, most of the prodrug (>95 %) had moved to the cecum and colon, and was easily hydrolyzed by an endodextranase. Recover of dexamethasone from colon and cecum after administration of DSD conjugate was 6-12 folds higher than the recovery after administration of unmodified dexamethasone (t=2.74, P<0.05). The preferential release of free dexamethasone in cecum and colon over that in the small intestine was statistically significant (t=2.27, P<0.05).
The results of this study indicate that dextran conjugates may be useful in selectively delivering glucocorticoids to the colon.
合成地塞米松琥珀酸酯 - 葡聚糖（DSD）缀合物，并评估DSD治疗炎症性肠病的潜力。
在4 - 二甲氨基吡啶和1,1'-羰基二咪唑催化的无水环境中，使用琥珀酸酐将地塞米松连接到葡聚糖（平均分子量 = 70,400道尔顿）上。通过紫外光谱、红外光谱和核磁共振鉴定DSD的化学结构，并在口服DSD悬浮液后研究该前药的体内药物释放行为。
分两步获得DSD缀合物，DSD中地塞米松的含量为11.28%。葡聚糖前药在大鼠胃和小肠中稳定，从这些部位的吸收可忽略不计。口服给药后4至9小时，大部分前药（>95%）转移到盲肠和结肠，并容易被内切葡聚糖酶水解。给予DSD缀合物后从结肠和盲肠回收的地塞米松比给予未修饰地塞米松后的回收率高6至12倍（t = 2.74，P<0.05）。盲肠和结肠中游离地塞米松的优先释放相对于小肠具有统计学意义（t = 2.27，P<0.05）。
本研究结果表明葡聚糖缀合物可能有助于将糖皮质激素选择性地递送至结肠。
