Budesonide-beta-D-glucuronide: a potential prodrug for treatment of ulcerative colitis.
Budesonide-beta-D-glucuronide: a potential prodrug for treatment of ulcerative colitis.
复制标题
布地奈德-β-D-葡萄糖醛酸苷：治疗溃疡性结肠炎的潜在前药。
DOI：
10.1002/jps.2600840603
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发表时间：
1995
影响因子：
3.8
通讯作者：
Friend,DR
中科院分区：
文献类型：
--
作者：
Nolen3rd,H;Fedorak,RN;Friend,DR
布地奈德-β-D-葡萄糖醛酸苷是一种潜在有用的口服前药，用于治疗结肠炎性肠病。布地奈德是一种局部活性糖皮质激素，在人类和实验室动物中表现出较低的口服生物利用度（15%）。布地奈德作为其葡糖苷酸前药口服递送至大肠的发炎组织应导致局部高浓度的活性药物。在活性药物释放和吸收后，大部分应由于肝脏代谢而失活。布地奈德-β-D-葡萄糖醛酸苷在37 °C下pH值为1.5、4.5、6.5和7.4的溶液中化学稳定。在体外条件下，在从常规、无菌和结肠炎大鼠获得的管腔内容物和粘膜中评估了前药的酶不稳定性。在常规和结肠炎大鼠管腔内容物中，小肠（近端和远端部分）和盲肠之间的糖苷酶活性发生了实质性变化。在无菌大鼠的整个胃肠道中，管腔水解活性沿着较低。在所有三种类型的大鼠的整个胃肠道中，粘多糖糖苷酶活性沿着相对较低。还测量了溃疡性结肠炎患者和正常志愿者的人粪便样本中前药布地奈德-β-D-葡萄糖醛酸苷和地塞米松-β-D-葡萄糖醛酸苷的水解。正常粪便样品和结肠粪便样品中任一前药的水解或两种前药的相对水解速率之间无统计学显著差异。与大鼠盲肠和结肠内容物相比，人粪便样品中前药的水解速率约低两个数量级。
Budesonide‐β‐D‐glucuronide is a potentially useful orally administered prodrug for the treatment of colonic inflammatory bowel disease. Budesonide is a topically active glucocorticosteroid that exhibits low oral bioavailability (15%) in humans and laboratory animals. Oral delivery of budesonide to the inflamed tissues of the large intestine as its glucuronide prodrug should lead to locally high concentrations of active drug. Following liberation and absorption of the active drug, a large portion should be inactivated due to hepatic metabolism. Budesonide‐β‐D‐glucuronide was chemically stable in solutions at pHs of 1.5, 4.5, 6.5, and 7.4 at 37 °C. The enzymatic lability of the prodrug was assessed in luminal contents and mucosa obtained from conventional, germ‐free, and colitic rats under in vitro conditions. There was a substantial change in glycosidase activity between the small intestine (proximal and distal portions) and the cecum in both conventional and colitic rat luminal contents. Luminal hydrolytic activity was low along the entire rat gastrointestinal tract of germ‐free rats. Mucosal glycosidase activity was relatively low along the entire gastrointestinal tract of all three types of rats. The hydrolysis of prodrugs budesonide‐β‐D‐glucuronide and dexamethasone‐β‐D‐glucuronide in human fecal samples from patients with ulcerative colitis and normal volunteers was also measured. There were no statistically significant differences between the normal and colitic fecal samples for hydrolysis of the either prodrug or between the relative rates of hydrolysis of the two prodrugs. Hydrolysis rates of the prodrugs were about two orders of magnitude less in human fecal samples compared with those in cecal and colonic contents from the rat.