Glucocorticoid‐dextran conjugates as potential prodrugs for colonspecific delivery: Steady‐state pharmacokinetics in the rat
Glucocorticoid‐dextran conjugates as potential prodrugs for colonspecific delivery: Steady‐state pharmacokinetics in the rat
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糖皮质激素-葡聚糖缀合物作为结肠特异性递送的潜在前药：大鼠的稳态药代动力学
DOI：
10.1002/bdd.2510150207
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发表时间：
1994
影响因子：
2.1
通讯作者：
T. Tozer
中科院分区：
文献类型：
--
作者：
A. McLeod;Lorna Tolentino;T. Tozer
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到结肠的前药，可以减少剂量，从而减少副作用。我们之前合成了糖皮质激素-葡聚糖缀合物，其中地塞米松使用二羧酸连接体（琥珀酸酯和戊二酸酯）连接到葡聚糖（重均分子量= 72 600）上。在本研究中，通过胃内输注对两组雄性Sprague道利大鼠给予地塞米松-琥珀酸-葡聚糖和地塞米松-戊二酸-葡聚糖。在另外两组中，分别通过皮下输注给予地塞米松磷酸二钠和地塞米松半琥珀酸酯。在第五组中，通过胃内输注给予地塞米松。所有组均输注足够的时间以达到稳态。使用药物递送指数（DDI）对结肠特异性递送进行定量，其中将盲肠和结肠中的稳态地塞米松浓度与地塞米松和地塞米松-葡聚糖缀合物单独给药后在血液中测量的浓度进行比较。地塞米松-琥珀酸-葡聚糖和地塞米松-戊二酸-葡聚糖的结肠DDI值分别约为7和4。这些值是与地塞米松的皮下和胃内施用相比，胃内施用缀合物后地塞米松的较高组织浓度和较低血液浓度的结果。还研究了皮下输注后甲基泼尼松龙的药代动力学。观察到的盲肠和结肠组织与血液的比例分别为19：1和12：1，表明即使在皮下给药后，该药物也广泛递送至大肠。
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 was attached to dextran (weight‐average molecular weight = 72 600) using dicarboxylic acid linkers (succinate and glutarate). In the present study, dexamethasone‐succinate‐dextran and dexamethasone‐glutarate‐dextran were administered to two groups of male Sprague‐Dawley rats by intragastric infusion. In two additional groups, disodium dexamethasone phosphate and dexamethasone hemisuccinate were each administered by subcutaneous infusion. In a fifth group, dexamethasone was administered by intragastric infusion. All groups were infused for sufficient time for steady state to be achieved. Colon‐specific delivery was quantified using a drug‐delivery index (DDI) in which steady‐state dexamethasone concentrations in the cecum and colon were compared with those measured in blood after separate administrations of dexamethasone and dexamethasone‐dextran conjugate. The colonic DDI values for dexamethasone‐succinate‐dextran and dexamethasone‐glutarate‐dextran were approximately seven and four, respectively. These values were a result of higher tissue concentrations and lower blood concentrations of dexamethasone after intragastric administration of the conjugates compared to subcutaneous and intragastric administration of dexamethasone. The pharmacokinetics of methyl‐prednisolone was also investigated after subcutaneous infusion. Observed cecal and colonic tissue‐to‐blood ratios of 19:1 and 12:1, respectively, showed that this drug is extensively delivered to the large intestine even after subcutaneous administration.