McLeod A D, Tolentino L, Tozer T N
Department of Pharmacy, School of Pharmacy, University of California, San Francisco 94143-0446.
Biopharm Drug Dispos. 1994 Mar;15(2):151-61. doi: 10.1002/bdd.2510150207.
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.
慢性结肠炎，如溃疡性结肠炎和克罗恩病，目前采用糖皮质激素和其他抗炎药进行治疗。副作用限制了糖皮质激素的长期治疗。使用能将药物选择性输送至结肠的前体药物，可以降低剂量，进而减少副作用。我们之前合成了糖皮质激素-葡聚糖缀合物，其中地塞米松通过二羧酸连接基（琥珀酸和戊二酸）连接到葡聚糖上（重均分子量 = 72,600）。在本研究中，通过胃内输注将琥珀酸地塞米松-葡聚糖和戊二酸地塞米松-葡聚糖给予两组雄性斯普拉格-道利大鼠。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半琥珀酸地塞米松。在第五组中，通过胃内输注给予地塞米松。所有组均输注足够长的时间以达到稳态。使用药物递送指数（DDI）对结肠特异性递送进行定量，该指数将盲肠和结肠中地塞米松的稳态浓度与分别给予地塞米松和地塞米松-葡聚糖缀合物后血液中测得的浓度进行比较。琥珀酸地塞米松-葡聚糖和戊二酸地塞米松-葡聚糖的结肠DDI值分别约为7和4。这些值是由于与皮下和胃内给予地塞米松相比，胃内给予缀合物后地塞米松在组织中的浓度更高而在血液中的浓度更低。皮下输注后还研究了甲泼尼龙的药代动力学。观察到的盲肠和结肠组织与血液的比率分别为19:1和12:1，表明即使在皮下给药后，该药物也能大量输送至大肠。
