Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas, USA.
J Pharm Sci. 2010 Mar;99(3):1626-37. doi: 10.1002/jps.21934.
The plasma and tissue disposition of two novel dextran prodrugs of methylprednisolone (MP) containing one (DMP-1) or five (DMP-5) amino acids as linkers were studied in rats. Single 5-mg/kg doses (MP equivalent) of each prodrug or MP were administered intravenously, and blood and tissue samples were collected. Prodrug and drug concentrations were quantitated using HPLC, and noncompartmental pharmacokinetic parameters were estimated. Whereas conjugation of MP with dextran in both prodrugs substantially decreased the clearance of the drug by approximately 200-fold, the accumulations of the drug in the liver, spleen, and kidneys were significantly increased by conjugation. However, the extent of accumulation of DMP-1 in these tissues was substantially greater than that for DMP-5. Substantial amounts of MP were regenerated from both prodrugs in the liver and spleen, with the rate of release from DMP-5 being twice as fast as that from DMP-1. However, the AUCs of MP regenerated from DMP-1 in the liver and spleen were substantially higher than those after DMP-5. In contrast, in the kidneys, the AUC of MP regenerated from DMP-5 was higher than that after DMP-1 administration. These data suggest that DMP-1 may be more suitable than DMP-5 for targeting immunosuppression to the liver and spleen.
研究了两种新型含有一（DMP-1）或五（DMP-5）个氨基酸作为连接物的甲泼尼龙（MP）葡聚糖前药在大鼠体内的血浆和组织分布。每种前药或 MP 均以 5mg/kg 单剂量（MP 当量）静脉给药，并采集血液和组织样本。使用 HPLC 定量检测前药和药物浓度，并估算非房室药代动力学参数。虽然两种前药均将 MP 与葡聚糖偶联，使药物的清除率降低了约 200 倍，但药物在肝脏、脾脏和肾脏中的蓄积显著增加。然而，DMP-1 在这些组织中的蓄积程度远高于 DMP-5。在肝脏和脾脏中，两种前药均大量生成 MP，DMP-5 的释放速度是 DMP-1 的两倍。然而，DMP-1 在肝脏和脾脏中再生的 MP 的 AUC 明显高于 DMP-5。相比之下，在肾脏中，DMP-5 再生的 MP 的 AUC 高于 DMP-1 给药后的 AUC。这些数据表明，与 DMP-5 相比，DMP-1 可能更适合将免疫抑制作用靶向肝脏和脾脏。
