Plasma pharmacokinetics and tissue disposition of novel dextran-methylprednisolone conjugates with peptide linkers in rats.
Plasma pharmacokinetics and tissue disposition of novel dextran-methylprednisolone conjugates with peptide linkers in rats.
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具有肽接头的新型右旋糖酐-甲基泼尼松龙缀合物在大鼠体内的血浆药代动力学和组织分布。
DOI：
10.1002/jps.21934
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发表时间：
2010
影响因子：
3.8
通讯作者：
Mehvar,Reza
中科院分区：
文献类型：
--
作者：
Penugonda,Suman;Agarwal,HiteshK;Parang,Keykavous;Mehvar,Reza
在大鼠中研究了含有一个（β-1）或五个（β-5）氨基酸作为接头的甲基强的松龙（MP）的两种新型右旋糖酐前药的血浆和组织处置。单次静脉给予每种前药或MP 5 mg/kg剂量（MP当量），并采集血液和组织样本。使用HPLC定量前药和药物浓度，并估计非房室药代动力学参数。尽管两种前药中MP与葡聚糖的偶联使药物的清除率显著降低了200倍，但药物在肝脏、脾脏和肾脏中的蓄积量因偶联而显著增加。然而，这些组织中β-1的蓄积程度远大于β-5。在肝脏和脾脏中，从两种前药中再生大量MP，从β-5释放的速率是从β-1释放的速率的两倍。然而，在肝脏和脾脏中，从β-1再生的MP的AUC显著高于β-5后的AUC。相反，在肾脏中，从β-5再生的MP的AUC高于β-1给药后的AUC。这些数据表明，β-1可能比β-5更适合用于靶向肝脏和脾脏的免疫抑制。© 2009 Wiley利斯公司和American Pharmacologist Association J Pharm Sci 99：1626-1637，2010
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 ∼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. © 2009 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 99: 1626–1637, 2010
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影响因子：
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作者：
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DOI：
10.1007/bf01062191
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