Dextran-methylprednisolone succinate as a prodrug of methylprednisolone: Local immunosuppressive effects in liver after systemic administration to rats
Dextran-methylprednisolone succinate as a prodrug of methylprednisolone: Local immunosuppressive effects in liver after systemic administration to rats
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DOI：
10.1023/a:1022358702643
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发表时间：
2003-02-01
影响因子：
3.7
通讯作者：
Mehvar, R
中科院分区：
文献类型：
--
作者：
Chimalakonda, AP;Mehvar, R
目的.本工作的目的是研究全身给药甲基强的松龙（MP）及其前体药物葡聚糖-甲基强的松龙（Dextran- methylprednisolone，MP）在大鼠肝脏中的局部免疫抑制作用。单次静脉注射5 mg/ kg（MP当量）剂量的MP或PGEX至大鼠，并在不同时间点（0-72 h; n = 4/时间点）分离肝脏。用细菌脂多糖离体刺激离体肝脏，并通过酶联免疫吸附测定法分析出口灌注液和胆汁样品的肿瘤坏死因子（TNF）-α浓度。灌注液TNF-α浓度-时间曲线下面积（AUC）用作免疫应答的量度。用高效液相色谱法测定肝组织中MP和PGE 2的浓度。MP和TNF-α均导致脂多糖诱导的TNF-α AUC增加减少。在肝脏分离前8小时注射MP导致TNF-α AUC最大降低50%。与MP相比，前药（PGEX）的最大作用更强烈（TNF-α AUC降低约80%）和延迟（在24小时时的最大抑制）。总的来说，作用下的面积（TNF-α的抑制%）-时间（抑制%）。h）（3680 +/- 406）约为母体药物（846 +/- 114）的4倍。而在注射母体药物后，肝脏中的MP浓度无法定量，在注射DMP的大鼠肝脏中发现相对较大浓度的cAMP和再生MP。大鼠全身给药后，MP和PGEX均在肝脏中表现出局部免疫抑制作用。然而，前药（DMP）的局部作用似乎比母体药物（MP）更强烈和持续。
Purpose. The purpose of this work was to study the local immunosuppressive effects of systemically administered methylprednisolone (MP) and its prodrug, dextran- methylprednisolone (DMP), in rat livers.Methods. Single 5 mg/ kg (MP equivalent) doses of MP or DMP were injected intravenously to rats, and livers were isolated at different time points (0-72 h; n = 4/ time point). Isolated livers were stimulated ex vivo with bacterial lipopolysaccharide, and outlet perfusate and bile samples were analyzed for their concentrations of tumor necrosis factor (TNF)-alpha by enzyme- linked immunosorbent assay. The area under the perfusate TNF-alpha concentration- time curve (AUC) was used as a measure of immune response. Hepatic concentrations of MP and DMP were also measured by high- performance liquid chromatography.Results. Both MP and DMP resulted in a decrease in lipopolysaccharide- induced increase in TNF-alpha AUC. MP injection 8 h before liver isolation resulted in a maximum of 50% decrease in TNF-alpha AUC. Compared with MP, the maximum effect of the prodrug (DMP) was both more intense ( -80% reduction in TNF-alpha AUC) and delayed (maximum inhibition at 24 h). Overall, the area under the effect (% inhibition of TNF-alpha)- time (% inhibition . h) for DMP (3680 +/- 406) was approximately four times more than that for the parent drug (846 +/- 114). Whereas the MP concentrations in the liver were not quantifiable after the injection of the parent drug, relatively large concentrations of DMP and regenerated MP were found in the liver of DMP-injected rats.Conclusions. After systemic administration to rats, both MP and DMP exhibit local immunosuppressive effects in the liver. The local effects of the prodrug (DMP), however, appear to be more intense and sustained than those of the parent drug (MP).