Therapeutic blood levels of sirolimus (rapamycin) in the allografted rat
Therapeutic blood levels of sirolimus (rapamycin) in the allografted rat
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DOI：
10.1097/00007890-199610270-00015
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发表时间：
1996-10-27
期刊：
影响因子：
6.2
通讯作者：
Sehgal, SN
中科院分区：
文献类型：
--
作者：
DiJoseph, JF;Fluhler, E;Sehgal, SN
进行了一项研究，以确定口服剂量之间的关系，全血谷浓度，移植物存活率，并在西罗莫司治疗的同种异体移植大鼠的副作用。使用Brown Norway供体和刘易斯大鼠受体的异位心脏同种异体移植模型。大鼠每日给予西罗莫司或溶媒，直至移植失败或最多28天。移植失败后，对大鼠放血以测量药物的谷血液水平，并将组织送去进行组织病理学分析。西罗莫司血药浓度与剂量和移植物存活率正相关。在0.3 mg/kg/天剂量下，当全血谷浓度达到0.5 ng/ml时，移植物存活率显著。使用S形E（max）模型分析浓度-效应数据，计算出移植物存活的全血EC（50）为2.0 ng/ml。平均谷浓度为7 ng/ml或更高时，停止药物治疗后移植物存活。在0.8 mg/kg/天剂量下，大鼠的体重增量显著降低。西罗莫司给药动物的病理学检查发现胸腺和淋巴萎缩，均被认为是西罗莫司免疫抑制活性的药理学扩展和局灶性心肌变性，是自发发生的病变的加重。这些结果表明西罗莫司以浓度依赖性方式在大鼠中维持移植物存活，治疗性全血水平为约10 ng/ml。
A study was conducted to determine the relationship among oral dose, trough whole blood levels, graft survival, and side effects in sirolimus-treated allografted rats. The heterotopic heart allograft model using Brown Norway donors and Lewis rat recipients was used. Rats were dosed daily with sirolimus or vehicle until graft failure or up to a maximum of 28 days. Upon graft failure, rats were bled for measurement of trough blood levels of drug and tissues sent for histopathologic analysis. Sirolimus blood concentration correlated positively with dose and graft survival. Significant graft survival occurred at whole blood trough levels of 0.5 ng/ml achieved at the 0.3 mg/kg/day dose. Analysis of the concentration-effect data using a sigmoidal E(max) model calculated a whole blood EC(50) of 2.0 ng/ml for graft survival. With mean trough concentrations of 7 ng/ml and higher, grafts survived after cessation of drug treatment. At the 0.8 mg/kg/day dose, there was a significant decrease in body weight gain in the rats. Histopathologic examination of sirolimus-treated animals detected thymic and lymphoid atrophy, both considered pharmacologic extensions of sirolimus's immunosuppressive activity and focal myocardial degeneration, an exacerbation of a spontaneous occurring lesion. These results demonstrate that sirolimus prolongs graft survival in rat in a concentration dependent manner with therapeutic whole blood levels of about 10 ng/ml.