Dynamics of Erythropoietic Biomarkers in Response to Treatment With Erythropoietin in Belgrade Rats
Dynamics of Erythropoietic Biomarkers in Response to Treatment With Erythropoietin in Belgrade Rats
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DOI：
10.3389/fphar.2018.00316
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发表时间：
2018-04-10
影响因子：
5.6
通讯作者：
Krzyzanski, Wojciech
中科院分区：
文献类型：
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作者：
Nguyen, Ly M.;Singh, Aman P.;Krzyzanski, Wojciech
重组人红细胞生成素（rHuEPO）被有效地用于治疗各种贫血疾病。贝尔格莱德大鼠是铁利用缺陷致贫血的有益动物模型。本研究的目的是研究贝尔格莱德大鼠接受rHuEPO后红细胞生成生物标志物的动态变化。单次静脉给药（100和1350 IU/kg）后，在贝尔格莱德大鼠和正常大鼠体内评价大黄epo的药代动力学。药效学生物标志物包括单次静脉注射rHuEPO （100 IU/kg）后红细胞、血红蛋白和网织红细胞的水平。用rHuEPO （450 IU/kg）治疗后评估红细胞存活，每周三次，持续2周。结果表明，大黄epo在贝尔格莱德大鼠和对照大鼠体内均表现出非线性药代动力学。低剂量时，贝尔格莱德大鼠血浆浓度和曲线下面积显著降低，清除率和分布体积显著升高（p < 0.05）。在较高的剂量下，两组之间的药代动力学没有差异。100iu /kg剂量时，rHuEPO对贝尔格莱德大鼠的促红细胞生成作用可以忽略不计，而在正常大鼠中，所有研究的促红细胞生成生物标志物均增加。与正常大鼠相比，贝尔格莱德大鼠红细胞、血红蛋白水平明显降低，网状红细胞百分比明显升高（p < 0.05）。RHuEPO提高了两组动物的红细胞存活率。综上所述，在研究剂量下，rHuEPO对正常大鼠红细胞生成生物标志物的影响强于贝尔格莱德大鼠。这项研究的发现可能为了解由二价金属转运体突变引起的贫血疾病提供进一步的见解。
Recombinant human erythropoietin (rHuEPO) is used effectively in the treatment of various anemic disorders. Belgrade rat is a useful animal model of anemia caused by defect in iron utilization. The objective of the present study was to investigate the dynamics of erythropoietic biomarkers in Belgrade rats receiving rHuEPO. Pharmacokinetics of rHuEPO was evaluated in Belgrade rats and normal rats after intravenous administration of single doses of the drug (100 and 1350 IU/kg). Pharmacodynamic biomarkers included levels of red blood cells, hemoglobin, and reticulocytes following administration of a single intravenous dose of rHuEPO (100 IU/kg). Red blood cell survival was assessed after treatment with rHuEPO (450 IU/kg), three times a week for 2 weeks. It was found that rHuEPO exhibited non-linear pharmacokinetics in both Belgrade and control rats. At the low dose, plasma concentrations and AUC (area under the curve) were significantly lower while clearance and volume of distribution were higher in Belgrade rats (p < 0.05). At the higher dose, there was no difference in pharmacokinetics between the two groups. Erythropoietic effect of rHuEPO was negligible in Belgrade rats at the dose of 100 IU/kg whereas all studied erythropoietic biomarkers were increased in normal rats. The levels of red blood cells, hemoglobin were significantly lower whereas the percentage of reticulocytes was higher in Belgrade rats compared to that in normal rats (p < 0.05). RHuEPO increased red blood cell survival in both animal groups. In conclusion, rHuEPO effect on erythropoietic biomarkers was stronger in normal rats than Belgrade rats at the studied doses. The findings from this study may provide further insights into understanding of anemic disorders resulting from mutations in the divalent metal transporter.