Increased erythropoietin elimination in fetal sheep following chronic phlebotomy
Increased erythropoietin elimination in fetal sheep following chronic phlebotomy
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DOI：
10.1007/s11095-007-9295-3
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发表时间：
2007-09-01
影响因子：
3.7
通讯作者：
Veng-Pedersen, Peter
中科院分区：
文献类型：
--
作者：
Freise, Kevin. J.;Widness, John A.;Veng-Pedersen, Peter
通过药代动力学（PK）来确定胎儿红细胞生成素受体（EPO- r）上调对红细胞生成素（EPO）消除的作用。6只胎羊在胎龄125 ~ 127天插管，每天抽血6天。利用重组人促生成素（rHuEPO）对绵羊胎儿进行配对示踪剂PK研究，分别在基线和放血后7天进行。采用Michaelis-Menten消去的PK模型同时拟合每个胎儿在基线和开颅后的PK数据。每日抽血后，血红蛋白水平从基线值10.8(5%)（平均（C.V.）） g/dl降至最低点4.5 (17%)g/dl。内源性EPO浓度在第一次静脉切开术后迅速升高，此后虽有变化，但仍保持升高。Michaelis-Menten最大rHuEPO消除率参数，V-max，在静脉切开术后显著高于基线（< 0.05），增加1.31倍。在极低浓度的rHuEPO下，胎儿基线“线性”清除率为117 ml/kg/h，与新生羊相似，但比成年羊高2-3倍。观察到的V-max的增加与EPO-R的上调是一致的，这是由于放血引起的贫血引起的正反馈。
To determine by pharmacokinetic (PK) means the role of erythropoietin-receptor (EPO-R) upregulation in fetuses on the elimination of erythropoietin (EPO).Six fetal sheep were catheterized at a gestational age of 125-127 days and phlebotomized daily for 6 days. Paired tracer PK studies using recombinant human EPO (rHuEPO) were conducted in the sheep fetuses at baseline and post-phlebotomy, 7 days later. A PK model with Michaelis-Menten elimination was simultaneously fit to the PK data at baseline and post-phlebotomy for each fetus.Daily phlebotomies reduced the hemoglobin levels from baseline values of 10.8 (5%) (mean (C.V.)) g/dl to a nadir of 4.5 (17%) g/dl post-phlebotomy. The endogenous EPO concentration rapidly increased after the first phlebotomy and remained elevated, although variable, thereafter. The Michaelis-Menten maximal rHuEPO elimination rate parameter, V-max, was significantly greater post-phlebotomy than at baseline (< 0.05), increasing 1.31 fold. The fetal baseline "linear" clearance at very low concentrations of rHuEPO was determined to be 117 ml/kg/h, similar to that determined in newborn sheep but 2-3 fold higher than that determined in adult sheep.The observed increase in V-max is consistent with an up-regulation of EPO-R due to a positive feedback resulting from the phlebotomy-induced anemia.