Increased Erythropoietin Elimination in Fetal Sheep Following Chronic Phlebotomy
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To determine by pharmacokinetic (PK) means the role of erythropoietin-receptor (EPO-R) upregulation in fetuses on the elimination of erythropoietin (EPO).
Materials and Methods
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, Vmax, was significantly greater post-phlebotomy than at baseline (p < 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 Vmax is consistent with an up-regulation of EPO-R due to a positive feedback resulting from the phlebotomy-induced anemia.
Key wordsdevelopmental comparison erythropoietin receptors fetus pharmacokinetics receptor regulation
burst forming unit-erythroid
colony forming unit-erythroid
clearance at “very low” concentrations
plasma 125I- rHuEPO concentration in cpms/ml (labeled)
constant rate infusion
plasma rHuEPO concentration in mU/ml (unlabeled)
IV bolus 125I- rHuEPO loading dose
first order rate constant of distribution out of the central compartment
first order rate constant of distribution into the central compartment
plasma rHuEPO concentration where 50% of Vmax occurs
IV infusion rate of 125I-rHuEPO
recombinant human erythropoietin
tracer interaction method
apparent volume of distribution
maximal rate of rHuEPO elimination
125I- rHuEPO distribution variable
The rabbit antiserum used in the erythropoietin radioimmunoassay was a generous gift from Gisela K. Clemons, PhD. This work is supported by United States Public Health Service, National Institute of Health grants R01 HL-64770 (JLS) and P01 HL49625 (JAW).
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