Pharmaceutical Research

, Volume 24, Issue 9, pp 1653–1659 | Cite as

Increased Erythropoietin Elimination in Fetal Sheep Following Chronic Phlebotomy

  • Kevin. J. Freise
  • John A. Widness
  • Jeffrey L. Segar
  • Robert L. Schmidt
  • Peter Veng-Pedersen
Research Paper



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 words

developmental comparison erythropoietin receptors fetus pharmacokinetics  receptor regulation 



125I-labeled rHuEPO


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




erythropoietin receptor






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


initial time


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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Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Kevin. J. Freise
    • 1
  • John A. Widness
    • 2
  • Jeffrey L. Segar
    • 2
  • Robert L. Schmidt
    • 2
  • Peter Veng-Pedersen
    • 1
  1. 1.College of PharmacyThe University of IowaIowa CityUSA
  2. 2.Department of Pediatrics, College of MedicineThe University of IowaIowa CityUSA

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