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Increased Erythropoietin Elimination in Fetal Sheep Following Chronic Phlebotomy

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Abstract

Purpose

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.

Results

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.

Conclusions

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.

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Abbreviations

125I-rHuEPO:

125I-labeled rHuEPO

BFU-E:

burst forming unit-erythroid

CFU-E:

colony forming unit-erythroid

Cl:

clearance at “very low” concentrations

CL :

plasma 125I- rHuEPO concentration in cpms/ml (labeled)

CRI:

constant rate infusion

CU :

plasma rHuEPO concentration in mU/ml (unlabeled)

DL :

IV bolus 125I- rHuEPO loading dose

EPO:

erythropoietin

EPO-R:

erythropoietin receptor

Hb:

hemoglobin

IV:

intravenous

k12 :

first order rate constant of distribution out of the central compartment

k21 :

first order rate constant of distribution into the central compartment

km :

plasma rHuEPO concentration where 50% of Vmax occurs

PD:

pharmacodynamic

PK:

pharmacokinetic

R:

IV infusion rate of 125I-rHuEPO

RhuEPO:

recombinant human erythropoietin

t0 :

initial time

TIM:

tracer interaction method

V:

apparent volume of distribution

Vmax :

maximal rate of rHuEPO elimination

Z:

125I- rHuEPO distribution variable

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Acknowledgements

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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Authors and Affiliations

  1. College of Pharmacy, The University of Iowa, 115 S. Grand Ave, Iowa City, Iowa, 52242, USA

    Kevin. J. Freise & Peter Veng-Pedersen

  2. Department of Pediatrics, College of Medicine, The University of Iowa, Iowa City, Iowa, 52242, USA

    John A. Widness, Jeffrey L. Segar & Robert L. Schmidt

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  1. Kevin. J. Freise
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Correspondence to Peter Veng-Pedersen.

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Freise, K.J., Widness, J.A., Segar, J.L. et al. Increased Erythropoietin Elimination in Fetal Sheep Following Chronic Phlebotomy. Pharm Res 24, 1653–1659 (2007). https://doi.org/10.1007/s11095-007-9295-3

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