Increased erythropoietin elimination in fetal sheep following chronic phlebotomy.
OBJECTIVE
To determine by pharmacokinetic (PK) means the role of erythropoietin-receptor (EPO-R) upregulation in fetuses on the elimination of erythropoietin (EPO).


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, V(max), 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 V(max) is consistent with an up-regulation of EPO-R due to a positive feedback resulting from the phlebotomy-induced anemia.
Freise
Kevin J
KJ
College of Pharmacy, The University of Iowa, 115 S. Grand Ave, Iowa City, Iowa 52242, USA.
Widness
John A
JA
Segar
Jeffrey L
JL
Schmidt
Robert L
RL
Veng-Pedersen
Peter
P
D000740:Anemia / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D004921:Erythropoietin / Q000493:pharmacokinetics*; D005260:Female; D005333:Fetus / Q000378:metabolism*; D018962:Phlebotomy; D011247:Pregnancy; D017467:Receptors, Erythropoietin / Q000502:physiology; D012756:Sheep
D017467:Receptors, Erythropoietin; D004921:Erythropoietin