Increased erythropoietin elimination in fetal sheep following chronic phlebotomy. Pharm Res 2007 Sep;24(9):1653-9
Date
04/26/2007Pubmed ID
17457660Pubmed Central ID
PMC2863314DOI
10.1007/s11095-007-9295-3Scopus ID
2-s2.0-34547613348 (requires institutional sign-in at Scopus site) 7 CitationsAbstract
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, 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.
Author List
Freise KJ, Widness JA, Segar JL, Schmidt RL, Veng-Pedersen PAuthor
Jeffrey L. Segar MD Professor in the Pediatrics department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnemiaAnimals
Animals, Newborn
Erythropoietin
Female
Fetus
Phlebotomy
Pregnancy
Receptors, Erythropoietin
Sheep
