Increased erythropoietin elimination in fetal sheep following chronic phlebotomy.

Autor: Freise KJ; College of Pharmacy, The University of Iowa, 115 S. Grand Ave, Iowa City, Iowa 52242, USA., Widness JA, Segar JL, Schmidt RL, Veng-Pedersen P
Jazyk: angličtina
Zdroj: Pharmaceutical research [Pharm Res] 2007 Sep; Vol. 24 (9), pp. 1653-9. Date of Electronic Publication: 2007 Apr 25.
DOI: 10.1007/s11095-007-9295-3
Abstrakt: 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.
Databáze: MEDLINE
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