Pharmacokinetic tracer kinetics analysis of changes in erythropoietin receptor population in phlebotomy-induced anemia and bone marrow ablation.

OBJECTIVES: The objective was to study in vivo erythropoietin (Epo) progenitor cell surface receptors (EpoR) in the bone marrow (BM) after phlebotomy and bone marrow ablation. METHODS: Serial tracer interaction method experiments were conducted in adult sheep at baseline and after phlebotomy (PH) and ablation (AB). PH was done 10 days after phlebotomy (to 3-4 g/dl Hb), and the AB was done 8 days after a 3-day oral treatment with bulsulfan (11 mg/kg/day). RESULTS: Bone marrow ablation changed the elimination from non-linear to linear, consistent with an abolition of the non-linear elimination via BM EpoRs. The phlebotomy increased the linear clearance of the ablated elimination pathway (from 63.6+/-12 to 126+/-64 ml/h/kg), consistent with an up-regulation of the erythroid progenitor BM-based EpoR pool, but did not change the clearance of the non-ablated elimination pathway (p>0.05). The EpoR pool size remaining after BM ablation was 7.4+/-2.7% of the pre-ablation pool. CONCLUSIONS: Erythropoietin elimination via EpoR in the bone marrow was non-linear and increased following phlebotomy-induced anemia. This is consistent with an up-regulation of the erythropoietic EpoR pool in BM. Assuming that the elimination of Epo after BM ablation was via non-hematopoietic EpoR, then this post-ablation EpoR population was not significantly up-regulated by the phlebotomy.

A differential pharmacokinetic analysis of the erythropoietin receptor population in newborn and adult sheep.

Strong evidence indicates that erythropoietin (Epo) is eliminated via Epo receptors (EpoR). Epo receptors may be classified as erythropoietic receptors that are largely located on erythroid progenitor cells in the bone marrow (BM) and nonerythropoietic receptors present in most tissues. Epo's elimination kinetics was studied using a very sensitive tracer interaction method (TIM) before and after chemical ablation of BM as an indirect way of evaluating the EpoR through an assortment of pharmacokinetic parameters (VM, KM, K, and CL) used in differentiating the EpoR population in newborn and adult sheep. TIM identified a parallel nonlinear Michaelis-Menten (VM and KM), and linear (K) elimination pathway and found the latter pathway to be significantly (p < 0.01) more dominant in lamb: K/(VM/KM + K) = 0.309 (25.3) versus 0.0895 (18.4) mean (CV%) lambs versus adult sheep. The significantly (p < 0.01) larger total clearance found for lambs indicates a larger nonhematopoietic tissue clearance of Epo (CL = 118 (10.9) ml/h/kg versus 67.8 (19.3) lamb versus adult sheep). The VM/KM ratio for the nonlinear pathway was not found to be significantly different (p > 0.05) between newborn and adults with values of 1.10 (15.8) and 1.30 (3.81) h-1, respectively. We proposed the hypothesis that the linear pathway is via nonhematopoietic EpoR. Assuming that Epo's elimination largely depends not only on erythropoietic EpoR but also on nonhematopoietic EpoR, this work shows a significant difference in the relative proportions of the two EpoR populations in lamb and adult sheep. The larger dominance of the nonhematopoietic EpoR in lamb supports the hypothesis that these receptors are more needed in early life, e.g., providing neuroprotection from perinatal hypoxemic-ischemic episodes.