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

Department of Internal Medicine, University of Iowa, Iowa City, Iowa, United States
Biopharmaceutics & Drug Disposition (Impact Factor: 2.34). 05/2004; 25(4):149-56. DOI: 10.1002/bdd.395
Source: PubMed


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.
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).
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.
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.

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    • "From previous research, it has been well established that EpoRs are found in all tissues of the body and not just in the bone marrow (Yamaji et al., 1996; Juul et al., 1998, 2001; Carlini et al., 1999). It is possible that these receptors have different Epo binding characteristics in mediating a linear (nonsaturable) clearance of Epo (Veng-Pedersen et al., 2004). However, it is not known whether these additional receptors are responsible for the linear Epo clearance. "
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