Pharmacokinetic tracer kinetics analysis of changes in erythropoietin receptor population in phylebotomy-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 3-4g/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.