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Abstract
Recombinant human erythropoietin (rHuEPO) is used effectively in the treatment of various anemic disorders. Belgrade rat is a useful animal model of anemia caused by defect in iron utilization. The objective of the present study was to investigate the dynamics of erythropoietic biomarkers in Belgrade rats receiving rHuEPO. Pharmacokinetics of rHuEPO was evaluated in Belgrade rats and normal rats after intravenous administration of single doses of the drug (100 and 1350 IU/kg). Pharmacodynamic biomarkers included levels of red blood cells, hemoglobin, and reticulocytes following administration of a single intravenous dose of rHuEPO (100 IU/kg). Red blood cell survival was assessed after treatment with rHuEPO (450 IU/kg), three times a week for 2 weeks. It was found that rHuEPO exhibited non-linear pharmacokinetics in both Belgrade and control rats. At the low dose, plasma concentrations and AUC (area under the curve) were significantly lower while clearance and volume of distribution were higher in Belgrade rats (p < 0.05). At the higher dose, there was no difference in pharmacokinetics between the two groups. Erythropoietic effect of rHuEPO was negligible in Belgrade rats at the dose of 100 IU/kg whereas all studied erythropoietic biomarkers were increased in normal rats. The levels of red blood cells, hemoglobin were significantly lower whereas the percentage of reticulocytes was higher in Belgrade rats compared to that in normal rats (p < 0.05). RHuEPO increased red blood cell survival in both animal groups. In conclusion, rHuEPO effect on erythropoietic biomarkers was stronger in normal rats than Belgrade rats at the studied doses. The findings from this study may provide further insights into understanding of anemic disorders resulting from mutations in the divalent metal transporter.
Highlights
Belgrade (b/b) rats originate from X-irradiated albino rats in Belgrade, Yugoslavia (Sladic-Simic et al, 1966)
In contrast to the results observed for HGB and red blood cell (RBC) where the measurements in the control group were greater than in the Belgrade group, the mean corpuscular hemoglobin (MCH) level in the Belgrade rats was about threefold higher than that in the control rats (e.g., 51.8 ± 4.0 vs. 18.2 ± 0.46 on day 4) at all time points (p < 0.001)
The MCH level in Belgrade rats after recombinant human erythropoietin (rHuEPO) dosing was not different compared to the baseline (p > 0.05), while in the control rats it increased to a plateau and decreased after several days
Summary
Belgrade (b/b) rats originate from X-irradiated albino rats in Belgrade, Yugoslavia (Sladic-Simic et al, 1966). These rats have a hereditary hypochromic microcytic anemia. The newborn anemic rats are pale yellow with growth retardation and distinguished from the normal littermates. Peripheral blood smears exhibit significant microcytosis, anisocytosis, and poikilocytosis which are exacerbated with age. The levels of RBC and HGB are significantly decreased and progressively decline over time (Sladic-Simic et al, 1966). A decrease in platelets and leukocytosis are observed in these animals (Ivanovic, 1997)
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