Metabolism of pure human erythropoietin in the rat

The metabolism of pure human erythropoietin (EPO) labeled with 125I was studied in the rat. Concentrations of the labeled hormone (125I-EPO) in plasma and urine were measured by both trichloroacetic acid precipitation and gel filtration. During steady-state conditions the metabolic clearance rate of 125I-EPO was slow, averaging 256 +/- 7 microliter. min-1 X kg-1 of which only 19 +/- 2 microliter X min-1 X kg-1 (or 7.4 +/- 0.8% of the metabolic clearance rate) could be accounted for by excretion of the labeled hormone in the urine. Urinary clearance of 125I-EPO amounted to less than 0.3% of the glomerular filtration rate, and there was no detectable arteriovenous concentration difference of 125I-EPO across the kidney. After both pulse injection and constant infusion to equilibrium, disappearance of 125I-EPO from the circulation could be approximated by a single exponential function: plasma half-life was 3.5 +/- 0.2 h in normal rats and was prolonged to 4.4 +/- 0.3 h (P less than 0.05) in animals with ligated renal pedicles. Although kidney homogenates degraded 125I-EPO in vitro (optimum pH 4.5), the hormone did not accumulate in the kidney when injected intravenously. We conclude that EPO metabolism is extremely sluggish compared with that of other polypeptide hormones. Whereas kidney tissue is capable of degrading EPO in vitro, the physicochemical characteristics of this glycoprotein (molecular size, shape, and charge) probably impede its access to degrading sites and therefore account for the limited contribution of renal extraction and excretion to the metabolic clearance of the hormone.