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The in vivo metabolism of recombinant human erythropoietin in the rat
JL Spivak and BB Hogans
Division of Hematology, Johns Hopkins University School of Medicine,
Baltimore, MD.
We compared the in vivo plasma clearance and organ accumulation in
anesthetized rats of 125I-labeled, recombinant human erythropoietin and
125I-labeled, desialylated recombinant erythropoietin. The immediate volume
of distribution of 125I-labeled, recombinant erythropoietin approximated
that of the plasma volume. Its plasma clearance was multiexponential, with
an initial rapid distribution phase (t1/2 = 53 minutes) and a slower
elimination phase (t1/2 = 180 minutes). Organ accumulation of labeled
recombinant erythropoietin, as compared with 125I-labeled human albumin,
was negligible until 30 minutes after injection when small amounts appeared
in the kidneys and bone marrow. Only 24% of the 125I-labeled, desialylated
recombinant erythropoietin was recovered immediately after injection, and
96% of the hormone was cleared from the plasma with a t1/2 of 2.0 minutes.
The bulk of the desialylated hormone accumulated in the liver where it was
rapidly catabolized and its breakdown products released back into the
plasma. Significantly, in contrast to unmodified erythropoietin, there was
also early accumulation of desialylated hormone in the kidneys, marrow, and
spleen. Desialylated orosomucoid but not orosomucoid, yeast mannan, or
dextran sulfate 500 inhibited the rapid plasma clearance and hepatic
accumulation of desialylated erythropoietin. Oxidation of the desialylated
hormone restored its plasma recovery and clearance to normal but rendered
it biologically inactive, and accumulation in organs other than the kidney
was negligible.
Volume 73,
Issue 1,
pp. 90-99,
01/01/1989
Copyright © 1989 by The American Society of Hematology
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