TY - JOUR
T1 - The in vivo metabolism of recombinant human erythropoietin in the rat
AU - Spivak, J. L.
AU - Hogans, B. B.
N1 - Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 1989
Y1 - 1989
N2 - We compared the in vivo plasma clearance and organ accumulation in anesthetized rats of 125I-labeled, recombinant human erythropoietin and 125I-labeled, desialated 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 (t( 1/2 ) = 53 minutes) and a slower elimination phase (t( 1/2 ) = 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, desialated recombinant erythropoietin was recovered immediately after injection, and 96% of the hormone was cleared from the plasma with a t( 1/2 ) of 2.0 minutes. The bulk of the desialated hormone accumulated in the liver where it was rapidly catebolized and its breakdown products released back into the plasma. Significantly, in contrast to unmodified erythropoietin, there was also early accumulation of desialated hormone in the kidneys, marrow, and spleen. Desialated orosomucoid but not orosomucoid, yeast mannan, or dextran sulfate 500 inhibited the rapid plasma clearance and hepatic accumulation of desialated erythropoietin. Oxidation of the desialated hormone restored its plasma recovery and clearance to normal but rendered it biologically inactive, and accumulation in organs other than the kidney was negligible.
AB - We compared the in vivo plasma clearance and organ accumulation in anesthetized rats of 125I-labeled, recombinant human erythropoietin and 125I-labeled, desialated 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 (t( 1/2 ) = 53 minutes) and a slower elimination phase (t( 1/2 ) = 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, desialated recombinant erythropoietin was recovered immediately after injection, and 96% of the hormone was cleared from the plasma with a t( 1/2 ) of 2.0 minutes. The bulk of the desialated hormone accumulated in the liver where it was rapidly catebolized and its breakdown products released back into the plasma. Significantly, in contrast to unmodified erythropoietin, there was also early accumulation of desialated hormone in the kidneys, marrow, and spleen. Desialated orosomucoid but not orosomucoid, yeast mannan, or dextran sulfate 500 inhibited the rapid plasma clearance and hepatic accumulation of desialated erythropoietin. Oxidation of the desialated hormone restored its plasma recovery and clearance to normal but rendered it biologically inactive, and accumulation in organs other than the kidney was negligible.
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U2 - 10.1182/blood.v73.1.90.bloodjournal73190
DO - 10.1182/blood.v73.1.90.bloodjournal73190
M3 - Article
C2 - 2462945
AN - SCOPUS:0024562079
VL - 73
SP - 90
EP - 99
JO - Blood
JF - Blood
SN - 0006-4971
IS - 1
ER -