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Research ArticleArticle

Immunological Response to Repeated Administration of Recombinant Human Erythropoietin in Rats

Biphasic Effect on Its Pharmacokinetics

Motohiro Kato, Kumi Miura, Hiroshi Kamiyama, Akira Okazaki, Kenji Kumaki, Yukio Kato and Yuichi Sugiyama
Drug Metabolism and Disposition September 1997, 25 (9) 1039-1044;
Motohiro Kato
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Kumi Miura
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Hiroshi Kamiyama
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Akira Okazaki
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Kenji Kumaki
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Yukio Kato
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Yuichi Sugiyama
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Biphasic Effect on Its Pharmacokinetics

Abstract

We studied changes in the pharmacokinetics of125I-recombinant human erythropoietin (125I-rh-EPO) after repeated subcutaneous administration once a week for 4 weeks. The plasma level of trichloroacetic acid-precipitable radioactivity after the fourth administration of125I-rh-EPO was minimal in 8 of 10 rats, whereas in the other two rats, the plasma level was almost the same or somewhat higher than that in control rats that had received the vehicle solution 3 times instead of the first three sequential administrations. Antibody against rh-EPO in serum was detected in all 10 rats receiving multiple administrations of 125I-rh-EPO. However, the binding capacity for 125I-rh-EPO in the latter two rats, assessed by an in vitro serum binding study, was lower than for the other eight rats, suggesting that the antibody level in these two was lower. The effect of intravenous preinjection of various volumes of anti-rh-EPO antiserum on the pharmacokinetics of125I-rh-EPO was examined. The half-life in the β-phase was prolonged at lower doses of antiserum. When the pretreatment dose of antiserum was further increased, the half-life in the β-phase rather shortened and the total body clearance (CLtotal) increased. These results suggest that repeated administration of rh-EPO induces the production of antibody against rh-EPO that affects the pharmacokinetics of rh-EPO in a biphasic manner; CLtotal was reduced when a small amount of antibody was produced, andCLtotal was increased when a large amount of antibody was produced.

Footnotes

  • Send reprint requests to: Dr. Yuichi Sugiyama, Professor and Chair, Faculty of Pharmaceutical Sciences, University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113, Japan.

  • Abbreviations used are::
    EPO
    erythropoietin
    rh-EPO
    recombinant human erythropoietin
    RME
    receptor-mediated endocytosis
    125I-rh-EPO
    125I-recombinant human erythropoietin
    BSA
    bovine serum albumin
    TCA
    trichloroacetic acid
    SD
    standard deviation
    AUC
    area under the plasma concentrationvs. time curve
    CLtotal
    total body clearance
    Bmax
    maximum binding capacity
    IgG
    immunoglobulin G
    t1/2β
    half-life in the β-phase
    Vc
    distribution volume of the central compartment
    rIFN-α2A
    recombinant interferon-α2A
    rIFN
    recombinant interferon
    rIL-2
    recombinant interleukin-2
    • Received January 21, 1997.
    • Accepted May 7, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition
Vol. 25, Issue 9
1 Sep 1997
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Research ArticleArticle

Immunological Response to Repeated Administration of Recombinant Human Erythropoietin in Rats

Motohiro Kato, Kumi Miura, Hiroshi Kamiyama, Akira Okazaki, Kenji Kumaki, Yukio Kato and Yuichi Sugiyama
Drug Metabolism and Disposition September 1, 1997, 25 (9) 1039-1044;

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Research ArticleArticle

Immunological Response to Repeated Administration of Recombinant Human Erythropoietin in Rats

Motohiro Kato, Kumi Miura, Hiroshi Kamiyama, Akira Okazaki, Kenji Kumaki, Yukio Kato and Yuichi Sugiyama
Drug Metabolism and Disposition September 1, 1997, 25 (9) 1039-1044;
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