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Research ArticleArticle

Repeated Injection of High Doses of Hemoglobin-Encapsulated Liposomes (Hemoglobin Vesicles) Induces Accelerated Blood Clearance in a Hemorrhagic Shock Rat Model

Kazuaki Taguchi, Yasunori Iwao, Hiroshi Watanabe, Daisuke Kadowaki, Hiromi Sakai, Koichi Kobayashi, Hirohisa Horinouchi, Toru Maruyama and Masaki Otagiri
Drug Metabolism and Disposition March 2011, 39 (3) 484-489; DOI: https://doi.org/10.1124/dmd.110.036913
Kazuaki Taguchi
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Yasunori Iwao
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Hiroshi Watanabe
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Daisuke Kadowaki
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Hiromi Sakai
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Koichi Kobayashi
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Hirohisa Horinouchi
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Toru Maruyama
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Masaki Otagiri
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Abstract

The hemoglobin vesicle (HbV) is an artificial oxygen carrier in which a concentrated hemoglobin solution is encapsulated in a liposome. To apply liposome preparations in clinics, it is important to consider the accelerated blood clearance phenomenon (ABC phenomenon), which involves a loss in the long-circulation half-life after being administered repeatedly to the same animals. The objective of this study was to determine whether the ABC phenomenon is induced by repeated injection of HbV under conditions of hemorrhagic shock. We created a rat model of hemorrhagic shock and performed a pharmacokinetic study using 125I-HbV, in which the Hb inside of HbV was labeled with 125I. At 4 and 7 days after resuscitation from hemorrhagic shock by nonlabeled HbV (1400 mg Hb/kg), the second dose of 125I-HbV (1400 mg Hb/kg) was rapidly cleared from the circulation compared with normal rats. Of interest, IgM against HbV was produced at 4 days after the first injection of HbV, but decreased at 7 days. In addition, phagocyte activity was increased at both 4 and 7 days after the first injection of HbV. These results suggest that repeated injections of HbV at a dose of 1400 mg Hb/kg induce the ABC phenomenon under conditions of hemorrhagic shock, which is strongly related to both the production of anti-HbV IgM and enhanced phagocyte activity. We thus conclude that it might be necessary to considerer the ABC phenomenon in the dose regimen of HbV treatment in clinical settings.

Footnotes

  • This work was supported in part by the Ministry of Health, Labor and Welfare of Japan ([Health Sciences Research Grants].

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

    doi:10.1124/dmd.110.036913.

  • ABBREVIATIONS:

    HBOC
    hemoglobin-based artificial oxygen carrier
    NO
    nitric oxide
    HbV
    hemoglobin vesicle
    RBC
    red blood cell
    PEG
    polyethylene glycol
    ABC phenomenon
    accelerated blood clearance phenomenon
    SD
    Sprague-Dawley
    HS
    hemorrhagic shock
    MZ
    marginal zone.

  • Received October 24, 2010.
  • Accepted December 1, 2010.
  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 39 (3)
Drug Metabolism and Disposition
Vol. 39, Issue 3
1 Mar 2011
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Research ArticleArticle

Repeated Injection of High Doses of Hemoglobin-Encapsulated Liposomes (Hemoglobin Vesicles) Induces Accelerated Blood Clearance in a Hemorrhagic Shock Rat Model

Kazuaki Taguchi, Yasunori Iwao, Hiroshi Watanabe, Daisuke Kadowaki, Hiromi Sakai, Koichi Kobayashi, Hirohisa Horinouchi, Toru Maruyama and Masaki Otagiri
Drug Metabolism and Disposition March 1, 2011, 39 (3) 484-489; DOI: https://doi.org/10.1124/dmd.110.036913

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Research ArticleArticle

Repeated Injection of High Doses of Hemoglobin-Encapsulated Liposomes (Hemoglobin Vesicles) Induces Accelerated Blood Clearance in a Hemorrhagic Shock Rat Model

Kazuaki Taguchi, Yasunori Iwao, Hiroshi Watanabe, Daisuke Kadowaki, Hiromi Sakai, Koichi Kobayashi, Hirohisa Horinouchi, Toru Maruyama and Masaki Otagiri
Drug Metabolism and Disposition March 1, 2011, 39 (3) 484-489; DOI: https://doi.org/10.1124/dmd.110.036913
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