Pharmacokinetic Properties of Single and Repeated Injection of Liposomal Platelet Substitute in a Rat Model of Red Blood Cell Transfusion-Induced Dilutional Thrombocytopenia

Mai Hashimoto, Kazuaki Taguchi, Shigeru Ogaki, Hiroshi Watanabe, Manabu Kinoshita, Kahoko Nishikawa, Shinji Takeoka, Yasuo Ikeda, Makoto Handa, Masaki Otagiri, Toru Maruyama

    Research output: Contribution to journalArticle

    Abstract

    A preclinical study of dodecapeptide (400HHLGGAKQAGDV411) (H12)-(adenosine diphosphate, ADP)-liposomes for use as a synthetic platelet (PLT) substitute under conditions of red blood cell (RBC) transfusion-induced dilutional thrombocytopenia is limited to pharmacological effect. In this study, the pharmacokinetics of H12-(ADP)-liposomes in RBC transfusion-induced dilutional thrombocytopenic rats were evaluated. As evidenced by the use of 14C, 3H double-radiolabeled H12-(ADP)-liposomes in which the encapsulated ADP and liposomal membrane were labeled with 14C and 3H, respectively, the H12-(ADP)-liposomes remained intact in the blood circulation for up to 3 h after injection, and were mainly distributed to the liver and spleen. The encapsulated ADP was mainly eliminated in the urine, whereas the outer membrane was mainly eliminated in the feces. These successive pharmacokinetic properties of the H12-(ADP)-liposomes in RBC transfusion-induced dilutional thrombocytopenic rats were similar to those in healthy rats, except for the shorter retention time in the circulation. When H12-(ADP)-liposomes were repeatedly injected into RBC transfusion-induced dilutional thrombocytopenic rats at intervals of 5 days at a dose of 10 mg lipids/kg, the second dose of injected H12-(ADP)-liposomes were rapidly cleared from the circulation, namely, via the accelerated blood clearance phenomenon. These novel pharmacokinetic findings provide useful information for the further development of H12-(ADP)-liposomes as a PLT substitute.

    Original languageEnglish
    Pages (from-to)3968-3976
    Number of pages9
    JournalJournal of Pharmaceutical Sciences
    Volume104
    Issue number11
    DOIs
    Publication statusPublished - 2015 Nov 1

    Fingerprint

    Erythrocyte Transfusion
    Thrombocytopenia
    Adenosine Diphosphate
    Blood Platelets
    Pharmacokinetics
    Liposomes
    Injections
    Membranes
    Blood Circulation
    Feces
    Spleen
    Urine
    Pharmacology

    Keywords

    • accelerated blood clearance phenomenon
    • adenosine-diphosphate
    • clearance
    • dodecapeptide
    • liposome
    • pegylation
    • pharmacokinetics
    • platelet substitute
    • thrombocytopenia
    • transfusion

    ASJC Scopus subject areas

    • Pharmaceutical Science

    Cite this

    Pharmacokinetic Properties of Single and Repeated Injection of Liposomal Platelet Substitute in a Rat Model of Red Blood Cell Transfusion-Induced Dilutional Thrombocytopenia. / Hashimoto, Mai; Taguchi, Kazuaki; Ogaki, Shigeru; Watanabe, Hiroshi; Kinoshita, Manabu; Nishikawa, Kahoko; Takeoka, Shinji; Ikeda, Yasuo; Handa, Makoto; Otagiri, Masaki; Maruyama, Toru.

    In: Journal of Pharmaceutical Sciences, Vol. 104, No. 11, 01.11.2015, p. 3968-3976.

    Research output: Contribution to journalArticle

    Hashimoto, Mai ; Taguchi, Kazuaki ; Ogaki, Shigeru ; Watanabe, Hiroshi ; Kinoshita, Manabu ; Nishikawa, Kahoko ; Takeoka, Shinji ; Ikeda, Yasuo ; Handa, Makoto ; Otagiri, Masaki ; Maruyama, Toru. / Pharmacokinetic Properties of Single and Repeated Injection of Liposomal Platelet Substitute in a Rat Model of Red Blood Cell Transfusion-Induced Dilutional Thrombocytopenia. In: Journal of Pharmaceutical Sciences. 2015 ; Vol. 104, No. 11. pp. 3968-3976.
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    abstract = "A preclinical study of dodecapeptide (400HHLGGAKQAGDV411) (H12)-(adenosine diphosphate, ADP)-liposomes for use as a synthetic platelet (PLT) substitute under conditions of red blood cell (RBC) transfusion-induced dilutional thrombocytopenia is limited to pharmacological effect. In this study, the pharmacokinetics of H12-(ADP)-liposomes in RBC transfusion-induced dilutional thrombocytopenic rats were evaluated. As evidenced by the use of 14C, 3H double-radiolabeled H12-(ADP)-liposomes in which the encapsulated ADP and liposomal membrane were labeled with 14C and 3H, respectively, the H12-(ADP)-liposomes remained intact in the blood circulation for up to 3 h after injection, and were mainly distributed to the liver and spleen. The encapsulated ADP was mainly eliminated in the urine, whereas the outer membrane was mainly eliminated in the feces. These successive pharmacokinetic properties of the H12-(ADP)-liposomes in RBC transfusion-induced dilutional thrombocytopenic rats were similar to those in healthy rats, except for the shorter retention time in the circulation. When H12-(ADP)-liposomes were repeatedly injected into RBC transfusion-induced dilutional thrombocytopenic rats at intervals of 5 days at a dose of 10 mg lipids/kg, the second dose of injected H12-(ADP)-liposomes were rapidly cleared from the circulation, namely, via the accelerated blood clearance phenomenon. These novel pharmacokinetic findings provide useful information for the further development of H12-(ADP)-liposomes as a PLT substitute.",
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    AU - Taguchi, Kazuaki

    AU - Ogaki, Shigeru

    AU - Watanabe, Hiroshi

    AU - Kinoshita, Manabu

    AU - Nishikawa, Kahoko

    AU - Takeoka, Shinji

    AU - Ikeda, Yasuo

    AU - Handa, Makoto

    AU - Otagiri, Masaki

    AU - Maruyama, Toru

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