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

Keywords

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

ASJC Scopus subject areas

  • Pharmaceutical Science

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