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

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

来源：Journal of Pharmaceutical Sciences, 2015, 104(11): 3968-3976.

DOI：10.1002/jps.24607

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

A preclinical study of dodecapeptide ((400)HHLGGAKQAGDV(411)) (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 C-14, H-3 double-radiolabeled H12-(ADP)-liposomes in which the encapsulated ADP and liposomal membrane were labeled with C-14 and H-3, 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.

• 出版日期2015-11