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

• Published in: Journal of pharmaceutical sciences 2015-11, Vol.104 (11), p.3968-3976
• Main Authors: Hashimoto, Mai, Taguchi, Kazuaki, Ogaki, Shigeru, Watanabe, Hiroshi, Kinoshita, Manabu, Nishikawa, Kahoko, Takeoka, Shinji, Ikeda, Yasuo, Handa, Makoto, Otagiri, Masaki, Maruyama, Toru
• Format: Article
• Language: English
• Subjects: accelerated blood clearance phenomenon; Adenosine Diphosphate - administration & dosage; Adenosine Diphosphate - analogs & derivatives; Adenosine Diphosphate - pharmacokinetics; adenosine-diphosphate; Amino Acid Sequence; Animals; Blood Platelets - cytology; Blood Substitutes - administration & dosage; Blood Substitutes - chemistry; Blood Substitutes - pharmacokinetics; clearance; Disease Models, Animal; dodecapeptide; Erythrocyte Transfusion - adverse effects; liposome; Liposomes; Male; Oligopeptides - administration & dosage; Oligopeptides - chemistry; Oligopeptides - pharmacokinetics; pegylation; pharmacokinetics; platelet substitute; Rats; Rats, Sprague-Dawley; thrombocytopenia; Thrombocytopenia - drug therapy; Thrombocytopenia - etiology; transfusion
• ISSN: 0022-3549; 1520-6017
• DOI: 10.1002/jps.24607

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 3h 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 10mg 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.