title: Pharmacokinetic Properties of Single and Repeated Injection of Liposomal Platelet Substitute in a Rat Model of Red Blood Cell Transfusion-Induced Dilutional Thrombocytopenia.
abstract: 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 (14) C, (3) H double-radiolabeled H12-(ADP)-liposomes in which the encapsulated ADP and liposomal membrane were labeled with (14) C and (3) H, 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.
authors.affiliation: Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Chuo-ku, Kumamoto 862-0973, Japan.
authors.forename: Mai
authors.initials: M
authors.lastname: Hashimoto
authors.affiliation: Faculty of Pharmaceutical Sciences, Sojo University, Nishi-ku, Kumamoto 862-0082, Japan.
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Taguchi
authors.affiliation: Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Chuo-ku, Kumamoto 862-0973, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Ogaki
authors.affiliation: Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Chuo-ku, Kumamoto 862-0973, Japan; Center for Clinical Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Watanabe
authors.affiliation: Department of Immunology and Microbiology, National Defense Medical College, Tokorozawa, Saitama 359-8513, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Kinoshita
authors.affiliation: Department of Traumatology and Critical Care Medicine, National Defense Medical College, Tokorozawa, Saitama, 359-8513, Japan.
authors.forename: Kahoko
authors.initials: K
authors.lastname: Nishikawa
authors.affiliation: Department of Life Science and Medical Bioscience, Graduate School of Advanced Science and Engineering, Waseda University, Shinjuku-ku, Tokyo 162-8480, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Takeoka
authors.affiliation: Department of Life Science and Medical Bioscience, Graduate School of Advanced Science and Engineering, Waseda University, Shinjuku-ku, Tokyo 162-8480, Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Ikeda
authors.affiliation: Center for Transfusion Medicine and Cell Therapy, Keio University, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Handa
authors.affiliation: Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Chuo-ku, Kumamoto 862-0973, Japan; Faculty of Pharmaceutical Sciences, Sojo University, Nishi-ku, Kumamoto 862-0082, Japan; DDS Research Institute, Sojo University, 4-22-1 Ikeda, Nishi-ku, Kumamoto 862-0082, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Otagiri
authors.affiliation: Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Chuo-ku, Kumamoto 862-0973, Japan; Center for Clinical Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan. Electronic address: tomaru@gpo.kumamoto-u.ac.jp.
authors.forename: Toru
authors.initials: T
authors.lastname: Maruyama
mesh_terms: D000244:Adenosine Diphosphate / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics*; D000595:Amino Acid Sequence; D000818:Animals; D001792:Blood Platelets / Q000166:cytology*; D001802:Blood Substitutes / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D004195:Disease Models, Animal; D017707:Erythrocyte Transfusion / Q000009:adverse effects*; D008081:Liposomes; D008297:Male; D009842:Oligopeptides / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013921:Thrombocytopenia / Q000188:drug therapy / Q000209:etiology*
chemical_list: D001802:Blood Substitutes; D008081:Liposomes; D009842:Oligopeptides; D000244:Adenosine Diphosphate
keywords: accelerated blood clearance phenomenon; adenosine-diphosphate; clearance; dodecapeptide; liposome; pegylation; pharmacokinetics; platelet substitute; thrombocytopenia; transfusion