title: Pharmacokinetic study of adenosine diphosphate-encapsulated liposomes coated with fibrinogen γ-chain dodecapeptide as a synthetic platelet substitute in an anticancer drug-induced thrombocytopenia rat model.
abstract: A fibrinogen γ-chain (dodecapeptide HHLGGAKQAGDV, H12)-coated, adenosine diphosphate (ADP)-encapsulated liposome [H12-(ADP)-liposome] was designed to achieve optimal performance as a homeostatic agent and expected as a synthetic platelet alternative. For the purpose of efficient function as platelet substitute, H12-(ADP)-liposomes should potentially have both acceptable pharmacokinetic and biodegradable properties under conditions of an adaptation disease including thrombocytopenia induced by anticancer drugs. The aim of this study was to characterize the pharmacokinetics of H12-(ADP)-liposomes in busulphan-induced thrombocytopenic rats using (14) C, (3) H double radiolabeled H12-(ADP)-liposomes, in which the encapsulated ADP and liposomal membrane (cholesterol) were labeled with (14) C and (3) H, respectively. After the administration of H12-(ADP)-liposomes, they were determined to be mainly distributed to the liver and spleen and disappeared from organs within 7 days after injection. The encapsulated ADP was mainly eliminated in the urine, whereas the outer membrane (cholesterol) was mainly eliminated in feces. The successive dispositions of the H12-(ADP)-liposomes were similar in both normal and thrombocytopenic rats. However, the kinetics of H12-(ADP)-liposomes in thrombocytopenic rats was more rapid, compared with the corresponding values for normal rats. These findings, which well reflect the clinical features of patients with anticancer drug-induced thrombocytopenia, provide useful information for the development of the H12-(ADP)-liposomes for future clinical use.
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.
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Taguchi
authors.forename: Hayato
authors.initials: H
authors.lastname: Ujihira
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Watanabe
authors.forename: Atsushi
authors.initials: A
authors.lastname: Fujiyama
authors.forename: Mami
authors.initials: M
authors.lastname: Doi
authors.forename: Shinji
authors.initials: S
authors.lastname: Takeoka
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Ikeda
authors.forename: Makoto
authors.initials: M
authors.lastname: Handa
authors.forename: Masaki
authors.initials: M
authors.lastname: Otagiri
authors.forename: Toru
authors.initials: T
authors.lastname: Maruyama
mesh_terms: D000244:Adenosine Diphosphate / Q000493:pharmacokinetics* / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D001792:Blood Platelets / Q000187:drug effects*; D001802:Blood Substitutes / Q000493:pharmacokinetics* / Q000494:pharmacology; D002066:Busulfan / Q000009:adverse effects; D005340:Fibrinogen / Q000493:pharmacokinetics* / Q000494:pharmacology; D008081:Liposomes / Q000493:pharmacokinetics* / Q000494:pharmacology; D008099:Liver / Q000187:drug effects; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013154:Spleen / Q000187:drug effects; D013921:Thrombocytopenia / Q000139:chemically induced*
chemical_list: D000970:Antineoplastic Agents; D001802:Blood Substitutes; D008081:Liposomes; C027539:fibrinopeptides gamma; D000244:Adenosine Diphosphate; D005340:Fibrinogen; D002066:Busulfan
keywords: adenosine-diphosphate; disposition; dodecapeptide; liposome; platelet substitute; biocompatibility; disease state; cancer chemothrapy; thrombocytopenia