title: Repeated injection of pegylated liposomal antitumour drugs induces the disappearance of the rapid distribution phase.
abstract: Upon repeated administration, empty pegylated liposomes lose their long-circulating characteristics, referred to as the accelerated blood clearance (ABC) phenomenon. To investigate whether cytotoxic drug-containing pegylated liposomes could also elicit a similar phenomenon, two pegylated liposomal antitumour drugs (doxorubicin and mitoxantrone) were prepared, and they were administrated twice in the same animals with a 10-day interval at a dose level of 8 mg kg(-1) (pegylated liposomal doxorubicin) and 4 mg kg(-1) (pegylated liposomal mitoxantrone). By comparing the overall pharmacokinetics after a single-dose injection with that in animals treated with two doses, it was surprising to find that repeated administration of pegylated liposomal antitumour drugs caused the disappearance of rapid distribution phase instead of the ABC phenomenon, resulting in the conversion of a two-compartment model to a one-compartment model. Further investigation revealed that repeated injection induced the decreased uptake of liposomal antitumour drugs by the spleen at the early time point of 0.5-8 h after injection. In contrast, the deposition of liposomal antitumour drugs into liver was not affected. Therefore, the disappearance of the rapid distribution phase might be related to the reduced spleen uptake at the early time point.
authors.affiliation: School of Pharmacy, Hebei Medical University, No. 361, ZhongShan East Road, Shijiazhuang City, Hebei Province, 050017, China.
authors.forename: Jingxia
authors.initials: J
authors.lastname: Cui
authors.forename: Chunlei
authors.initials: C
authors.lastname: Li
authors.forename: Caixia
authors.initials: C
authors.lastname: Wang
authors.forename: Yanhui
authors.initials: Y
authors.lastname: Li
authors.forename: Lan
authors.initials: L
authors.lastname: Zhang
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.forename: Haiyan
authors.initials: H
authors.lastname: Yang
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000493:pharmacokinetics; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004317:Doxorubicin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004337:Drug Carriers / Q000737:chemistry; D008081:Liposomes; D051379:Mice; D008942:Mitoxantrone / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011092:Polyethylene Glycols / Q000737:chemistry*; D013154:Spleen / Q000378:metabolism; D013997:Time Factors; D014018:Tissue Distribution
chemical_list: D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D004337:Drug Carriers; D008081:Liposomes; D011092:Polyethylene Glycols; D004317:Doxorubicin; D008942:Mitoxantrone