PT  - JOURNAL ARTICLE
AU  - Laverman, Peter
AU  - Carstens, Myrra G.
AU  - Boerman, Otto C.
AU  - Th. M. Dams, Els
AU  - Oyen, Wim J. G.
AU  - van Rooijen, Nico
AU  - Corstens, Frans H. M.
AU  - Storm, Gert
TI  - Factors Affecting the Accelerated Blood Clearance of Polyethylene Glycol-Liposomes upon Repeated Injection
DP  - 2001 Aug 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 607--612
VI  - 298
IP  - 2
4099  - http://jpet.aspetjournals.org/content/298/2/607.short
4100  - http://jpet.aspetjournals.org/content/298/2/607.full
SO  - J Pharmacol Exp Ther2001 Aug 01; 298
AB  - Previously, we showed that long-circulating polyethylene glycol (PEG)-liposomes are cleared rapidly from the circulation when injected repeatedly in the same animal. In this article, we describe the effects of PEG-coating, the circulation time, the lipid dose, and the presence of encapsulated doxorubicin on the pharmacokinetics upon repeated injection in rats. Furthermore, the role of liver and splenic macrophages was investigated. Liposomes without PEG-coating also showed the so-called “enhanced clearance effect”: blood levels at 4 h post injection decreased from 62.8 ± 13.7% of injected dose (%ID) after the first injection to 0.54 ± 0.21%ID after the second injection. This decrease was independent of the circulation time of the first dose. Decreasing the first lipid dose of PEG-liposomes to 0.05 μmol/kg still led to enhanced clearance of a second dose of 5 μmol/kg. No changes in pharmacokinetics were observed when the second dose was 50 μmol/kg. When hepatosplenic macrophages were depleted, no enhanced clearance of repeated liposome injections was observed. A dose of doxorubicin containing PEG-liposomes (Doxil1,2), injected 1 week after injection of empty PEG-liposomes, was cleared rapidly from the circulation in rats. Our results indicate that hepatosplenic macrophages play an essential role in the enhanced clearance effect and that the change in pharmacokinetic behavior upon repeated injection is a general characteristic of liposomes, unrelated to the presence of PEG. Therefore, these findings may have a considerable impact on the clinical application of liposomal formulations that are administered repeatedly. The American Society for Pharmacology and Experimental Therapeutics