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Vol. 298, Issue 2, 607-612, August 2001

Factors Affecting the Accelerated Blood Clearance of Polyethylene Glycol-Liposomes upon Repeated Injection

Peter Laverman, Myrra G. Carstens , Otto C. Boerman, Els Th. M. Dams, Wim J. G. Oyen, Nico van Rooijen, Frans H. M. Corstens and Gert Storm

Department of Nuclear Medicine, University Medical Center Nijmegen, Nijmegen, The Netherlands (P.L., M.G.C., O.C.B., E.Th.M.D., W.J.G.O., F.H.M.C.); Utrecht Institute for Pharmaceutical Sciences, Department of Pharmaceutics, Utrecht University, Utrecht, The Netherlands (M.G.C., G.S.); and Department of Cell Biology and Immunology, Faculty of Medicine, Free University, Amsterdam, The Netherlands (N.v.R.).

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.

1 Doxil is a registered trademark of ALZA Pharmaceuticals, Inc., Mountain View, CA.

2 Caelyx is a registered trademark of Schering-Plough Pharmaceuticals NV/SA, Brussels, Belgium.

0022-3565/01/2982-0607$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2001 by The American Society for Pharmacology and Experimental Therapeutics


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