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Accelerated clearance of a second injection of PEGylated liposomes in mice.
- Source :
-
International journal of pharmaceutics [Int J Pharm] 2003 Apr 14; Vol. 255 (1-2), pp. 167-74. - Publication Year :
- 2003
-
Abstract
- We recently reported that the firstly injected PEGylated liposomes dramatically affected the rate of blood clearance of secondly injected PEGylated liposomes in rats in a time interval of injection dependent manner [J. Control. Release (2003)]. Mice are frequently used in evaluations of the therapeutic efficacy of PEGylated liposomal formulations, but the pharmacokinetics of repeatedly injected PEGylated liposomes in mice is not fully understood. In this study, therefore, we examined in mice the effect of the repeated injection of PEGylated liposomes on their pharmacokinetics. An intravenous pretreatment with PEGylated liposomes produced a striking change in the biodistribution of the second dose which was given several days after the first injection. The first dose resulted in a reduction in the circulation half-life of the second dose. The degree of alteration was dependent on the time interval between the injections. The rapid clearance of the second dose was strongly related to hepatic clearance (CLh). This finding suggests that a considerable increase in hepatic accumulation accounts for this phenomenon. But, no liver injury or an increase in the number of Kupffer cells were detected in histopathological evaluations. Collectively, although the multiple injections of the PEGylated liposomes had no obvious physical effects, such as inflammation, their pharmacokinetic behavior was clearly altered in mice. The results obtained here have important implications not only with respect to the design and engineering of liposomes for human use, but for evaluating the therapeutic efficacy of liposomal formulations in experimental animal models as well.
- Subjects :
- Animals
Area Under Curve
Chemistry, Pharmaceutical
Cholesterol administration & dosage
Cholesterol toxicity
Dose-Response Relationship, Drug
Injections, Intravenous
Liposomes
Liver drug effects
Liver metabolism
Liver pathology
Male
Metabolic Clearance Rate
Mice
Phosphatidylethanolamines administration & dosage
Phosphatidylethanolamines toxicity
Phosphatidylglycerols administration & dosage
Phosphatidylglycerols toxicity
Polyethylene Glycols administration & dosage
Polyethylene Glycols toxicity
Spleen drug effects
Spleen metabolism
Tissue Distribution
Cholesterol pharmacokinetics
Phosphatidylethanolamines pharmacokinetics
Phosphatidylglycerols pharmacokinetics
Polyethylene Glycols pharmacokinetics
Subjects
Details
- Language :
- English
- ISSN :
- 0378-5173
- Volume :
- 255
- Issue :
- 1-2
- Database :
- MEDLINE
- Journal :
- International journal of pharmaceutics
- Publication Type :
- Academic Journal
- Accession number :
- 12672612
- Full Text :
- https://doi.org/10.1016/s0378-5173(03)00085-1