Pharmacokinetics of paclitaxel-containing liposomes in rats

Abstract

In animal models, liposomal formulations of paclitaxel possess lower toxicity and equal antitumor efficacy compared with the clinical formulation, Taxol. The goal of this study was to determine the formulation dependence of paclitaxel pharmacokinetics in rats, in order to test the hypothesis that altered biodistribution of paclitaxel modifies the exposure of critical normal tissues. Paclitaxel was administered intravenously in either multilamellar (MLV) liposomes composed of phosphatidylglycerol/phosphatidylcholine (L-pac) or in the Cremophor EL/ethanol vehicle used for the Taxol formulation (Cre-pac). The dose was 40 mg/kg, and the infusion time was 8 to 9 minutes. Animals were killed at various times, and pharmacokinetic parameters were determined from the blood and tissue distribution of paclitaxel. The area under the concentration vs time curve (AUC) for blood was similar for the 2 formulations (L-pac: 38.1 ± 3.32 μg-h/mL; Cre-pac: 34.5 ± 0.994 μg-h/mL), however, the AUC for various tissues was formulation-dependent. For bone marrow, skin, kidney, brain, adipose, and muscle tissue, the AUC was statistically higher for Cre-pac. For spleen, a tissue of the reticuloendothelial system that is important in the clearance of liposomes, the AUC was statistically higher for L-pac. Apparent tissue partition coefficients (K p ) also were calculated. For bone marrow, a tissue in which paclitaxel exerts significant toxicity, K p was 5-fold greater for paclitaxel in Cre-pac. The data are consistent with paclitaxel release from circulating liposomes, but with efflux delayed sufficiently to retain drug to a greater extent in the central (blood) compartment and reduce penetration into peripheral tissues. These effects may contribute to the reduced toxicity of liposomal formulations of paclitaxel.

In vivopharmacokinetics, biodistribution and anti-tumor effect of paclitaxel-loaded targeted chitosan-based polymeric micelle

“…Hence, many attempts have been devoted to substitute the Cremophor Õ EL-based formulation with alternative carriers which enable delivering PTX selectively to the tumor tissues with significantly reduced adverse effects on normal cells. Numerous drug delivery systems including parenteral emulsions (He et al, 2003;Nornoo et al, 2008), liposomes (Fetterly et al, 2003;Soenpenberg et al, 2004), nanoparticles (Hawkins et al, 2008;Zhu et al, 2010) and polymeric micelles (Qu et al, 2009;Tao et al, 2012;Qu et al, 2013;Wang et al, 2013) have extensively been studied and evaluated for parenteral delivery of PTX into cancer cells.…”

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“…NE formulated targeted drug delivery has the capability to increase bio distribution of therapeutic agents to target organs and improve the pharmacokinetics, which will result in improved efficacy 62,[67][68][69][70] .Camptothecin is a topoisomerase I inhibitor acting against a broad spectrum of cancers 71 . But due to its insolubility, instability and toxicity, clinical application are limited.…”

Comparison of Two Pharmacodynamic Transduction Models for the Analysis of Tumor Therapeutic Responses in Model Systems

“…Cre-pac exists as a microemulsion at the time of administration (19), from which drug is released to plasma. Liposomes similarly represent a circulating reservoir from which drug may be released (20). Therefore, the PK model included an additional compartment (A 1 ) to represent drug incorporated in the circulating carrier (Fig.…”

“…2a). A key assumption is that after release of paclitaxel from either vehicle in the blood, the free drug binds rapidly to plasma proteins (20)(21)(22), and the subsequent pharmacokinetic processes affecting released drug are identical for both formulations. This is consistent with a previous mechanism-based analysis of Cre-pac PK (23).…”