Abstract
The pharmacokinetics of doxorubicin (DOX) encapsulated in liposomes containing polyethylene glycol-derivatized distearoylphosphatidylethanolamine (PEG/DSPE) were investigated in rodents and dogs. The plasma levels of DOX obtained with PEG/DSPE-containing liposomes were consistently higher than those without PEG/DSPE or when PEG/DSPE was replaced with hydrogenated phosphatidylinositol (HPI). Despite the inclusion of PEG/DSPE in liposomes, there was a significant drop in the plasma levels of DOX when the main phospholipid component, hydrogenated phosphatidylcholine, was replaced with lipids of lower phase transition temperature (dipalmitoylphosphatidylcholine, egg phosphatidylcholine), indicating that phase transition temperature affects the pharmacokinetics of liposome-encapsulated DOX. In beagle dogs, clearance was significantly slower for DOX encapsulated in PEG/ DSPE-containing liposomes than in HPI-containing liposomes, with distribution half-lives of 29 and 13 hr, respectively. In both instances, almost 100% of the drug measured in plasma was liposome-associated. The apparent volume of distribution was only slightly above the estimated plasma volume of the dogs, indicating that drug leakage from circulating liposomes is insignificant and that the distribution of liposomal drug is limited mostly to the intravascular compartment in healthy animals.
Similar content being viewed by others
REFERENCES
T. M. Allen and A. Chonn. Large unilamellar liposomes with low uptake by the reticuloendothelial system. FEBS Lett. 223:42–46 (1987).
A. Gabizon and D. Papahadjopoulos. Liposome formulations with prolonged circulation time in blood and enhanced uptake by tumors. Proc. Natl. Acad. Sci. USA 85:6949–6953 (1988).
T. M. Allen, C. Hansen, and J. Rutledge. Liposome with prolonged circulation times: Factors affecting uptake by reticuloendothelial system and other tissues. Biochim. Biophys. Acta 981:27–35 (1989).
A. L. Klibanov, K. Maruyama, V. P. Torchilin, and L. Huang. Amphipathic polyethyleneglycols effectively prolong the circulation time of liposomes. FEBS Lett. 268:235–237 (1990).
G. Blume and G. Cevc. Liposomes for sustained drug release in vivo. Biochim. Biophys. Acta 1029:91–97 (1990).
J. Senior, C. Delgado, D. Fisher, C. Tilock, and G. Gregoriadis. Influence of surface hydrophilicity of liposomes on their interaction with plasma protein and clearance from the circulation: Studies with polyethyleneglycol-coated vesicles. Biochim. Biophys. Acta 1062:77–82 (1991).
D. Papahadjopoulos, T. Allen, A. Gabizon, E. Mayhew, K. Matthay, S. K. Huang, K.-D. Lee, M. C. Woodle, D. D. Lasic, C. Redemann, and F. J. Martin. Sterically stabilized liposomes: Improvements in pharmacokinetics and anti-tumor therapeutic efficacy. Proc. Natl. Acad. Sci. USA 88:11460–11464 (1991).
T. M. Allen, C. Hansen, F. Martin, C. Redemann, and A. Yau-Young. Liposomes containing synthetic lipid derivatives of polyethylene glycol show prolonged circulation half-lives in vivo. Biochim. Biophys. Acta 1066:29–36 (1991).
A. Gabizon and D. Papahadjopoulos. The role of surface charge and hydrophilic groups on liposome clearance in vivo. Biochim. Biophys. Acta 1103:94–100 (1992).
A. Gabizon, D. C. Price, J. Huberty, R. S. Bresalier, and D. Papahadjopoulos. Effect of liposome composition and other factors on the targeting of liposomes to experimental tumors: Biodistribution and imaging studies. Cancer Res. 50:6371–6378 (1990).
A. Gabizon. Selective tumor localization and improved therapeutic index of anthracyclines encapsulated in long-circulating liposomes. Cancer Res. 52:891–896 (1992).
A. Gabizon, R. Shiota, and D. Papahadjopoulos. Pharmacokinetics and tissue distribution of doxorubicin encapsulated in stable liposomes with long-circulation times. J. Natl. Cancer Inst. 81:1484–1488 (1989).
G. Storm, L. Van Bloois, M. Brouwer, and D. J. Crommelin. The interaction of cytostatic drugs with adsorbents in aqueous media: The potential implications for liposome preparations. Biochim. Biophys. Acta 818:343–351 (1992).
S. Druckmann, A. Gabizon, and Y. Barenholz. Separation of liposome-associated doxorubicin from non-liposome-associated doxorubicin in human plasma: Implications for pharmacokinetic studies. Biochim. Biophys. Acta 980:381–384 (1989).
P. A. Andrews, D. E. Brenner, F. E. Chou, H. Kubo, and N. R. Bachur. Facile and definitive determination of human adriamycin and daunorubicin metabolites by high-pressure liquid chromatography. Drug Metab. Disp. 8:152–156 (1980).
J. H. Beijnen, H. Rosing, P. A. De Vries, and W. J. Underberg. Stability of anthracycline antitumor agents in infusion fluids. J. Parent. Sci. Technol. 39:220–223 (1985).
S. Amselem, R. Cohen, S. Druckmann. A. Gabizon, D. Goren, R. M. Abra, A. Huang, R. New, and Y. Barenholz. Preparation and characterization of liposomal doxorubicin for human use. J. Liposome Res. 2:93–123 (1992).
S. Takanashi and N. R. Bachur. Adriamycin metabolism in man: evidence from urinary metabolites. Drug Metab. Disp. 4:79–87 (1976).
A. Gabizon, R. Chisin, S. Amselem, S. Druckmann, R. Cohen, D. Goren, I. Fromer, T. Peretz, A. Sulkes, and Y. Barenholz. Pharmacokinetic and imaging studies in patients receiving a formulation of liposome-associated adriamycin. Br. J. Cancer 64:1125–1132 (1991).
M. Gibaldi and D. Perrier. Pharmacokinetics, Marcel Dekker, New York, 1982, pp. 445–449.
L. Z. Benet and R. L. Galazzi. Non-compartmental determination of steady state volume of distribution. J. Pharm. Sci. 68:1071–1074 (1979).
K. Yamaoka, T. Nakagawa, and T. Uno. Statistical moments in pharmacokinetics. J. Pharmacokinet. Biopharm. 6:547–558 (1978).
K. Yamaoka. Methods for Pharmacokinetic Analysis for Personal Computers, Nanko-D Ltd., Tokyo, 1986, pp. 145–175.
R. F. Greene, J. M. Collins, J. F. Jenkins, J. L. Speyer, and C. E. Myers. Plasma pharmacokinetics of adriamycin and adriamycinol: Implications for the design of in vitro experiments and treatment protocols. Cancer Res. 43:3417–3421 (1983).
J. H. Senior. Fate and behavior of liposomes in vivo: A review of controlling fators. CRC Crit. Rev. Ther. Drug Carrier Syst. 3:123–193 (1987).
R. K. Jain. Vascular and interstitial barriers to delivery of therapeutic agents in tumors. Cancer Metastas. Rev. 9:253–266 (1990).
M. C. Woodle and D. D. Lasic. Sterically stabilized liposomes. Biochim. Biophys. Acta 1113:171–199 (1992).
D. D. Lasic, F. J. Martin, A. Gabizon, S. K. Huang, and D. Papahadjopoulos. Sterically stabilized liposomes: A hypothesis on the molecular origin of the extended circulation times. Biochim. Biophys. Acta 1070:187–192 (1991).
A. Gabizon, R. Catane, B. Uziely, B. Kaufman, T. Safra, Y. Barenholz, and A. Huang. A pilot study of doxorubicin encapsulated in long-circulating (Stealth®) liposomes in cancer patients. Proc. Am. Soc. Clin. Oncol. 11:124 (1992).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Gabizon, A.A., Barenholz, Y. & Bialer, M. Prolongation of the Circulation Time of Doxorubicin Encapsulated in Liposomes Containing a Polyethylene Glycol-Derivatized Phospholipid: Pharmacokinetic Studies in Rodents and Dogs. Pharm Res 10, 703–708 (1993). https://doi.org/10.1023/A:1018907715905
Issue Date:
DOI: https://doi.org/10.1023/A:1018907715905