Pharmaceutical Research

, Volume 10, Issue 5, pp 703–708 | Cite as

Prolongation of the Circulation Time of Doxorubicin Encapsulated in Liposomes Containing a Polyethylene Glycol-Derivatized Phospholipid: Pharmacokinetic Studies in Rodents and Dogs

  • Alberto A. Gabizon
  • Yechezkel Barenholz
  • Meir Bialer


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.

liposome doxorubicin pharmacokinetics polyethylene glycol 


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  1. 1.
    T. M. Allen and A. Chonn. Large unilamellar liposomes with low uptake by the reticuloendothelial system. FEBS Lett. 223:42–46 (1987).Google Scholar
  2. 2.
    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).Google Scholar
  3. 3.
    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).Google Scholar
  4. 4.
    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).Google Scholar
  5. 5.
    G. Blume and G. Cevc. Liposomes for sustained drug release in vivo. Biochim. Biophys. Acta 1029:91–97 (1990).Google Scholar
  6. 6.
    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).Google Scholar
  7. 7.
    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).Google Scholar
  8. 8.
    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).Google Scholar
  9. 9.
    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).Google Scholar
  10. 10.
    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).Google Scholar
  11. 11.
    A. Gabizon. Selective tumor localization and improved therapeutic index of anthracyclines encapsulated in long-circulating liposomes. Cancer Res. 52:891–896 (1992).Google Scholar
  12. 12.
    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).Google Scholar
  13. 13.
    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).Google Scholar
  14. 14.
    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).Google Scholar
  15. 15.
    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).Google Scholar
  16. 16.
    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).Google Scholar
  17. 17.
    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).Google Scholar
  18. 18.
    S. Takanashi and N. R. Bachur. Adriamycin metabolism in man: evidence from urinary metabolites. Drug Metab. Disp. 4:79–87 (1976).Google Scholar
  19. 19.
    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).Google Scholar
  20. 20.
    M. Gibaldi and D. Perrier. Pharmacokinetics, Marcel Dekker, New York, 1982, pp. 445–449.Google Scholar
  21. 21.
    L. Z. Benet and R. L. Galazzi. Non-compartmental determination of steady state volume of distribution. J. Pharm. Sci. 68:1071–1074 (1979).Google Scholar
  22. 22.
    K. Yamaoka, T. Nakagawa, and T. Uno. Statistical moments in pharmacokinetics. J. Pharmacokinet. Biopharm. 6:547–558 (1978).Google Scholar
  23. 23.
    K. Yamaoka. Methods for Pharmacokinetic Analysis for Personal Computers, Nanko-D Ltd., Tokyo, 1986, pp. 145–175.Google Scholar
  24. 24.
    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).Google Scholar
  25. 25.
    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).Google Scholar
  26. 26.
    R. K. Jain. Vascular and interstitial barriers to delivery of therapeutic agents in tumors. Cancer Metastas. Rev. 9:253–266 (1990).Google Scholar
  27. 27.
    M. C. Woodle and D. D. Lasic. Sterically stabilized liposomes. Biochim. Biophys. Acta 1113:171–199 (1992).Google Scholar
  28. 28.
    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).Google Scholar
  29. 29.
    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).Google Scholar

Copyright information

© Plenum Publishing Corporation 1993

Authors and Affiliations

  • Alberto A. Gabizon
    • 1
  • Yechezkel Barenholz
    • 2
  • Meir Bialer
    • 3
  1. 1.Sharett Institute of OncologyHadassah University HospitalIsrael
  2. 2.Department of Membrane BiochemistryHebrew University–Hadassah School of MedicineIsrael
  3. 3.Department of Pharmacy, School of PharmacyThe Hebrew University of JerusalemIsrael

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