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AAPS PharmSci

, Volume 5, Issue 4, pp 90–100 | Cite as

Pharmacokinetics of paclitaxel-containing liposomes in rats

  • Gerald J. Fetterly
  • Robert M. StraubingerEmail author
Article

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 (Kp) also were calculated. For bone marrow, a tissue in which paclitaxel exerts significant toxicity, Kp 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.

Keywords

drug delivery paclitaxel liposomes physiological modeling cancer chemotherapy 

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References

  1. 1.
    Guastalla JP, Lhomme C, Dauplat J, et al. Taxol (paclitaxel) safety in patients with platinum pretreated ovarian carcinoma: an interim analysis of a Phase II multicenter study. Ann Oncol. 1994;5(suppl 6):S33–38.Google Scholar
  2. 2.
    Kubota T, Matsuzaki SW, Hoshiya Y, et al. Antitumor activity of paclitaxel against human breast carcinoma xenografts serially transplanted into nude mice. J Surg Oncol. 1997;64:115–121.PubMedCrossRefGoogle Scholar
  3. 3.
    Adler LM, Herzog TJ, Williams S, Rader JS, Mutch DG. Analysis of exposure times and dose escalation of paclitaxel in ovarian cancer cell lines. Cancer. 1994;74:1891–1898.PubMedCrossRefGoogle Scholar
  4. 4.
    Sharma A, Mayhew E, Straubinger RM. Antitumor effect of taxol-containing liposomes in a taxol-resistant murine tumor model. Cancer Res. 1993;53:5877–5881.PubMedGoogle Scholar
  5. 5.
    Murphy WK, Fossella FV, Winn RJ, et al. Phase II study of taxol in patients with untreated advanced non-small-cell lung cancer. J Natl Cancer Inst. 1993;85:384–388.PubMedCrossRefGoogle Scholar
  6. 6.
    Weiss RB, Donehower RC, Wiernik PH, et al. Hypersensitivity reactions from taxol. J Clin Oncol. 1990;8:1263–1268.PubMedGoogle Scholar
  7. 7.
    Szebeni J, Muggia FM, Alving CR. Complement activation by Cremophor EL as a possible contributor to hypersensitivity to paclitaxel: an in vitro study. J Natl Cancer Inst. 1998;90:300–306.PubMedCrossRefGoogle Scholar
  8. 8.
    van Zuylen L, Karlsson MO, Verweij J, et al. Pharmacokinetic modeling of paclitaxel encapsulation in Cremophor EL micelles. Cancer Chemother Pharmacol. 2001;47:309–318.PubMedCrossRefGoogle Scholar
  9. 9.
    Bookman MA, Kloth DD, Kover PE, Smolinski S, Ozols RF. Short-course intravenous prophylaxis for paclitaxel-related hypersensitivity reactions. Ann Oncol. 1997;8:611–614.PubMedCrossRefGoogle Scholar
  10. 10.
    Jamis-Dow CA, Klecker RW, Katki AG, Collins JM. Metabolism of taxol by human and rat liver in vitro: a screen for drug interactions and interspecies differences. Cancer Chemother Pharmacol. 1995;36:107–114.PubMedCrossRefGoogle Scholar
  11. 11.
    Sparreboom A, van Zuylen L, Brouwer E, et al. Cremophor EL-mediated alteration of paclitaxel distribution in human blood: clinical pharmacokinetic implications. Cancer Res. 1999;59:1454–1457.PubMedGoogle Scholar
  12. 12.
    Ellis AG, Webster LK. Inhibition of paclitaxel elimination in the isolated perfused rat liver by Cremophor EL. Cancer Chemother Pharmacol. 1999;43:13–18.PubMedCrossRefGoogle Scholar
  13. 13.
    Sparreboom A, Verweij J, van der Burg ME, et al. Disposition of Cremophor EL in humans limits the potential for modulation of the multidrug resistance phenotype in vivo. Clin Cancer Res. 1998;4:1937–1942.PubMedGoogle Scholar
  14. 14.
    van Tellingen O, Huizing MT, Panday VR, et al. Cremophor EL causes (pseudo-) non-linear pharmacokinetics of paclitaxel in patients. Br J Cancer. 1999;81:330–335.PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    Bartoli MH, Boitard M, Fessi H, et al. In vitro and in vivo antitumoral activity of free and encapsulated taxol. J Microencap. 1990;7:191–197.CrossRefGoogle Scholar
  16. 16.
    Straubinger RM, Sharma A, Murray M, Mayhew E. Novel taxol formulations: Taxol-containing liposomes. J Natl Cancer Inst Monogr. 1993;(15):69–78.PubMedGoogle Scholar
  17. 17.
    Sharma A, Straubinger RM. Novel taxol formulations: preparation and characterization of taxol-containing liposomes. Pharm Res. 1994;11:889–896.PubMedCrossRefGoogle Scholar
  18. 18.
    Alkan-Onyuksel H, Ramakrishnan S, Chai HB, Pezzuto JM. A mixel micellar formulation suitable for the parenteral administration of taxol. Pharm Res. 1994;11:206–212.PubMedCrossRefGoogle Scholar
  19. 19.
    Sharma D, Chelvi TP, Kaur J, et al. Novel Taxol formulation: polyvinylpyrrolidone nanoparticle-encapsulated Taxol for drug delivery in cancer therapy. Oncol Res. 1996;8:281–286.PubMedGoogle Scholar
  20. 20.
    Scialli AR, Waterhouse TB, Desesso JM, Rahman A, Goeringer GC. Protective effect of liposome encapsulation on paclitaxel developmental toxicity in the rat. Teratology. 1997;56:305–310.PubMedCrossRefGoogle Scholar
  21. 21.
    Papahadjopoulos D, Allen T, Gabizon A, et al. Sterically-stabilized liposomes: improvements in pharmacokinetics and anti-tumor therapeutic efficacy. Proc Natl Acad Sci U S A. 1991;88:11460–11464.PubMedCentralPubMedCrossRefGoogle Scholar
  22. 22.
    Drummond DC, Meyer O, Hong K, Kirpotin DB, Papahadjopoulos D. Optimizing liposomes for delivery of chemotherapeutic agents to solid tumors. Pharmacol Rev. 1999;51:691–743.PubMedGoogle Scholar
  23. 23.
    Mayer LD, Tai LCL, Ko DSC, et al. Influence of vesicle size, lipid composition, and drug-to-lipid ratio on the biological activity of liposomal doxorubicin in mice. Cancer Res. 1989;49:5922–5930.PubMedGoogle Scholar
  24. 24.
    Sharma A, Sharma US, Straubinger RM. Paclitaxel-liposomes for intracavitary therapy of intraperitoneal P388 leukemia. Cancer Lett. 1996;107:265–272.PubMedCrossRefGoogle Scholar
  25. 25.
    Sharma A, Straubinger RM, Ojima I, Bernacki RJ. Antitumor efficacy of taxane liposomes on a human ovarian tumor xenograft in nude athymic mice. J Pharm Sci. 1995;84(12):1400–1404.PubMedCrossRefGoogle Scholar
  26. 26.
    Cabanes A, Briggs KE, Gokhale PC, Treat JA, Rahman A. Comparative in vivo studies with paclitaxel and liposome-encapsulated paclitaxel. Int J Oncol. 1998;12:1035–1040.PubMedGoogle Scholar
  27. 27.
    Perez-Soler R, Lopez-Berestein G, Lautersztain J, et al. Phase I clinical and pharmacological study of liposome-entrapped cis-bis-neodecanoato-trans-R,R-1,2-diaminocyclohexane platinum(II). Cancer Res. 1990;50:4254–4259.PubMedGoogle Scholar
  28. 28.
    Campbell RB, Balasubramanian SV, Straubinger RM. Influence of cationic lipids on the stability and membrane properties of paclitaxel-containing liposomes. J Pharm Sci. 2001;90(8):1091–1105.PubMedCrossRefGoogle Scholar
  29. 29.
    Balasubramanian SV, Alderfer JL, Straubinger RM. Solvent-and concentration-dependent molecular interactions of taxol (paclitaxel). J Pharm Sci. 1994;83(10):1470–1476.PubMedCrossRefGoogle Scholar
  30. 30.
    Balasubramanian SV, Straubinger RM. Taxol-lipid interactions: taxol-dependent effects on the physical properties of model membranes. Biochemistry. 1994;33:8941–8947.PubMedCrossRefGoogle Scholar
  31. 31.
    Sharma US, Balasubramanian SV, Straubinger RM. Pharmaceutical and physical properties of paclitaxel (Taxol) complexes with cyclodextrins. J Pharm Sci. 1995;84(10):1223–1230.PubMedCrossRefGoogle Scholar
  32. 32.
    National Institutes of Health. Principals of Laboratory Animal Care. Bethesda, MD: National Institutes of Health. Revised 1985. Publication No. 85-23.Google Scholar
  33. 33.
    Sharma A, Conway WD, Straubinger RM. Reversed-phase high-performance liquid chromatographic determination of taxol in mouse plasma. J Chromatogr B. 1994;655:315–319.CrossRefGoogle Scholar
  34. 34.
    D Argenio DZ, Schumitzky A. A program package for simulation and parameter estimation in pharmacokinetic systems. Comput Meth Prog Biomed. 1979;9:115–134.CrossRefGoogle Scholar
  35. 35.
    Yamaoka K, Nakagawa T, Uno T. Statistical moments in pharmacokinetics. J Pharmacokinet Biopharm. 1978;6:547–558.PubMedCrossRefGoogle Scholar
  36. 36.
    Benet L, Galeazzi RL. Noncompartmental determination of the steady-state volume of distribution. J Pharm Sci. 1979;68(8):1071–1074.PubMedCrossRefGoogle Scholar
  37. 37.
    Gallo JM, Lam FC, Perrier DG. Area method for the estimation of partition coefficients for physiological pharmacokinetic models. J Pharmacokinet Biopharm. 1987;15:271–280.PubMedCrossRefGoogle Scholar
  38. 38.
    Gerlowski LE, Jain RK. Physiologically based pharmacokinetic modeling: principles and applications. J Pharm Sci 1983;72:1103–1127.PubMedCrossRefGoogle Scholar
  39. 39.
    Mordenti J. Man versus beast: pharmacokinetic scaling in mammals. J Pharm Sci. 1986;75:1028–1040.PubMedCrossRefGoogle Scholar
  40. 40.
    Yuan J. Estimation of variance of AUC in animal studies. J Pharm Sci. 1993;82:761–763.PubMedCrossRefGoogle Scholar
  41. 41.
    Kumar GN, Walle UK, Bhalla KN, Walle T. Binding of Taxol to human plasma, albumin, and al-acid glycoprotein. Res Commun Chem Pathol Pharmacol. 1993;80:337–344.PubMedGoogle Scholar
  42. 42.
    Sharma A, Mayhew E, Bolcsak L. et al. Activity of paclitaxel liposome formulations against human ovarian tumor xenografts. Int J Cancer. 1997;71:103–107.PubMedCrossRefGoogle Scholar
  43. 43.
    Zhang X, Burt HM, Mangold G, et al. Anti-tumor efficacy and biodistribution of intravenous polymeric micellar paclitaxel. Anti-cancer Drugs. 1997;8:696–701.PubMedCrossRefGoogle Scholar
  44. 44.
    Gabizon A, Shiota R, Papahadjopoulos D. Pharmacokinetics and tissue distribution of doxorubicin encapsulated in stable liposomes with long circulation times. J Natl Cancer Inst. 1989;81:1484–1488.PubMedCrossRefGoogle Scholar
  45. 45.
    Chonn A, Semple S, Cullis P. Separation of large unilamellar liposomes from blood components by a spin column procedure: towards identifying plasma proteins which mediate liposome clearance in vivo. Biochim Biophys Acta. 1991;1070:215–222.PubMedCrossRefGoogle Scholar
  46. 46.
    Sparreboom A, van Tellingen O, Nooijen WJ, Beijnen JH. Tissue distribution, metabolism and excretion of paclitaxel in mice. Anticancer Drugs. 1996;7:78–86.PubMedCrossRefGoogle Scholar
  47. 47.
    Straubinger RM, Hong K, Friend DS, Papahadjopoulos D. Endocytosis of liposomes and intracellular fate of encapsulated molecules: encounter with a low pH compartment after internalization in coated vesicles. Cell. 1983;32:1069–1079.PubMedCrossRefGoogle Scholar
  48. 48.
    Mayer LD, Bally MB, Cullis PR. Uptake of adriamycin into large unilamellar vesicles in response to a pH gradient. Biochim Biophys Acta. 1986;857:123–126.PubMedCrossRefGoogle Scholar
  49. 49.
    Haran G, Cohen R, Bar LK, Barenholz Y. Transmembrane ammonium sulfate gradients in liposomes produce efficient and stable entrapment of amphipathic weak bases. Biochim Biophys Acta. 1993;1151:201–215.PubMedCrossRefGoogle Scholar
  50. 50.
    Allen T, Chonn A. Large unilamellar liposomes with low uptake into the reticuloenthelial system. FEBS Lett. 1987;223:42–46.PubMedCrossRefGoogle Scholar
  51. 51.
    Gabizon A, Papahadjopoulos D. Liposome formulations with prolonged circulation time in blood and enhanced uptake by tumors. Proc Natl Acad Sci U S A. 1988;85:6949–6953.PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2003

Authors and Affiliations

  1. 1.Department of Pharmaceutical Sciences, University at BuffaloState University of New YorkAmherst
  2. 2.Cognigen CorporationBuffalo

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