Pharmaceutical Research

, Volume 8, Issue 3, pp 380–384

The Effects of Cyclodextrins on the Disposition of Intravenously Injected Drugs in the Rat

  • Henderik W. Frijlink
  • Eric J. F. Franssen
  • Anko C. Eissens
  • Roelof Oosting
  • Coenraad F. Lerk
  • Dirk K. F. Meijer


Naproxen and flurbiprofen form complexes with hydroxypropyl-β-cyclodextrin; with stability constants of 2207 and 12515 M−1 respectively. However, only small fractions of the drug remain complexed when the drug–cyclodextrin complex is added to plasma in vitro. This result can be explained by albumin effectively competing with cyclodextrin for drug binding and by the simultaneous displacement of the drug from cyclodextrins by plasma cholesterol. Naproxen and flurbiprofen were administered intravenously to rats as cyclodextrin complexes. The disposition in the body of naproxen was not significantly altered by the complexation. This indicates that immediately after administration all drug is removed from the cyclodextrin complex. However, the initial distribution of flurbiprofen was changed upon complexation. Drug concentrations in liver, brain, kidney, and spleen were increased, indicating that hydroxypropyl-β-cyclodextrin may improve the presentation of the flurbiprofen to biomembranes, as compared with plasma proteins. The effect was transient; 60 min after injection the differences in tissue concentration compared with controls were dissipated. Finally, the importance of protein binding in determining the mode of interaction of cyclodextrins on drug disposition is discussed.

hydroxypropyl-β-cyclodextrin naproxen flurbiprofen intravenous administration tissue concentration protein binding 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    M. E. Brewster, K. S. Estes, T. Loftsson, R. Perchalski, H. Derendorf, G. Mullersman, and N. Bodor. Improved delivery through biological membranes. XXXI. Solubilization and stabilization of an estradiol chemical delivery system by modified β-cyclodextrins. J. Pharm. Sci. 77:981–985 (1988).Google Scholar
  2. 2.
    G. Taylor, J. Weiss, and J. Pitha. Testosteron in a cyclodextrin-containing formulation: Behavioral and physiological effects of episode-like pulses in rats. Pharm. Res. 6:641–646 (1989).Google Scholar
  3. 3.
    M. Kajtar, M. Vikmon, E. Morlin, and J. Szejtli. Aggregation of amphotericin B in the presence of γ-cyclodextrin. Biopolymers 28:1585–1596 (1989).Google Scholar
  4. 4.
    K. Uekama, F. Hirayama, T. Wakuda, and M. Otagiri. Effects of cyclodextrins on the hydrolysis of prostacyclin and its methyl ester in aqueous solution. Chem. Pharm. Bull. 29:213–219 (1981).Google Scholar
  5. 5.
    F. Hirayama, M. Kunhara, and K. Uekama. Mechanisms of deceleration by methylated cyclodextrins in the dehydration of prostaglandin E2 and the isomerization of prostaglandin A2 in aqueous solution. Chem Pharm. Bull. 34:5093–5101 (1986).Google Scholar
  6. 6.
    F. Hirayama, M. Kurihara, and K. Uekama. Improvement of chemical instability of prostacyclin in aqueous solution by complexation with methylated cyclodextrins. Int. J. Pharm. 35:193–199 (1987).Google Scholar
  7. 7.
    O. Bekers, J. H. Beijnen, E. H. Groot Brammel, M. Otagiri, A. Bult, and W. J. M. Underberg. Stabilization of mitomycins on complexation with cyclodextrins in aqueous acid media. Int. J. Pharm. 52:239–248 (1989).Google Scholar
  8. 8.
    M. Otagiri, K. Uekama, T. Irie, M. Sunada, T. Miyata, and Y. Kase. Effects of cyclodextrins on the hemolysis induced with phenothiazide neuroleptics. In J. Szejtli (ed.), I. Int. Symp. Cyclodextrins Budapest, 1981, D. Reidel, Dortrecht, 1982, pp. 389–398.Google Scholar
  9. 9.
    K. Uekama, T. Irie, M. Sunada, M. Otagiri, K. Iwasaki, Y. Okano, T. Miyata, and K. Kase. Effects of cyclodextrins on chlorpromazine-induced haemolysis and central nervous system responses. J. Pharm. Pharmacol. 33:707–710 (1981).Google Scholar
  10. 10.
    T. Hoshino, F. Hirayama, K. Uekama, and M. Yamasaki. Reduction of protriptyline-photosensitized hemolysis by β-cyclodextrin complexations. Int. J. Pharm. 50:45–52 (1989).Google Scholar
  11. 11.
    T. Irie, M. Otagiri, K. Uekama, Y. Okano, and T. Miyata. Alleviation of the chlorpromazine-induced muscular tissue damage by β-cyclodextrin complexation. J. Incl. Phenom. 2:637–644 (1984).Google Scholar
  12. 12.
    T. Irie, S. Kuwahar, M. Otagiri, K. Uekama, and T. Iwamasa. Reduction in the local tissue toxicity of chlorpromazine by β-cyclodextrin complexation. J. Pharmacobio-Dyn. 6:790–792 (1983).Google Scholar
  13. 13.
    T. Nagai, O. Shirakura, and N. Nambu. Hypnotic potency, and the plasma and the brain concentration of hexobarbital in the presence of cyclodextrins. In 3rd Int. Conf. Pharm. Technol., Paris, 31 May/2 June 1983, Vol. V, pp. 253–262.Google Scholar
  14. 14.
    O. Shirakura, N. Nambu, and T. Nagai. Effect of β-cyclodextrin on disposition of hexobarbital and phenobarbital in mice. J. Inch Phenom. 2:613–621 (1984).Google Scholar
  15. 15.
    K. Arimori and K. Uekama. Effects of β-and γ-cyclodextrins on the pharmacokinetic behaviour of prednisolone after intravenous and intramuscular administration to rabbits J. Pharmacobio-Dyn. 10:390–395 (1987).Google Scholar
  16. 16.
    H. W. Frijlink, J. Visser, N. R. Hefting, R. Oosting, D. K. F. Meijer, and C. F. Lerk. The pharmacokinetics of β-cyclodextrin in the rat. Pharm. Res. 7:1248–1252 (1990).Google Scholar
  17. 17.
    H. W. Frijlink, A. C. Eissens, N. R Hefting, K. Poelstra, C. F. Lerk, and D. K. F. Meijer. The effect of parenterally administered cyclodextrins on cholesterol levels in the rat. Pharm. Res. 8:9–16 (1991).Google Scholar
  18. 18.
    T. Higuchi and K. Connors. Phase-solubility techniques. Adv. Anal. Chem. Instr. 4:117–212 (1965).Google Scholar
  19. 19.
    H. W. Frijlink, J. Visser, and B. F. H. Drenth. Determination of cyclodextrins in biological fluids by high-performance liquid chromatography with negative colorimetric detection using post-column complexation with phenolphthalein. J. Chromatogr. 415:325–333 (1987).Google Scholar
  20. 20.
    J. H. Lin, D. M. Cocchetto, and D. E. Duggan. Protein binding as a primary determinant of the clinical pharmacokinetic properties of non-steroidal anti-inflammatory drugs. Clin. Pharmacokinet. 12:402–432 (1987).Google Scholar
  21. 21.
    F. Cramer and H. Hettler. Inclusion compounds of cyclodextrins. Naturwissenschaften 54:624–632 (1967).Google Scholar
  22. 22.
    J. J. Vallner. Binding of drugs by albumin and plasma protein. J. Pharm. Sci. 66:447–465 (1977).Google Scholar
  23. 23.
    M. H. Bickel, R. M. Raaflaub, M. Hellmuller, and E. J. Stauffer. Characterization of drug distribution and binding competition by two-chamber and multi-chamber distribution dialysis. J. Pharm. Sci. 76:68–74 (1987).Google Scholar

Copyright information

© Plenum Publishing Corporation 1991

Authors and Affiliations

  • Henderik W. Frijlink
    • 1
  • Eric J. F. Franssen
    • 2
  • Anko C. Eissens
    • 1
  • Roelof Oosting
    • 2
  • Coenraad F. Lerk
    • 1
  • Dirk K. F. Meijer
    • 2
  1. 1.Department of Pharmaceutical Technology and BiopharmacyUniversity of GroningenAW GroningenThe Netherlands
  2. 2.Department of Pharmacology and TherapeuticsUniversity of GroningenAW GroningenThe Netherlands

Personalised recommendations