Pharmaceutical Research

, Volume 14, Issue 5, pp 650–656

Blood-to-Brain Transfer of Various Oxicams: Effects of Plasma Binding on Their Brain Delivery

  • Pascale Jolliet
  • Nicolas Simon
  • Francoise Brée
  • Saïk Urien
  • Alessandra Pagliara
  • Pierre-Alain Carrupt
  • Bernard Testa
  • Jean-Paul Tillement


Purpose. The objective of this work was to assess the influence of binding to plasma proteins and to serum on the brain extraction of four antiinflammatory oxicams.

Methods. The brain extraction of isoxicam, tenoxicam, meloxicam and piroxicam was investigated in rats using the carotid injection technique. Blood protein binding parameters were determined by equilibrium dialysis using human serum, human serum albumin (HSA) and alpha-1-acid glycoprotein (AAG) solutions at various concentrations.

Results. All oxicams had low values of brain extraction, between 19% and 39% when dissolved in serum, i.e. under physiological conditions. Brain efflux rate constants calculated from the wash-out curves were the same in the absence or presence of serum. Brain efflux was inversely related to the polarity of the oxicams, such that the higher their H-bonding capacity, the lower their brain efflux. The free dialyzable drug fraction was inversely related to protein concentration. However, rat brain extraction was always higher than expected from in vitro measurements of the dialyzable fraction.

Conclusions. Except for piroxicam whose brain extraction was partially decreased in the presence of proteins, the serum unbound and initially bound fractions of oxicams both seem available for transfer into the brain. Modest affinities for AAG rule out any related effect. More surprising is the apparent lack of effect on brain transfer of the high-affinity binding to HSA and serum. The enhanced brain uptake of meloxicam in the presence of AAG could be a result of interactions between this globular protein and the endothelial wall.

blood-brain barrier drug brain transfer in vivo brain extraction plasma protein binding oxicams 


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  1. 1.
    B. B. Brodie, H. Kurtz, and L. J. Schanker. J. Pharmacol. Exp. Ther. 130:20–25 (1960).PubMedGoogle Scholar
  2. 2.
    P. Riant, S. Urien, E. Albengres, A. Renouard, and J. P. Tillement. J. Neurochem. 51:421–425 (1990).Google Scholar
  3. 3.
    W. M. Pardridge, R. Sakiyama, and G. Fierer. J. Clin. Invest. 71:900–908 (1983).PubMedGoogle Scholar
  4. 4.
    R. S. Tsai, P. A. Carrupt, N. El Tayar, Y. Giroud, P. Andrade, F. Brée, and J. P. Tillement. Helv. Chim. Acta 76:842–854 (1993).Google Scholar
  5. 5.
    P. Luger, K. Daneck, W. Engel, G. Trummlitz, and K. Wagner. Eur. J. Pharm. Sci. 4:175–187 (1996).Google Scholar
  6. 6.
    W. H. Oldendorf. Am. J. Physiol. 221:1629–1639 (1971).PubMedGoogle Scholar
  7. 7.
    D. Triguero, J. Buciak, and W. M. Pardridge. J. Neurochem. 54:1882–1888 (1990).PubMedGoogle Scholar
  8. 8.
    W. M. Pardridge and E. M. Landaw. J. Clin. Invest. 74:745–752 (1984).PubMedGoogle Scholar
  9. 9.
    S. Urien, E. Albengres, A. Comte, J. R. Kiechel, and J. P. Tillement. J. Cardiovascular. Pharmacol. 7:891–898 (1985).Google Scholar
  10. 10.
    C. Crone. Acta Physiol. Scand. 58:292–305 (1973).Google Scholar
  11. 11.
    A. Gavezzotti. J. Am. Chem. Soc. 105:5220–5225 (1983).Google Scholar
  12. 12.
    H. van de Waterbeemd and B. Testa. In B. Testa (Ed.), Advances in Drug Research, Academic Press, London, 1987, Vol. 16, pp. 87–227.Google Scholar
  13. 13.
    N. El Tayar, B. Testa, and P. A. Carrupt. J. Phys. Chem. 96:1455–1459 (1992).Google Scholar
  14. 14.
    P. Vallat, P. Gaillard, P. A. Carrupt, R. S. Tsai, and B. Testa. Helv. Chim. Acta. 78:471–485 (1995).Google Scholar
  15. 15.
    F. Brée, P. Nguyen, S. Urien, P. Riant, E. Albengres, H. Fenner, and J. P. Tillement. Fundam. Clin. Pharm. 3:267–279 (1989).Google Scholar
  16. 16.
    F. Brée, P. Nguyen, E. Albengres, S. Urien, P. Riant, P. G. Welling, and J. P. Tillement. Biochem. Pharmacol. 38:753–758 (1989).PubMedGoogle Scholar
  17. 17.
    F. Brée, S. Urien, P. Nguyen, P. Riant, E. Albengres, and J. P. Tillement. Eur J. Drug Metab. Pharmacokin. 15:303–307 (1990).Google Scholar
  18. 18.
    P. Nguyen. Thèse de l'Université Paris XII (1994).Google Scholar
  19. 19.
    M. P. Dehouck, P. Jolliet-Riant, F. Brée, J. C. Fruchart, R. Cecchelli, and J. P. Tillement. J. Neurochem. 58:1790–1797 (1992).PubMedGoogle Scholar
  20. 20.
    W. M. Pardridge, D. Triguero, J. Yang, and P. A. Cancilla. J. Pharmacol. Exp. Ther. 253:884–891 (1990).PubMedGoogle Scholar
  21. 21.
    W. H. Oldendorf, S. Hyman, L. Braun, and S. Z. Oldendorf. Science 178:984–988 (1972).PubMedGoogle Scholar
  22. 22.
    E. Albengres, S. Urien, J. Barré, P. Nguyen, F. Brée, P. Jolliet, J. P. Tillement, R. S. Tsai, P. A. Carrupt, and B. Testa. Int. J. Tiss. Reac. 15:125–134 (1993).Google Scholar
  23. 23.
    J. P. Tillement, S. Urien, P. Chaumet-Riffaud, P. Riant, F. Brée, D. Morin, E. Albengres, and J. Barré. Fundam. Clin. Pharmacol. 2:223–228 (1988).PubMedGoogle Scholar
  24. 24.
    R. Belaiba, P. Riant, S. Urien, F. Brée, E. Albengres, J. Barré, and J. P. Tillement. In P. Baumann, C. B. Eap, W. E. Muller, and J. P. Tillement (Eds.), Alpha-l-Acid Glycoprotein: Genetics, Biochemistry, Physiological Functions, and Pharmacology, Alan R. Liss, New York, 1989, pp. 287–305.Google Scholar
  25. 25.
    P. Riant, F. Brée, S. Urien, C. Hamberger, E. Albengres, and J. P. Tillement. Fundam. Clin. Pharmacol. 4:105–114 (1990).PubMedGoogle Scholar
  26. 26.
    S. Urien, D. Morin, and J. P. Tillement. J. Pharmacol. Exp. Ther. 248:781–785 (1989).PubMedGoogle Scholar
  27. 27.
    S. Oie and Y. H. Yang. J. Pharm. Sci. 77:948–951 (1988).PubMedGoogle Scholar
  28. 28.
    F. E. Curry, J. C. Rutledge, and J. F. Lenz. Am. J. Physiol. 257:H1354–H1359 (1989).PubMedGoogle Scholar
  29. 29.
    B. L. Clarke, J. A. Oka, and P. H. Weige. J. Biol. Chem. 262:17384–17392 (1987).PubMedGoogle Scholar
  30. 30.
    W. M. Pardridge. Steroid hormone transport through blood-brain barrier: methods and concepts. Methods in Neurosciences 22:3–22 (1994).Google Scholar

Copyright information

© Plenum Publishing Corporation 1997

Authors and Affiliations

  • Pascale Jolliet
    • 1
  • Nicolas Simon
    • 1
  • Francoise Brée
    • 1
  • Saïk Urien
    • 1
  • Alessandra Pagliara
    • 2
  • Pierre-Alain Carrupt
    • 2
  • Bernard Testa
    • 2
  • Jean-Paul Tillement
    • 1
  1. 1.Service de Pharmacologie, Faculté de Médecine PARIS XII, F-CréteilFrance
  2. 2.Ecole de PharmacieUniversité de Lausanne, CH-LausanneSwitzerland

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