Summary
The brain penetration of a novel MDR-reversing cyclosporin, SDZ PSC 833, was studied by measuring brain and blood concentrations after intravenous administration either as a bolus or as a constant-rate infusion. At lower blood concentrations of SDZ PSC 833, the brain penetration defined as the brain-to-blood concentration ratio (Kp), was very low in spite of the high lipophilicity of this compound. At higher blood concentrations, however, the brain penetration of SDZ PSC 833 was markedly increased. Since the blood pharmacokinetic of SDZ PSC 833 was found to be linear in the dosage range studied, these results demonstrated a non-linear brain penetration of SDZ PSC 833. The brain passage of cyclosporin A was also found to obey a non-linear kinetic. However the potency of SDZ PSC 833 to inhibit the efflux mechanism at the blood-brain barrier (BBB) was higher than that of the cyclosporin A since 10 times higher doses of cyclosporin A were required to obtain the same Kp values as SDZ PSC 833. Moreover, the coadministration of SDZ PSC 833 increased the brain penetration of cyclosporin A whereas the latter did not modify that of SDZ PSC 833. The increase in Kp values for SDZ PSC 833 observed at high blood levels of SDZ PSC 833 are consistent with the hypothesis that SDZ PSC 833 governs its own brain passage possibly by inhibition of the P-glycoprotein pump present in the brain microcapillary endothelial cells.
Résumé
Le SDZ PSC 833, un nouvel analogue de la cyclosporine A dépourvu de propriétés immunosuppressives, semble avoir la propriété d’annuler la résistance des cellules tumorales vis-à -vis de nombreux agents anticancereux. La pénétration cérébrale de ce composé a été étudiée en mesurant les concentrations sanguines et cérébrales obtenues soit après un bolus intraveineux, soit au cours d’une perfusion intraveineuse à vitesse constante. Pour de faibles concentrations sanguines de SDZ PSC 833, sa pénétration cérébrale, définie par le rapport des concentrations cérébrales et sanguines Kp, est très faible malgré la forte liposolubilité de ce composé. Par contre, pour des concentrations sanguines élevées, la pénétration cérébrale du SDZ PSC 833 est considérablement augmentée. Etant donné que la pharmacocinétique sanguine du SDZ PSC 833 est linéaire pour la gamme de doses étudiées, ces résultats démontrent que la pénétration cérébrale du SDZ PSC 833 obéit à une pharmacocinétique non linéaire. Cette non-linéarité a également été démontrée pour la cyclosporine A. Cependant, la capacité du SDZ PSC 833 à inhiber le mécanisme d’efflux au niveau de la barrière hémato-encéphalique est plus importante que celle de la cyclosporine A. En effet, des doses de cyclosporine A 10 fois supérieures à celles du PSC sont nécessaires pour obtenir le même Kp. De plus, la coadministration de SDZ PSC 833 entraîne une augmentation de la pénétration cérébrale de la cyclosporine A, alors que l’inverse ne peut être démontré. Cette augmentation des valeurs de Kp pour le SDZ PSC 833 observée pour des concentrations sanguines de SDZ PSC 833 élevées confirme l’hypothèse selon laquelle le SDZ PSC 833 contrôle son propre passage cérébral probablement en inhibant la pompe P-glycoprotéine présente dans les cellules endothéliales des microcapillaires cérébraux.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Boesch, D., Gaveriaux, C., Jachez, B., Pourtier-Manzanedo, A., Bollinger, P., and Loor, F.: In vivo circumvention of P-glycoprotein-mediated multidrug resistance of cells with SDZ PSC 833. Cancer Res. 51: 4226–4233, 1991.
Gaveriaux, C., Boesch, D., Jachez, B., Bollinger, P., Payne, T., and Loor, F.: SDZ PSC 833, a non-immunosuppressive cyclosporin analog, is a very potent multidrug-resistance modifier. J. Cell. Pharmacol. 2: 225–234, 1991.
Boekhorst, P.a.w., Kapel J.v., Schoester, M., and Sonneveld, P.: Reversal of typical multidrug resistance by cyclosporin and its non-immunosuppressive SDZ PSC 833 in Chinese hamster ovary cell exppressing the mdrl phenotype. Cancer Chemother. Pharmacol. 30; 238–142, 1992.
Niederberger, W., Lemaire, M., Maurer, G., Nussbaumer, K., and Wagner, O.: Distribution and binding of cyclosporin in blood and tissues. Transplant. Proc. 15: 2419–2421, 1983.
Cefalu, W.t., and Pardridge, W.m.: Restrictive transport of a lipid soluble peptide (cyclosporin) through the blood-brain barrier. J. Neurochem. 44: 1954–1956. 1985.
Sakata, A., Tamai, I., K.wazu, K., Deguchi, Y., Ohnishi, T., Saheki, A., and Tsuji, A.: In vivo evidence for ATP-dependent and P-glycoprotein mediated transport of cyclosporin A at the blood-brain barrier. Biochem. Pharmacol. 48: 1989–1992, 1994.
Tsuji, A., Tamai, L, Sakata, A., Tenda, Y., and Terasaki, T.: Restricted transport of cyclosporin A across the blood-brain barrier by a multidrug transporter, P-glycoprotein. Biochem. Pharmacol. 46: 1096–1099, 1993.
Shirai, A., Naito, M., Tatsuta, T., Dong, J., Hanaoka, K., Mikami, K., Oh- Hara, T., and Tsuruo, T.: Transport of cyclosporin A across the brain capillary endothelial cell monolayer by P-glycoprotein. Biochem. Biophys. Acta 1222: 400–404, 1994.
Wagner, O., Schreier, E., Heitz, F., and Maurer, G.: Tissue distribution, disposition, and metabolism of cyclosporine in rats. Drug Metab. Dispos. 15: 377–383, 1987.
Lemaire, M., Pardridge, W.m., and Chaudhuri, G.: Influence of blood components on the tissue uptake indices of cyclosporin in rats. J. Pharmacol. Exp. Ther. 244: 740–743, 1988.
Pardridge, W.M.: Peptide lipidization and liposomes. In Peptide drug delivery to the brain, ed. by W.M. Pardridge, pp. 123–148, Raven Press, New-York, 1991.
Tatsuta, T., Naito, M., Oh-bara, T., Sugawara, I., and Tsuruo, T.: Functional involvement of P-glycoprotcin in blood-brain barrier. J. Biol. Chem. 267: 20383–20391, 1992.
Tsuji, A., Terasaki, T., Takabatake, Y., Tenda, Y., Tamai, I., Yamashima, T., Moritani, S., Tsuruo, T., and Yamashita, J.: P-glycoprotein as the drug efflux pump in primary cultured bovine brain cappillary endothelial cells. Life Sci. 51: 1427–1437, 1992.
Thiebaut, F., Tsuruo, T., Hamada, H., Gottesman, M.M., Pastan, I., and Willingham, M.C.: Immunohistochemical localization in normal tissues of different epitopes in the multidrug transport protein P 170: evidence for localization in brain capillaries and crossreactivity of one antibody with a muscle protein. J. Histochem. Cytochem. 37: 159–164, 1989.
Cordon-cardo, L., O’brien, J.P., Casals, D., Rittman-grauer, L., Biedler, J.L., Melamed, M.R., and Bertino, J.r.: Multi-resistance gene (P-glycoprotein) is expressed by endothelial cells at blood-brain barrier sites. Proc. Natl. Acad. Sci. USA 86: 695–698, 1989.
Lemaire, M., and Tillement, J.P.: Role of lipoproteins and erythrocytes in the in vitro binding and distribution of cyclosporin A in the blood. J. Pharm. Pharmacol. 34: 715–718, 1982.
Lemaire, M.: SDZ PSC 833: Distribution and binding to blood components. Document, Sandoz Pharma Ltd., 1992.
Chikhale, E.G., Burton, P.S., and Borchardt, R.T.: The effect of verapamil on the transport of peptides across the blood-brain barrier in rats: kinetic evidence for an apically polarized efflux mechanism, J. Pharmacol. Exp. Ther. 273: 298–303, 1995.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 1996 Springer Science+Business Media New York
About this chapter
Cite this chapter
Desrayaud, S., Lemaire, M. (1996). Brain Penetration of SDZ PSC 833 in Rats. In: Couraud, PO., Scherman, D. (eds) Biology and Physiology of the Blood-Brain Barrier. Advances in Behavioral Biology, vol 46. Springer, Boston, MA. https://doi.org/10.1007/978-1-4757-9489-2_33
Download citation
DOI: https://doi.org/10.1007/978-1-4757-9489-2_33
Publisher Name: Springer, Boston, MA
Print ISBN: 978-1-4757-9491-5
Online ISBN: 978-1-4757-9489-2
eBook Packages: Springer Book Archive