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Brain Penetration of SDZ PSC 833 in Rats

A Comparison with Cyclosporin A
  • Sandrine Desrayaud
  • Michel Lemaire
Part of the Advances in Behavioral Biology book series (ABBI, volume 46)

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.

Keywords

Brain Penetration Brain Capillary Endothelial Cell Brain Distribution High Blood Concentration Lower Blood Concentration 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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.

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Copyright information

© Springer Science+Business Media New York 1996

Authors and Affiliations

  • Sandrine Desrayaud
    • 1
  • Michel Lemaire
    • 1
  1. 1.Drug Metabolism and PharmacokineticsSandoz Pharma LdtBasleSwitzerland

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