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OtherCHEMOTHERAPY/GENE THERAPY

Effect of the Mdr1a P-Glycoprotein Gene Disruption on the Tissue Distribution of SDZ PSC 833, a Multidrug Resistance-Reversing Agent, in Mice

S. Desrayaud, E. C. M. De Lange, M. Lemaire, A. Bruelisauer, A. G. De Boer and D. D. Breimer
Journal of Pharmacology and Experimental Therapeutics May 1998, 285 (2) 438-443;
S. Desrayaud
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E. C. M. De Lange
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M. Lemaire
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A. Bruelisauer
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A. G. De Boer
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D. D. Breimer
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Abstract

The involvement of mdr1a P-glycoprotein (P-gP) on the tissue distribution of the multidrug resistance-reversing agent SDZ PSC 833 was assessed by use of mdr1a (–/–) mice. Themdr1a (–/–) and wild-type mdr1a (+/+) mice received a 4-h constant-rate i.v. infusion (2 μg/min) of [14C]SDZ PSC 833. Mice were sacrificed at 0, 0.5, 1, 2 and 4 h during infusion and at 0.5, 1, 3, 8 and 24 h after stopping the infusion. Blood and tissues were analyzed on total (14C) and parental SDZ PSC 833 concentrations.Mdr1a (–/–) mice exhibited increased SDZ PSC 833 accumulation in cerebrum, cerebellum and somewhat in testes and small intestine compared with the wild-type mice. The difference betweenmdr1a (–/–) and (+/+) brain (cerebrum and cerebellum) penetration depended on SDZ PSC 833 blood concentrations, because this cyclosporin analog apparently governs its own brain penetration by inhibiting the P-glycoprotein pump in mdr1a (+/+) mice. Thus the mdr1a (–/–)/(+/+) ratio of brain concentrations tended to decrease and increase at high and low blood concentrations, respectively. These findings clearly demonstrate the interaction of SDZ PSC 833 with the P-glycoprotein present at the blood-brain barrier. The SDZ PSC 833 distribution in othermdr1a P-glycoprotein-expressed tissues, as well as its metabolism and elimination, was not affected by themdr1a gene disruption. This suggests that factors other than mdr1a P-gP are involved in the disposition of this multidrug resistance-reversing agent.

Footnotes

  • Send reprint requests to: Dr. Michel Lemaire, Drug Metabolism & Pharmacokinetics, CFSS, Novartis Pharma A.G., CH-4002, Basel, Switzerland.

  • Abbreviation:
    BBB
    blood-brain barrier
    P-gP
    P-glycoprotein
    MDR
    multidrug resistance
    GIT
    gastrointestinal tract without the small intestine
    • Received February 10, 1997.
    • Accepted January 20, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 285, Issue 2
1 May 1998
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OtherCHEMOTHERAPY/GENE THERAPY

Effect of the Mdr1a P-Glycoprotein Gene Disruption on the Tissue Distribution of SDZ PSC 833, a Multidrug Resistance-Reversing Agent, in Mice

S. Desrayaud, E. C. M. De Lange, M. Lemaire, A. Bruelisauer, A. G. De Boer and D. D. Breimer
Journal of Pharmacology and Experimental Therapeutics May 1, 1998, 285 (2) 438-443;

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OtherCHEMOTHERAPY/GENE THERAPY

Effect of the Mdr1a P-Glycoprotein Gene Disruption on the Tissue Distribution of SDZ PSC 833, a Multidrug Resistance-Reversing Agent, in Mice

S. Desrayaud, E. C. M. De Lange, M. Lemaire, A. Bruelisauer, A. G. De Boer and D. D. Breimer
Journal of Pharmacology and Experimental Therapeutics May 1, 1998, 285 (2) 438-443;
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