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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

AIT-082, a Cognitive Enhancer, Is Transported into Brain by a Nonsaturable Influx Mechanism and out of Brain by a Saturable Efflux Mechanism

Eve M. Taylor, Rongzi Yan, Nils Hauptmann, Timothy J. Maher, Daniela Djahandideh and Alvin J. Glasky
Journal of Pharmacology and Experimental Therapeutics June 2000, 293 (3) 813-821;
Eve M. Taylor
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Rongzi Yan
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Nils Hauptmann
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Timothy J. Maher
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Daniela Djahandideh
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Alvin J. Glasky
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Abstract

A fundamental feature of any drug designed to treat a disease of the central nervous system is the ability to cross the blood-brain barrier. Passage across the blood-brain barrier of AIT-082, a cognitive enhancer, was investigated in mice. [14C]AIT-082 crossed the blood-brain barrier in young male Swiss-Webster mice with a mean influx constant (Ki) of 0.6 ± 0.2 μl g−1 min−1. Furthermore, [14C]AIT-082 was transported into brain of both young and old male C57BL/6 mice with a Ki of 0.35 ± 0.06 and 0.33 ± 0.02 μl g−1 min−1, respectively. There was no significant effect of age or strain on the movement of [14C]AIT-082 across the blood-brain barrier in mice. When 110- or 650-fold excess unlabeled AIT-082 was included in the injection solution, the Ki was not significantly changed in either Swiss-Webster or C57BL/6 mice. This indicated that [14C]AIT-082 crossed the blood-brain barrier by a nonsaturable mechanism. The passage of AIT-082 into brain extracellular fluid was confirmed with capillary depletion and microdialysis. The efflux of [14C]AIT-082 from brain also was examined. After i.c.v. injection, [14C]AIT-082 levels in brain decreased over time with a t1/2 of 20.0 ± 1.0 min. Excess unlabeled AIT-082 (600-fold) increased thet1/2 to 35.5 ± 3.6 min. Together, these data indicate that AIT-082 moves into brain via a nonsaturable mechanism and is actively transported out of brain.

Footnotes

  • Send reprint requests to: Eve M. Taylor, Ph.D., NeoTherapeutics Inc., 157 Technology Dr., Irvine, CA 92618. E-mail:etaylor{at}neotherapeutics.com

  • ↵1 This study was supported by NeoTherapeutics Inc., Irvine, CA.

  • ↵2 Current address: Massachusetts College of Pharmacy and Health Sciences, Boston, MA 02115.

  • Abbreviations:
    NMDA
    N-methyl-d-aspartate
    LC-MS-MS
    liquid chromatography-tandem mass spectrometry
    • Received January 13, 2000.
    • Accepted February 29, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 293 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 293, Issue 3
1 Jun 2000
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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

AIT-082, a Cognitive Enhancer, Is Transported into Brain by a Nonsaturable Influx Mechanism and out of Brain by a Saturable Efflux Mechanism

Eve M. Taylor, Rongzi Yan, Nils Hauptmann, Timothy J. Maher, Daniela Djahandideh and Alvin J. Glasky
Journal of Pharmacology and Experimental Therapeutics June 1, 2000, 293 (3) 813-821;

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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

AIT-082, a Cognitive Enhancer, Is Transported into Brain by a Nonsaturable Influx Mechanism and out of Brain by a Saturable Efflux Mechanism

Eve M. Taylor, Rongzi Yan, Nils Hauptmann, Timothy J. Maher, Daniela Djahandideh and Alvin J. Glasky
Journal of Pharmacology and Experimental Therapeutics June 1, 2000, 293 (3) 813-821;
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