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Research ArticleArticle

Novel, Highly Lipophilic Antioxidants Readily Diffuse Across the Blood-Brain Barrier and Access Intracellular Sites

Geri A. Sawada, Lawrence R. Williams, Barry S. Lutzke and Thomas J. Raub
Journal of Pharmacology and Experimental Therapeutics March 1999, 288 (3) 1327-1333;
Geri A. Sawada
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Lawrence R. Williams
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Barry S. Lutzke
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Thomas J. Raub
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Abstract

In an accompanying article, an in vitro assay for permeability predicts that membrane-protective, antioxidant 2,4-diamino-pyrrolo[2,3-d]pyrimidines should have improved blood-brain barrier (BBB) permeation over previously described lipophilic antioxidants. Using a first-pass extraction method and brain/plasma quantification, we show here that two of the pyrrolopyrimidines, one of which is markedly less permeable, readily partition into rat brain. The efficiency of extraction was dependent on serum protein binding, and in situ efflux confirms the in vitro data showing that PNU-87663 is retained in brain longer than PNU-89843. By exploiting inherent fluorescence properties of PNU-87663, its distribution within brain and within cells in culture was demonstrated using confocal scanning laser microscopy. PNU-87663 rapidly partitioned into the cell membrane and equilibrates with cytoplasmic compartments via passive diffusion. Although partitioning of PNU-87663 favors intracytoplasmic lipid storage droplets, the compound was readily exchangeable as shown by efflux of compound from cells to buffer when protein was present. The results demonstrated that pyrrolopyrimidines were well suited for quickly accessing target cells within the central nervous system as well as in other target tissues.

Footnotes

  • Send reprint requests to: Thomas J. Raub, Ph.D., Drug Absorption & Transport, Mailstop 7271-209-623, Pharmacia & Upjohn, Inc., 301 Henrietta Street, Kalamazoo, MI 49007. E-mail:thomas.j.raub{at}am.pnu.com

  • ↵1 Present address: Guilford Pharm., Inc., Baltimore, MD.

  • Abbreviations:
    BUI
    brain uptake index
    CSLM
    confocal scanning laser microscopy
    SLM
    scanning laser microscopy
    • Received May 6, 1998.
    • Accepted September 8, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 288 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 288, Issue 3
1 Mar 1999
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Research ArticleArticle

Novel, Highly Lipophilic Antioxidants Readily Diffuse Across the Blood-Brain Barrier and Access Intracellular Sites

Geri A. Sawada, Lawrence R. Williams, Barry S. Lutzke and Thomas J. Raub
Journal of Pharmacology and Experimental Therapeutics March 1, 1999, 288 (3) 1327-1333;

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Research ArticleArticle

Novel, Highly Lipophilic Antioxidants Readily Diffuse Across the Blood-Brain Barrier and Access Intracellular Sites

Geri A. Sawada, Lawrence R. Williams, Barry S. Lutzke and Thomas J. Raub
Journal of Pharmacology and Experimental Therapeutics March 1, 1999, 288 (3) 1327-1333;
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