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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Transport Characteristics of the Anti-human Immunodeficiency Virus Nucleoside Analog, Abacavir, into Brain and Cerebrospinal Fluid

S. A. Thomas, A. Bye and M. B. Segal
Journal of Pharmacology and Experimental Therapeutics September 2001, 298 (3) 947-953;
S. A. Thomas
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A. Bye
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M. B. Segal
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Abstract

The role of the blood-brain and blood-cerebrospinal fluid (CSF) barriers in the distribution of anti-human immunodeficiency virus (HIV) drugs is integral to the design of effective treatment regimens for HIV infection within the brain. Abacavir (formerly 1592U89) is a nucleoside analog reverse transcriptase inhibitor, which has activity against HIV. The ability of this drug to reach the brain at therapeutic concentrations has been explored by means of an established bilateral in situ brain perfusion model in combination with high-performance liquid chromatography analysis in the anesthetized guinea pig. The influence of other drugs on the entry of abacavir into the brain was also investigated and is of special significance with the use of three of more anti-HIV drugs as the recommended treatment for HIV infection. The results of this study indicate that intact [14C]abacavir can cross the blood-brain and blood-CSF barriers and enter the brain and cisternal CSF. Further studies, at a perfusion time of 10 min, revealed that the uptake (Rcerebrum) of this 14C-labeled drug (10.1 ± 0.6%) was not affected by the presence of 0.86 to 200 μM unlabeled abacavir (6.8 μM; 11.0 ± 1.4%), the nucleoside transport inhibitor [10 μM 6-(4-nitrobenzyl)thio-9-β-d-ribofuranosylpurine; 9.7 ± 3.3%], or a substrate for the nucleobase transporter (100 μM adenine; 12.7 ± 3.0%). This would suggest that the entry of abacavir into the brain would not be affected by the presence of other anti-HIV drugs. The results of this animal study indicate that abacavir would be a useful addition to a treatment regimen against HIV-infection within the brain.

Footnotes

  • This work was supported by grants from Glaxo Wellcome Research and Development and The Wellcome Trust. S.A.T. is a Wellcome Research Career Development Fellow.

  • Abbreviations:
    CSF
    cerebrospinal fluid
    BBB
    blood-brain barrier
    HIV
    human immunodeficiency virus
    RTI
    reverse transcriptase inhibitor
    AZT
    azidodeoxythymidine
    CNS
    central nervous system
    NBMPR
    6-(4-nitrobenzyl)thio-9-β-d-ribofuranosylpurine
    HPLC
    high-performance liquid chromatography
    • Received March 26, 2001.
    • Accepted May 14, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 298 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 298, Issue 3
1 Sep 2001
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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Transport Characteristics of the Anti-human Immunodeficiency Virus Nucleoside Analog, Abacavir, into Brain and Cerebrospinal Fluid

S. A. Thomas, A. Bye and M. B. Segal
Journal of Pharmacology and Experimental Therapeutics September 1, 2001, 298 (3) 947-953;

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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Transport Characteristics of the Anti-human Immunodeficiency Virus Nucleoside Analog, Abacavir, into Brain and Cerebrospinal Fluid

S. A. Thomas, A. Bye and M. B. Segal
Journal of Pharmacology and Experimental Therapeutics September 1, 2001, 298 (3) 947-953;
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