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OtherNEUROPHARMACOLOGY

The Passage of Azidodeoxythymidine into and within the Central Nervous System: Does It Follow the Parent Compound, Thymidine?

Sarah A. Thomas and Malcolm B. Segal
Journal of Pharmacology and Experimental Therapeutics June 1997, 281 (3) 1211-1218;
Sarah A. Thomas
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Abstract

The transport of azidodeoxythymidine (AZT) into and within the central nervous system (CNS) has special clinical significance due to the ability of AZT to alleviate certain neurological symptoms associated with the acquired immunodeficiency syndrome (AIDS). AZT was thought to be similar to its parent compound, thymidine, in that it entered the CNS via the choroid plexuses (blood-CSF barrier) and could not cross the blood-brain barrier (BBB). However, a saturable transport system for thymidine at the BBB has recently been identified. The aim of this study was to test the hypothesis that AZT follows its physiological counterpart in its mode of entry into and movement within the CNS. Initial experiments using the in situ brain perfusion technique indicated that the blood-to-CNS transfer constants for [3H]AZT (blood-to-cerebrum; 0.95 ± 0.12 μl/min/g) were significantly lower than those determined for [3H]thymidine. Also, [3H]AZT entered the CNS purely by a diffusive process. The movement of [3H]AZT within the CNS was further investigated by a ventriculocisternal perfusion technique and indicated that the majority of intraventricularly perfused [3H]AZT remained within the ventricles (79.9%), with little escaping to blood (14.1 ± 3.1%) or brain (6.0 ± 1.3%). Overall, these results suggest that the choroid plexus/CSF pathway was unlikely to be solely responsible for the levels of [3H]AZT observed in brain and that the BBB plays a significant role in the brain entry of this analog. However, in contrast to thymidine, AZT enters the CNS purely by a diffusional process.

Footnotes

  • Send reprint requests to: Dr. Sarah A. Thomas, Sherrington School of Physiology, UMDS St. Thomas Hospital Campus, Lambeth Palace Rd., London SE1 7EH, UK. E-mail: sarah.thomas{at}umds.ac.uk

  • ↵1 We are grateful for the support of The Wellcome Foundation Ltd. and the Special Trustees of St. Thomas Hospital.

  • Abbreviations:
    AIDS
    acquired immunodeficiency syndrome
    HIV
    human immunodeficiency virus
    AZT
    azidodeoxythymidine
    BBB
    blood-brain barrier
    BUI
    brain uptake index
    CSF
    cerebrospinal fluid
    CNS
    central nervous system
    NBMPR
    6-(4-nitrobenzyl)-thio-9-β-d-ribofuranosylpurine
    RBR
    brain uptake
    RCP
    choroid plexus uptake
    RCSF
    steady-state ratio
    • Received October 7, 1996.
    • Accepted February 18, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 281, Issue 3
1 Jun 1997
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OtherNEUROPHARMACOLOGY

The Passage of Azidodeoxythymidine into and within the Central Nervous System: Does It Follow the Parent Compound, Thymidine?

Sarah A. Thomas and Malcolm B. Segal
Journal of Pharmacology and Experimental Therapeutics June 1, 1997, 281 (3) 1211-1218;

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OtherNEUROPHARMACOLOGY

The Passage of Azidodeoxythymidine into and within the Central Nervous System: Does It Follow the Parent Compound, Thymidine?

Sarah A. Thomas and Malcolm B. Segal
Journal of Pharmacology and Experimental Therapeutics June 1, 1997, 281 (3) 1211-1218;
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