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Kinetics of Entry and Distribution of 5-Fluorouracil in Cerebrospinal Fluid and Brain following Intravenous Injection in a Primate

Robert S. Bourke, Charles R. West, Girish Chheda and Donald B. Tower
Robert S. Bourke
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Charles R. West
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Girish Chheda
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Donald B. Tower
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DOI:  Published July 1973
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Summary

The distribution of systemically or locally administered 5-fluorouracil-2-14C (5-FU) in brain and cerebrospinal fluid (CSF) of the monkey (Macaca mulatta) has been investigated. Following controlled i.v. injection, there was rapid penetration of the 5-FU into brain and CSF, concomitant with a rapid loss of 5-FU from the systemic plasma compartment. CSF repeatedly sampled from various sites (lumbar, cisternal, intraventricular, and cortical surface) displayed characteristic and different kinetic profiles (drug concentrations versus time) following initial i.v. injection of 5-FU. Despite the fact that 91% of the injected dose of 5-FU was cleared from the vascular compartment within 5 min after the start of the i.v. injection (5 ml at 1.086 ml/min) and 98% of the injected dose was cleared by 1 hr, approximately 0.126% of the total administered dose represented the average integrated content of the drug in the entire CSF compartment over the experimental hr. Similarly, the average integrated content of the drug in the brain over the experimental hr represented 0.172% of the total administered dose of 5-FU, as determined by sampling cerebral and cerebellar cortex, subcortical cerebral and cerebellar white matter, striatum, pons, and medulla oblongata.

Labeled 5-FU gained access to the CSF from the plasma by simple diffusion. The average integrated concentration of 5-FU in CSF over the experimental hr was increased by 48% when the rate of i.v. injection was increased fourfold. As demonstrated by bilateral perfusion over the exposed cerebral cortex or by bilateral ventriculocisternal perfusion, 5-FU in the CSF was an adequate source for delivery of the drug to contiguous brain tissue. Studies of the regional brain contents of 5-FU following combined i.v. and ventriculocisternal administration of the drug are presented, together with investigations of the physicochemical and metabolic characteristics of the drug. Our studies provide in the primate a model for the determination of the kinetics of distribution of antineoplastic agents in brain and CSF following i.v. administration or following perfusion into the CSF pathway.

Footnotes

  • ↵1 Supported by Contract NIH, NINDS-72-2328.

  • ↵2 To whom requests for reprints should be sent.

  • Received January 5, 1973.
  • Accepted March 28, 1973.
  • ©1973 American Association for Cancer Research.
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July 1973
Volume 33, Issue 7
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Kinetics of Entry and Distribution of 5-Fluorouracil in Cerebrospinal Fluid and Brain following Intravenous Injection in a Primate
Robert S. Bourke, Charles R. West, Girish Chheda and Donald B. Tower
Cancer Res July 1 1973 (33) (7) 1735-1746;

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Kinetics of Entry and Distribution of 5-Fluorouracil in Cerebrospinal Fluid and Brain following Intravenous Injection in a Primate
Robert S. Bourke, Charles R. West, Girish Chheda and Donald B. Tower
Cancer Res July 1 1973 (33) (7) 1735-1746;
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Cancer Research Online ISSN: 1538-7445
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