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Research ArticleArticle

Quantitative Brain Microdialysis Study on the Mechanism of Quinolones Distribution in the Central Nervous System

Tsuyoshi Ooie, Tetsuya Terasaki, Hiroshi Suzuki and Yuichi Sugiyama
Drug Metabolism and Disposition July 1997, 25 (7) 784-0789;
Tsuyoshi Ooie
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Tetsuya Terasaki
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Hiroshi Suzuki
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Yuichi Sugiyama
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Abstract

Brain interstitial fluid (ISF) concentrations, which regulate the toxicodynamic effect of quinolone antimicrobial agents (quinolones) in the central nervous system, have been determined for norfloxacin, ofloxacin, fleroxacin, and pefloxacin using a quantitative brain microdialysis technique. Steady-state brain ISF concentrations of the quinolones were 7–30 times lower than the unbound serum concentrations due to restricted distribution in the brain. Cerebrospinal fluid concentrations of the quinolones were approximately twice as high as the brain ISF concentrations, except for norfloxacin. Thus, it seems that an active efflux transport system across the blood-brain barrier is responsible for maintaining brain ISF concentrations lower than unbound serum concentrations at steady-state. A good correlation was observed for norfloxacin, ofloxacin, fleroxacin, and pefloxacin between brain ISF concentrations and total brain concentrations. Moreover, a relatively small difference was observed among the quinolones for thein vitro brain slice-to-medium concentration ratio, compared with an 11-fold difference in the in vivobrain-to-unbound serum concentration ratio after intravenous infusion. These results indicate that the different quinolones studied all exhibit similar apparent binding and/or uptake by brain parenchyma, with an average brain ISF-to-total brain concentration ratio of 0.688.

Footnotes

  • Send reprint requests to: Dr. Yuichi Sugiyama, Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113, Japan.

  • ↵1 Present address: Central Research Laboratories, Kyorin Pharmaceutical Co., Ltd., Nogi-machi, Shimotsuga-gun, Tochigi 329-01, Japan.

  • ↵2 Present address: Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Tohoku University, Aoba-ku, Sendai 980-77, Japan.

  • This research was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, and Culture, Japan and the Research Fund from the Human Science Foundation.

  • Abbreviations used are::
    CNS
    central nervous system
    GABA
    γ-aminobutyric acid
    ISF
    interstitial fluid
    CSF
    cerebrospinal fluid
    BBB
    blood-brain barrier
    NFLX
    norfloxacin
    FLRX
    fleroxacin
    OFLX
    ofloxacin
    SPFX
    sparfloxacin
    PFLX
    pefloxacin
    AM-1155
    (±)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(3-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid
    RHB
    Ringer’s HEPES buffer
    • Received August 22, 1996.
    • Accepted March 12, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition
Vol. 25, Issue 7
1 Jul 1997
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Research ArticleArticle

Quantitative Brain Microdialysis Study on the Mechanism of Quinolones Distribution in the Central Nervous System

Tsuyoshi Ooie, Tetsuya Terasaki, Hiroshi Suzuki and Yuichi Sugiyama
Drug Metabolism and Disposition July 1, 1997, 25 (7) 784-0789;

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Research ArticleArticle

Quantitative Brain Microdialysis Study on the Mechanism of Quinolones Distribution in the Central Nervous System

Tsuyoshi Ooie, Tetsuya Terasaki, Hiroshi Suzuki and Yuichi Sugiyama
Drug Metabolism and Disposition July 1, 1997, 25 (7) 784-0789;
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