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Research ArticleMetabolism, Transport, and Pharmacogenomics

Quantitative Evaluation of the Impact of Active Efflux by P-Glycoprotein and Breast Cancer Resistance Protein at the Blood-Brain Barrier on the Predictability of the Unbound Concentrations of Drugs in the Brain Using Cerebrospinal Fluid Concentration as a Surrogate

Hiroshi Kodaira, Hiroyuki Kusuhara, Takuya Fujita, Junko Ushiki, Eiichi Fuse and Yuichi Sugiyama
Journal of Pharmacology and Experimental Therapeutics December 2011, 339 (3) 935-944; DOI: https://doi.org/10.1124/jpet.111.180398
Hiroshi Kodaira
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Hiroyuki Kusuhara
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Takuya Fujita
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Junko Ushiki
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Eiichi Fuse
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Yuichi Sugiyama
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Abstract

This study investigated the impact of the active efflux mediated by P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp) at the blood-brain barrier (BBB) on the predictability of the unbound brain concentration (Cu,brain) by the concentration in the cerebrospinal fluid (CSF) (Cu,CSF) in rats. Cu,brain is obtained as the product of the total brain concentration and unbound fraction in the brain (fu,brain) determined in vitro in brain slices. Twenty-five compounds, including P-gp and/or Bcrp substrates, were given a constant intravenous infusion, and their plasma, brain, and CSF concentrations were determined. P-gp and/or Bcrp substrates, such as verapamil, loperamide, flavopiridol, genistein, quinidine, dantrolene, daidzein, cimetidine, and pefloxacin, showed a higher CSF-to-brain unbound concentration ratio (Kp,uu,CSF/brain) compared with non-P-gp and non-Bcrp substrates. Kp,uu,CSF/brain values of P-gp-specific (quinidine and verapamil) and Bcrp-specific (daidzein and genistein) substrates were significantly decreased in Mdr1a/1b(−/−) and Bcrp(−/−) mice, respectively. Furthermore, consistent with the contribution of P-gp and Bcrp to the net efflux at the BBB, Kp,uu,CSF/brain values of the common substrates (flavopiridol and erlotinib) were markedly decreased in Mdr1a/1b(−/−)/Bcrp(−/−) mice, but only moderately or weakly in Mdr1a/1b(−/−) mice and negligibly in Bcrp(−/−) mice. In conclusion, predictability of Cu,brain by Cu,CSF decreases along with the net transport activities by P-gp and Bcrp at the BBB. Cu,CSF of non-P-gp and non-Bcrp substrates can be a reliable surrogate of Cu,brain for lipophilic compounds.

Footnotes

  • This study was supported in part by the Japan Society for the Promotion of Science [Grant-in-Aid for Scientific Research (A) 20249008 (to Y.S.) and Grant-in-Aid for Scientific Research (B) 23390034 (to H.K.)].

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    doi:10.1124/jpet.111.180398.

  • ↵Embedded Image The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    CNS
    central nervous system
    BBB
    blood-brain barrier
    CSF
    cerebrospinal fluid
    CCSF
    total drug concentration in cerebrospinal fluid
    Cbrain
    total drug concentration in brain
    Cu,CSF
    unbound drug concentration in cerebrospinal fluid
    Cu,brain
    unbound drug concentration in brain
    Kp,brain
    brain-to-plasma drug concentration ratio
    Kp,CSF
    cerebrospinal fluid-to-plasma drug concentration ratio
    Kp,uu,brain
    brain-to-plasma unbound drug concentration ratio
    Kp,uu,CSF
    cerebrospinal fluid-to-plasma unbound drug concentration ratio
    Kp,uu,CSF/brain
    cerebrospinal fluid-to-brain unbound drug concentration ratio
    Mdr
    multidrug resistance protein
    P-gp
    P-glycoprotein
    Bcrp
    breast cancer resistance protein
    MDCK
    Madin-Darby canine kidney
    GFP
    green fluorescent protein
    L-Mdr1a
    LLC-PK1 cells expressing mouse Mdr1a
    LC
    liquid chromatography
    MS/MS
    tandem mass spectrometry
    PBS
    phosphate-buffered saline
    ABC
    ATP-binding cassette.

  • Received February 8, 2011.
  • Accepted September 19, 2011.
  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 339 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 339, Issue 3
1 Dec 2011
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Research ArticleMetabolism, Transport, and Pharmacogenomics

CSF Drug Concentration as a Surrogate of CNS Drug Exposure

Hiroshi Kodaira, Hiroyuki Kusuhara, Takuya Fujita, Junko Ushiki, Eiichi Fuse and Yuichi Sugiyama
Journal of Pharmacology and Experimental Therapeutics December 1, 2011, 339 (3) 935-944; DOI: https://doi.org/10.1124/jpet.111.180398

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Research ArticleMetabolism, Transport, and Pharmacogenomics

CSF Drug Concentration as a Surrogate of CNS Drug Exposure

Hiroshi Kodaira, Hiroyuki Kusuhara, Takuya Fujita, Junko Ushiki, Eiichi Fuse and Yuichi Sugiyama
Journal of Pharmacology and Experimental Therapeutics December 1, 2011, 339 (3) 935-944; DOI: https://doi.org/10.1124/jpet.111.180398
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