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Rapid CommunicationAccelerated Communication

Drug Transporters on Arachnoid Barrier Cells Contribute to the Blood–Cerebrospinal Fluid Barrier

Kazuto Yasuda, Cynthia Cline, Peter Vogel, Mihaela Onciu, Soghra Fatima, Brian P. Sorrentino, Ranjit K. Thirumaran, Sean Ekins, Yoshihiro Urade, Ko Fujimori and Erin G. Schuetz
Drug Metabolism and Disposition April 2013, 41 (4) 923-931; DOI: https://doi.org/10.1124/dmd.112.050344
Kazuto Yasuda
Department of Pharmaceutical Sciences (K.Y., C.C., R.K.T., E.G.S.), Department of Pathology (P.V., M.O.), and Department of Hematology (S.F., B.P.S.), St. Jude Children’s Research Hospital, Memphis, Tennessee; Collaborations in Chemistry, Fuquay-Varina, North Carolina (S.E.); Department of Molecular Behavioral Biology, Osaka Bioscience Institute, Osaka, Japan (Y.U.); and Laboratory of Biodefense and Regulation, Osaka University of Pharmaceutical Sciences, Osaka, Japan (K.F.)
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Cynthia Cline
Department of Pharmaceutical Sciences (K.Y., C.C., R.K.T., E.G.S.), Department of Pathology (P.V., M.O.), and Department of Hematology (S.F., B.P.S.), St. Jude Children’s Research Hospital, Memphis, Tennessee; Collaborations in Chemistry, Fuquay-Varina, North Carolina (S.E.); Department of Molecular Behavioral Biology, Osaka Bioscience Institute, Osaka, Japan (Y.U.); and Laboratory of Biodefense and Regulation, Osaka University of Pharmaceutical Sciences, Osaka, Japan (K.F.)
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Peter Vogel
Department of Pharmaceutical Sciences (K.Y., C.C., R.K.T., E.G.S.), Department of Pathology (P.V., M.O.), and Department of Hematology (S.F., B.P.S.), St. Jude Children’s Research Hospital, Memphis, Tennessee; Collaborations in Chemistry, Fuquay-Varina, North Carolina (S.E.); Department of Molecular Behavioral Biology, Osaka Bioscience Institute, Osaka, Japan (Y.U.); and Laboratory of Biodefense and Regulation, Osaka University of Pharmaceutical Sciences, Osaka, Japan (K.F.)
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Mihaela Onciu
Department of Pharmaceutical Sciences (K.Y., C.C., R.K.T., E.G.S.), Department of Pathology (P.V., M.O.), and Department of Hematology (S.F., B.P.S.), St. Jude Children’s Research Hospital, Memphis, Tennessee; Collaborations in Chemistry, Fuquay-Varina, North Carolina (S.E.); Department of Molecular Behavioral Biology, Osaka Bioscience Institute, Osaka, Japan (Y.U.); and Laboratory of Biodefense and Regulation, Osaka University of Pharmaceutical Sciences, Osaka, Japan (K.F.)
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Soghra Fatima
Department of Pharmaceutical Sciences (K.Y., C.C., R.K.T., E.G.S.), Department of Pathology (P.V., M.O.), and Department of Hematology (S.F., B.P.S.), St. Jude Children’s Research Hospital, Memphis, Tennessee; Collaborations in Chemistry, Fuquay-Varina, North Carolina (S.E.); Department of Molecular Behavioral Biology, Osaka Bioscience Institute, Osaka, Japan (Y.U.); and Laboratory of Biodefense and Regulation, Osaka University of Pharmaceutical Sciences, Osaka, Japan (K.F.)
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Brian P. Sorrentino
Department of Pharmaceutical Sciences (K.Y., C.C., R.K.T., E.G.S.), Department of Pathology (P.V., M.O.), and Department of Hematology (S.F., B.P.S.), St. Jude Children’s Research Hospital, Memphis, Tennessee; Collaborations in Chemistry, Fuquay-Varina, North Carolina (S.E.); Department of Molecular Behavioral Biology, Osaka Bioscience Institute, Osaka, Japan (Y.U.); and Laboratory of Biodefense and Regulation, Osaka University of Pharmaceutical Sciences, Osaka, Japan (K.F.)
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Ranjit K. Thirumaran
Department of Pharmaceutical Sciences (K.Y., C.C., R.K.T., E.G.S.), Department of Pathology (P.V., M.O.), and Department of Hematology (S.F., B.P.S.), St. Jude Children’s Research Hospital, Memphis, Tennessee; Collaborations in Chemistry, Fuquay-Varina, North Carolina (S.E.); Department of Molecular Behavioral Biology, Osaka Bioscience Institute, Osaka, Japan (Y.U.); and Laboratory of Biodefense and Regulation, Osaka University of Pharmaceutical Sciences, Osaka, Japan (K.F.)
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Sean Ekins
Department of Pharmaceutical Sciences (K.Y., C.C., R.K.T., E.G.S.), Department of Pathology (P.V., M.O.), and Department of Hematology (S.F., B.P.S.), St. Jude Children’s Research Hospital, Memphis, Tennessee; Collaborations in Chemistry, Fuquay-Varina, North Carolina (S.E.); Department of Molecular Behavioral Biology, Osaka Bioscience Institute, Osaka, Japan (Y.U.); and Laboratory of Biodefense and Regulation, Osaka University of Pharmaceutical Sciences, Osaka, Japan (K.F.)
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Yoshihiro Urade
Department of Pharmaceutical Sciences (K.Y., C.C., R.K.T., E.G.S.), Department of Pathology (P.V., M.O.), and Department of Hematology (S.F., B.P.S.), St. Jude Children’s Research Hospital, Memphis, Tennessee; Collaborations in Chemistry, Fuquay-Varina, North Carolina (S.E.); Department of Molecular Behavioral Biology, Osaka Bioscience Institute, Osaka, Japan (Y.U.); and Laboratory of Biodefense and Regulation, Osaka University of Pharmaceutical Sciences, Osaka, Japan (K.F.)
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Ko Fujimori
Department of Pharmaceutical Sciences (K.Y., C.C., R.K.T., E.G.S.), Department of Pathology (P.V., M.O.), and Department of Hematology (S.F., B.P.S.), St. Jude Children’s Research Hospital, Memphis, Tennessee; Collaborations in Chemistry, Fuquay-Varina, North Carolina (S.E.); Department of Molecular Behavioral Biology, Osaka Bioscience Institute, Osaka, Japan (Y.U.); and Laboratory of Biodefense and Regulation, Osaka University of Pharmaceutical Sciences, Osaka, Japan (K.F.)
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Erin G. Schuetz
Department of Pharmaceutical Sciences (K.Y., C.C., R.K.T., E.G.S.), Department of Pathology (P.V., M.O.), and Department of Hematology (S.F., B.P.S.), St. Jude Children’s Research Hospital, Memphis, Tennessee; Collaborations in Chemistry, Fuquay-Varina, North Carolina (S.E.); Department of Molecular Behavioral Biology, Osaka Bioscience Institute, Osaka, Japan (Y.U.); and Laboratory of Biodefense and Regulation, Osaka University of Pharmaceutical Sciences, Osaka, Japan (K.F.)
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Abstract

The subarachnoid space, where cerebrospinal fluid (CSF) flows over the brain and spinal cord, is lined on one side by arachnoid barrier (AB) cells that form part of the blood-CSF barrier. However, despite the fact that drugs are administered into the CSF and CSF drug concentrations are used as a surrogate for brain drug concentration following systemic drug administration, the tight-junctioned AB cells have never been examined for whether they express drug transporters that would influence CSF and central nervous system drug disposition. Hence, we characterized drug transporter expression and function in AB cells. Immunohistochemical analysis showed P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) in mouse AB cells but not other meningeal tissue. The Gene Expression Nervous System Atlas (GENSAT) database and the Allen Mouse Brain Atlas confirmed these observations. Microarray analysis of mouse and human arachnoidal tissue revealed expression of many drug transporters and some drug-metabolizing enzymes. Immortalized mouse AB cells express functional P-gp on the apical (dura-facing) membrane and BCRP on both apical and basal (CSF-facing) membranes. Thus, like blood-brain barrier cells and choroid plexus cells, AB cells highly express drug transport proteins and likely contribute to the blood-CSF drug permeation barrier.

Footnotes

  • The work was supported by a National Institutes of Health Cancer Center Support Grant [Grant P30 CA21765]; by Cancer Center Developmental Funds; and by the American Lebanese Syrian Associated Charities.

  • dx.doi.org/10.1124/dmd.112.050344.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Received November 26, 2012.
  • Accepted January 8, 2013.
  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 41 (4)
Drug Metabolism and Disposition
Vol. 41, Issue 4
1 Apr 2013
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Rapid CommunicationAccelerated Communication

Drug Transporters on Arachnoid Barrier Cells

Kazuto Yasuda, Cynthia Cline, Peter Vogel, Mihaela Onciu, Soghra Fatima, Brian P. Sorrentino, Ranjit K. Thirumaran, Sean Ekins, Yoshihiro Urade, Ko Fujimori and Erin G. Schuetz
Drug Metabolism and Disposition April 1, 2013, 41 (4) 923-931; DOI: https://doi.org/10.1124/dmd.112.050344

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Rapid CommunicationAccelerated Communication

Drug Transporters on Arachnoid Barrier Cells

Kazuto Yasuda, Cynthia Cline, Peter Vogel, Mihaela Onciu, Soghra Fatima, Brian P. Sorrentino, Ranjit K. Thirumaran, Sean Ekins, Yoshihiro Urade, Ko Fujimori and Erin G. Schuetz
Drug Metabolism and Disposition April 1, 2013, 41 (4) 923-931; DOI: https://doi.org/10.1124/dmd.112.050344
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