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Molecular Pharmacology

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Research ArticleArticle

Molecular Mechanisms of Organic Anion Transporting Polypeptide–Mediated Organic Anion Clearance at the Blood–Cerebrospinal Fluid Barrier

Austin Sun, Bruno Hagenbuch, Edward J. Kelly and Joanne Wang
Molecular Pharmacology December 2023, 104 (6) 255-265; DOI: https://doi.org/10.1124/molpharm.123.000703
Austin Sun
Department of Pharmaceutics (A.S., E.J.K., J.W.) and Kidney Research Institute (E.J.K.), University of Washington, Seattle, Washington; and Department of Pharmacology, Toxicology, and Therapeutics, The University of Kansas Medical Center, Kansas City, Kansas (B.H.)
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Bruno Hagenbuch
Department of Pharmaceutics (A.S., E.J.K., J.W.) and Kidney Research Institute (E.J.K.), University of Washington, Seattle, Washington; and Department of Pharmacology, Toxicology, and Therapeutics, The University of Kansas Medical Center, Kansas City, Kansas (B.H.)
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Edward J. Kelly
Department of Pharmaceutics (A.S., E.J.K., J.W.) and Kidney Research Institute (E.J.K.), University of Washington, Seattle, Washington; and Department of Pharmacology, Toxicology, and Therapeutics, The University of Kansas Medical Center, Kansas City, Kansas (B.H.)
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Joanne Wang
Department of Pharmaceutics (A.S., E.J.K., J.W.) and Kidney Research Institute (E.J.K.), University of Washington, Seattle, Washington; and Department of Pharmacology, Toxicology, and Therapeutics, The University of Kansas Medical Center, Kansas City, Kansas (B.H.)
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Abstract

The blood-cerebrospinal fluid barrier (BCSFB), formed by the choroid plexus epithelial (CPE) cells, plays an active role in removing drugs and metabolic wastes from the brain. Recent functional studies in isolated mouse choroid plexus (CP) tissues suggested the presence of organic anion transporting polypeptides (OATPs, encoded by SLCOs) at the apical membrane of BCSFB, which may clear large organic anions from the cerebrospinal fluid (CSF). However, the specific OATP isoform involved is unclear. Using quantitative fluorescence imaging, we showed that the fluorescent anions sulforhodamine 101 (SR101), fluorescein methotrexate (FL-MTX), and 8-fluorescein-cAMP (fluo-cAMP) are actively transported from the CSF to the subepithelial space in CP tissues isolated from wild-type mice. In contrast, transepithelial transport of these compounds across the CPE cells was abolished in Oatp1a/1b−/− mice due to impaired apical uptake. Using transporter-expressing cell lines, SR101, FL-MTX, and fluo-cAMP were additionally shown to be transported by mouse OATP1A5 and its human counterpart OATP1A2. Kinetic analysis showed that estrone-3-sulfate and SR101 are transported by OATP1A2 and OATP1A5 with similar Michaelis-Menten constants (Km). Immunofluorescence staining further revealed the presence of OATP1A2 protein in human CP tissues. Together, our results suggest that large organic anions in the CSF are actively transported into CPE cells by apical OATP1A2 (OATP1A5 in mice), then subsequently effluxed into the blood by basolateral multidrug resistance-associated proteins (MRPs). As OATP1A2 transports a wide array of endogenous compounds and xenobiotics, the presence of this transporter at the BCSFB may imply a novel clearance route for drugs and neurohormones from the CSF.

SIGNIFICANCE STATEMENT Drug transporters at the blood–cerebrospinal fluid (CSF) barrier play an important but understudied role in brain drug disposition. This study revealed a functional contribution of rodent organic anion transporting polypeptide (OATP) 1A5 towards the CSF clearance of organic anions and suggested a similar role for OATP1A2 in humans. Delineating the molecular mechanisms governing CSF organic anion clearance may help to improve the prediction of central nervous system (CNS) pharmacokinetics and identify drug candidates with favorable CNS pharmacokinetic properties.

Footnotes

    • Received March 23, 2023.
    • Accepted August 14, 2023.
  • This work was supported in part by National Institutes of Health National Institute on Aging [Grant R21AG071827] (to J.W.) and National Center for Advancing Translational Sciences [Grant TL1TR002319] (to A.S.).

  • No author has an actual or perceived conflict of interest with the contents of this article.

  • dx.doi.org/10.1124/molpharm.123.000703.

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

  • Copyright © 2023 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 104 (6)
Molecular Pharmacology
Vol. 104, Issue 6
1 Dec 2023
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Research ArticleArticle

Role of OATP in Transcellular Transport across the BCSFB

Austin Sun, Bruno Hagenbuch, Edward J. Kelly and Joanne Wang
Molecular Pharmacology December 1, 2023, 104 (6) 255-265; DOI: https://doi.org/10.1124/molpharm.123.000703

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Research ArticleArticle

Role of OATP in Transcellular Transport across the BCSFB

Austin Sun, Bruno Hagenbuch, Edward J. Kelly and Joanne Wang
Molecular Pharmacology December 1, 2023, 104 (6) 255-265; DOI: https://doi.org/10.1124/molpharm.123.000703
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