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Research ArticleMetabolism, Transport, and Pharmacogenetics

Transport Properties of Statins by Organic Anion Transporting Polypeptide 1A2 and Regulation by Transforming Growth Factor-β Signaling in Human Endothelial Cells

Patrick T. Ronaldson, Hrvoje Brzica, Wazir Abdullahi, Bianca G. Reilly and Thomas P. Davis
Journal of Pharmacology and Experimental Therapeutics February 2021, 376 (2) 148-160; DOI: https://doi.org/10.1124/jpet.120.000267
Patrick T. Ronaldson
Department of Pharmacology, College of Medicine, University of Arizona, Tucson, Arizona
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Hrvoje Brzica
Department of Pharmacology, College of Medicine, University of Arizona, Tucson, Arizona
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Wazir Abdullahi
Department of Pharmacology, College of Medicine, University of Arizona, Tucson, Arizona
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Bianca G. Reilly
Department of Pharmacology, College of Medicine, University of Arizona, Tucson, Arizona
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Thomas P. Davis
Department of Pharmacology, College of Medicine, University of Arizona, Tucson, Arizona
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Abstract

Our in vivo rodent studies have shown that organic anion transporting polypeptide (Oatp) 1a4 is critical for blood-to-brain transport of statins, drugs that are effective neuroprotectants. Additionally, transforming growth factor-β (TGF-β) signaling via the activin receptor-like kinase 1 (ALK1) receptor regulates Oatp1a4 functional expression. The human ortholog of Oatp1a4 is OATP1A2. Therefore, the translational significance of our work requires demonstration that OATP1A2 can transport statins and is regulated by TGF-β/ALK1 signaling. Cellular uptake and monolayer permeability of atorvastatin, pravastatin, and rosuvastatin were investigated in vitro using human umbilical vein endothelial cells (HUVECs). Regulation of OATP1A2 by the TGF-β/ALK1 pathway was evaluated using bone morphogenetic protein 9 (BMP-9), a selective ALK1 agonist, and LDN193189, an ALK1 antagonist. We showed that statin accumulation in HUVECs requires OATP1A2-mediated uptake but is also affected by efflux transporters (i.e., P-glycoprotein, breast cancer resistance protein). Absorptive flux (i.e., apical-to-basolateral) for all statins was higher than secretory flux (i.e., basolateral-to-apical) and was decreased by an OATP inhibitor (i.e., estrone-3-sulfate). OATP1A2 protein expression, statin uptake, and cellular monolayer permeability were increased by BMP-9 treatment. This effect was attenuated in the presence of LDN193189. Apical-to-basolateral statin transport across human endothelial cellular monolayers requires functional expression of OATP1A2, which can be controlled by therapeutically targeting TGF-β/ALK1 signaling. Taken together with our previous work, the present data show that OATP-mediated drug transport is a critical mechanism in facilitating neuroprotective drug disposition across endothelial barriers of the blood-brain barrier.

SIGNIFICANCE STATEMENT Transporter data derived from rodent models requires validation in human models. Using human umbilical vein endothelial cells, this study has shown that statin transport is mediated by OATP1A2. Additionally, we demonstrated that OATP1A2 is regulated by transforming growth factor-β/activin receptor-like kinase 1 signaling. This work emphasizes the need to consider endothelial transporter kinetics and regulation during preclinical drug development. Furthermore, our forward-thinking approach can identify effective therapeutics for diseases for which drug development has been challenging (i.e., neurological diseases).

Footnotes

    • Received August 3, 2020.
    • Accepted November 3, 2020.
  • This work is funded by grants from the National Institutes of Health National Institute of Neurologic Diseases and Stroke [R01-NS084941] (to P.T.R.) and the American Heart Association (19TPA34910113) to P.T.R. as well as by a grant from the National Institute on Drug Abuse [R01-DA051812] (to T.P.D. and P.T.R.)

  • The authors have no conflicts of interest to declare.

  • https://doi.org/10.1124/jpet.120.000267.

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

  • Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 376 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 376, Issue 2
1 Feb 2021
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Research ArticleMetabolism, Transport, and Pharmacogenetics

OATP1A2 Transport of Statins in Human Endothelial Cells

Patrick T. Ronaldson, Hrvoje Brzica, Wazir Abdullahi, Bianca G. Reilly and Thomas P. Davis
Journal of Pharmacology and Experimental Therapeutics February 1, 2021, 376 (2) 148-160; DOI: https://doi.org/10.1124/jpet.120.000267

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Research ArticleMetabolism, Transport, and Pharmacogenetics

OATP1A2 Transport of Statins in Human Endothelial Cells

Patrick T. Ronaldson, Hrvoje Brzica, Wazir Abdullahi, Bianca G. Reilly and Thomas P. Davis
Journal of Pharmacology and Experimental Therapeutics February 1, 2021, 376 (2) 148-160; DOI: https://doi.org/10.1124/jpet.120.000267
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