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Molecular Pharmacology

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Research ArticleArticle

Acetaminophen Modulates P-Glycoprotein Functional Expression at the Blood-Brain Barrier by a Constitutive Androstane Receptor–Dependent Mechanism

Lauren M. Slosky, Brandon J. Thompson, Lucy Sanchez-Covarrubias, Yifeng Zhang, Mei-Li Laracuente, Todd W. Vanderah, Patrick T. Ronaldson and Thomas P. Davis
Molecular Pharmacology November 2013, 84 (5) 774-786; DOI: https://doi.org/10.1124/mol.113.086298
Lauren M. Slosky
Department of Medical Pharmacology, University of Arizona College of Medicine, Tucson, Arizona
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Brandon J. Thompson
Department of Medical Pharmacology, University of Arizona College of Medicine, Tucson, Arizona
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Lucy Sanchez-Covarrubias
Department of Medical Pharmacology, University of Arizona College of Medicine, Tucson, Arizona
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Yifeng Zhang
Department of Medical Pharmacology, University of Arizona College of Medicine, Tucson, Arizona
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Mei-Li Laracuente
Department of Medical Pharmacology, University of Arizona College of Medicine, Tucson, Arizona
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Todd W. Vanderah
Department of Medical Pharmacology, University of Arizona College of Medicine, Tucson, Arizona
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Patrick T. Ronaldson
Department of Medical Pharmacology, University of Arizona College of Medicine, Tucson, Arizona
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Thomas P. Davis
Department of Medical Pharmacology, University of Arizona College of Medicine, Tucson, Arizona
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Abstract

Effective pharmacologic treatment of pain with opioids requires that these drugs attain efficacious concentrations in the central nervous system (CNS). A primary determinant of CNS drug permeation is P-glycoprotein (P-gp), an endogenous blood-brain barrier (BBB) efflux transporter that is involved in brain-to-blood transport of opioid analgesics (i.e., morphine). Recently, the nuclear receptor constitutive androstane receptor (CAR) has been identified as a regulator of P-gp functional expression at the BBB. This is critical to pharmacotherapy of pain/inflammation, as patients are often administered acetaminophen (APAP), a CAR-activating ligand, in conjunction with an opioid. Our objective was to investigate, in vivo, the role of CAR in regulation of P-gp at the BBB. Following APAP treatment, P-gp protein expression was increased up to 1.4–1.6-fold in a concentration-dependent manner. Additionally, APAP increased P-gp transport of BODIPY-verapamil in freshly isolated rat brain capillaries. This APAP-induced increase in P-gp expression and activity was attenuated in the presence of CAR pathway inhibitor okadaic acid or transcriptional inhibitor actinomycin D, suggesting P-gp regulation is CAR-dependent. Furthermore, morphine brain accumulation was enhanced by P-gp inhibitors in APAP-treated animals, suggesting P-gp–mediated transport. A warm-water (50°C) tail-flick assay revealed a significant decrease in morphine analgesia in animals treated with morphine 3 or 6 hours after APAP treatment, as compared with animals treated concurrently. Taken together, our data imply that inclusion of APAP in a pain treatment regimen activates CAR at the BBB and increases P-gp functional expression, a clinically significant drug-drug interaction that modulates opioid analgesic efficacy.

Footnotes

    • Received March 13, 2013.
    • Accepted September 9, 2013.
  • This work was supported by the National Institutes of Health National Institute on Drug Abuse [Grant R01DA11271]; the American Association of Pharmaceutical Scientists’ New Investigator Grant in Pharmacokinetics, Pharmacodynamics, and Drug Metabolism; and a University of Arizona Faculty Seed Grant.

  • dx.doi.org/10.1124/mol.113.086298.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 84 (5)
Molecular Pharmacology
Vol. 84, Issue 5
1 Nov 2013
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Research ArticleArticle

APAP Modulates P-gp at the BBB and Morphine Analgesia

Lauren M. Slosky, Brandon J. Thompson, Lucy Sanchez-Covarrubias, Yifeng Zhang, Mei-Li Laracuente, Todd W. Vanderah, Patrick T. Ronaldson and Thomas P. Davis
Molecular Pharmacology November 1, 2013, 84 (5) 774-786; DOI: https://doi.org/10.1124/mol.113.086298

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Research ArticleArticle

APAP Modulates P-gp at the BBB and Morphine Analgesia

Lauren M. Slosky, Brandon J. Thompson, Lucy Sanchez-Covarrubias, Yifeng Zhang, Mei-Li Laracuente, Todd W. Vanderah, Patrick T. Ronaldson and Thomas P. Davis
Molecular Pharmacology November 1, 2013, 84 (5) 774-786; DOI: https://doi.org/10.1124/mol.113.086298
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