Acetaminophen Modulates P-Glycoprotein Functional Expression at the Blood-Brain Barrier by a Constitutive Androstane Receptor–Dependent Mechanism
| Autor: | Lauren M. Slosky, Thomas P. Davis, Patrick T. Ronaldson, Lucy Sanchez-Covarrubias, Brandon J. Thompson, Mei Li Laracuente, Yifeng Zhang, Todd W. Vanderah |
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| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
medicine.medical_specialty
Receptors Cytoplasmic and Nuclear Pharmacology Blood–brain barrier Permeability Rats Sprague-Dawley In vivo Internal medicine Constitutive androstane receptor medicine Animals ATP Binding Cassette Transporter Subfamily B Member 1 Receptor Constitutive Androstane Receptor P-glycoprotein Acetaminophen biology Morphine Chemistry digestive oral and skin physiology Brain Biological Transport Articles Analgesics Non-Narcotic Rats medicine.anatomical_structure Endocrinology Opioid Blood-Brain Barrier biology.protein Molecular Medicine Female medicine.drug |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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