title: Acetaminophen modulates P-glycoprotein functional expression at the blood-brain barrier by a constitutive androstane receptor-dependent mechanism.
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.
authors.affiliation: Department of Medical Pharmacology, University of Arizona College of Medicine, Tucson, Arizona.
authors.forename: Lauren M
authors.initials: LM
authors.lastname: Slosky
authors.forename: Brandon J
authors.initials: BJ
authors.lastname: Thompson
authors.forename: Lucy
authors.initials: L
authors.lastname: Sanchez-Covarrubias
authors.forename: Yifeng
authors.initials: Y
authors.lastname: Zhang
authors.forename: Mei-Li
authors.initials: ML
authors.lastname: Laracuente
authors.forename: Todd W
authors.initials: TW
authors.lastname: Vanderah
authors.forename: Patrick T
authors.initials: PT
authors.lastname: Ronaldson
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Davis
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000082:Acetaminophen / Q000494:pharmacology*; D018712:Analgesics, Non-Narcotic / Q000494:pharmacology*; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001921:Brain / Q000098:blood supply; D000090702:Constitutive Androstane Receptor; D005260:Female; D009020:Morphine / Q000493:pharmacokinetics; D010539:Permeability; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018712:Analgesics, Non-Narcotic; D000090702:Constitutive Androstane Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D000082:Acetaminophen; D009020:Morphine
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