Acetaminophen modulates P-glycoprotein functional expression at the blood-brain barrier by a constitutive androstane receptor-dependent mechanism.

TitleAcetaminophen modulates P-glycoprotein functional expression at the blood-brain barrier by a constitutive androstane receptor-dependent mechanism.
Publication TypeJournal Article
Year of Publication2013
AuthorsSlosky LM, Thompson BJ, Sanchez-Covarrubias L, Zhang Y, Laracuente M-L, Vanderah TW, Ronaldson PT, Davis TP
JournalMol Pharmacol
Date Published2013 Nov
KeywordsAcetaminophen, Analgesics, Non-Narcotic, Animals, Biological Transport, Blood-Brain Barrier, Brain, Female, Morphine, P-Glycoprotein, Permeability, Rats, Rats, Sprague-Dawley, Receptors, Cytoplasmic and Nuclear

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.

Alternate JournalMol. Pharmacol.
PubMed ID24019224
PubMed Central IDPMC3807077
Grant ListP30 CA023074 / CA / NCI NIH HHS / United States
R01 DA011271 / DA / NIDA NIH HHS / United States
R01 NS042652 / NS / NINDS NIH HHS / United States
R01DA11271 / DA / NIDA NIH HHS / United States
Faculty Member Reference: 
Thomas P Davis, PhD
Patrick T Ronaldson, PhD
Todd Vanderah, PhD