High-Dose Acetaminophen Alters the Integrity of the Blood–Brain Barrier and Leads to Increased CNS Uptake of Codeine in Rats

• Published in: Pharmaceutics Vol. 14; no. 5; p. 949
• Main Authors: Yang, Junzhi, Betterton, Robert D., Williams, Erica I., Stanton, Joshua A., Reddell, Elizabeth S., Ogbonnaya, Chidinma E., Dorn, Emma, Davis, Thomas P., Lochhead, Jeffrey J., Ronaldson, Patrick T.
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 27.04.2022; MDPI
• Subjects: acetaminophen; Alzheimer's disease; Analgesics; Animals; blood–brain barrier; Brain research; claudin-5; CNS drug delivery; Computerized physician order entry; Drug dosages; Ecstasy; Experiments; Homeostasis; Narcotics; opioids; Permeability; Polypharmacy; Proteins; Sucrose; tight junction; United States > US; acetaminophen; blood–brain barrier; CNS drug delivery; tight junction; claudin-5; opioids
• ISSN: 1999-4923; 1999-4923
• DOI: 10.3390/pharmaceutics14050949

The consumption of acetaminophen (APAP) can induce neurological changes in human subjects; however, effects of APAP on blood–brain barrier (BBB) integrity are unknown. BBB changes by APAP can have profound consequences for brain delivery of co-administered drugs. To study APAP effects, female Sprague–Dawley rats (12–16 weeks old) were administered vehicle (i.e., 100% dimethyl sulfoxide (DMSO), intraperitoneally (i.p.)) or APAP (80 mg/kg or 500 mg/kg in DMSO, i.p.; equivalent to a 900 mg or 5600 mg daily dose for a 70 kg human subject). BBB permeability was measured via in situ brain perfusion using [14C]sucrose and [3H]codeine, an opioid analgesic drug that is co-administered with APAP (i.e., Tylenol #3). Localization and protein expression of tight junction proteins (i.e., claudin-5, occludin, ZO-1) were studied in rat brain microvessels using Western blot analysis and confocal microscopy, respectively. Paracellular [14C]sucrose “leak” and brain [3H]codeine accumulation were significantly enhanced in rats treated with 500 mg/kg APAP only. Additionally, claudin-5 localization and protein expression were altered in brain microvessels isolated from rats administered 500 mg/kg APAP. Our novel and translational data show that BBB integrity is altered following a single high APAP dose, results that are relevant to patients abusing or misusing APAP and/or APAP/opioid combination products.