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First evidence of the conversion of paracetamol to AM404 in human cerebrospinal fluid

 

Authors Sharma CV, Long JH, Shah S, Rahman J, Perrett D, Ayoub SS, Mehta V

Received 8 June 2017

Accepted for publication 4 September 2017

Published 28 November 2017 Volume 2017:10 Pages 2703—2709

DOI https://doi.org/10.2147/JPR.S143500

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Colin Mak

Peer reviewer comments 3

Editor who approved publication: Dr Michael Schatman

Abstract: Paracetamol is arguably the most commonly used analgesic and antipyretic drug worldwide, however its mechanism of action is still not fully established. It has been shown to exert effects through multiple pathways, some actions suggested to be mediated via N-arachidonoylphenolamine (AM404). AM404, formed through conjugation of paracetamol-derived p-aminophenol with arachidonic acid in the brain, is an activator of the capsaicin receptor, TRPV1, and inhibits the reuptake of the endocannabinoid, anandamide, into postsynaptic ­neurons, as well as inhibiting synthesis of PGE2 by COX-2. However, the presence of AM404 in the central nervous system following administration of paracetamol has not yet been demonstrated in humans. Cerebrospinal fluid (CSF) and blood were collected from 26 adult male patients between 10 and 211 minutes following intravenous administration of 1 g of paracetamol. Paracetamol was measured by high-performance liquid chromatography with UV detection. AM404 was measured by liquid chromatography-tandem mass spectrometry. AM404 was detected in 17 of the 26 evaluable CSF samples at 5–40 nmolL–1. Paracetamol was measurable in CSF within 10 minutes, with a maximum measured concentration of 60 μmolL–1 at 206 minutes. This study is the first to report on the presence of AM404 in human CSF following paracetamol administration. This may represent an important finding in our understanding of paracetamol’s mechanism of action, although measured concentrations were far below the previously documented IC50 for this metabolite.
Keywords: acetaminophen, paracetamol, paracetamol: mechanism of action, AM404, N-­arachidonoylphenolamine, pharmacology - theories of analgesic action


 

摘要视频链接Paracetamol metabolism to AM404 in human CSF