RESEARCH - Acetaminophen (paracetamol) is a selective COX-2 inhibitor in man

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FASEB J. 2008 Feb;22(2):383-90. Epub 2007 Sep 20.

Acetaminophen (paracetamol) is a selective cyclooxygenase-2 inhibitor in man.

Hinz B, Cheremina O, Brune K.

Institute of Toxicology and Pharmacology, University of Rostock,

Schillingallee 70, D-18057 Rostock, Germany.

For more than three decades, acetaminophen (INN, paracetamol) has been

claimed to be devoid of significant inhibition of peripheral

prostanoids. Meanwhile, attempts to explain its action by inhibition

of a central cyclooxygenase (COX)-3 have been rejected. The fact that

acetaminophen acts functionally as a selective COX-2 inhibitor led us

to investigate the hypothesis of whether it works via preferential

COX-2 blockade. Ex vivo COX inhibition and pharmacokinetics of

acetaminophen were assessed in 5 volunteers receiving single 1000 mg

doses orally. Coagulation-induced thromboxane B(2) and

lipopolysaccharide-induced prostaglandin E(2) were measured ex vivo

and in vitro in human whole blood as indices of COX-1 and COX-2

activity. In vitro, acetaminophen elicited a 4.4-fold selectivity

toward COX-2 inhibition (IC(50)=113.7 micromol/L for COX-1;

IC(50)=25.8 micromol/L for COX-2). Following oral administration of

the drug, maximal ex vivo inhibitions were 56% (COX-1) and 83%

(COX-2). Acetaminophen plasma concentrations remained above the in

vitro IC(50) for COX-2 for at least 5 h postadministration. Ex vivo

IC(50) values (COX-1: 105.2 micromol/L; COX-2: 26.3 micromol/L) of

acetaminophen compared favorably with its in vitro IC(50) values. In

contrast to previous concepts, acetaminophen inhibited COX-2 by more

than 80%, i.e., to a degree comparable to nonsteroidal

antiinflammatory drugs (NSAIDs) and selective COX-2 inhibitors.

However, a >95% COX-1 blockade relevant for suppression of platelet

function was not achieved. Our data may explain acetaminophen's

analgesic and antiinflammatory action as well as its superior overall

gastrointestinal safety profile compared with NSAIDs. In view of its

substantial COX-2 inhibition, recently defined cardiovascular warnings

for use of COX-2 inhibitors should also be considered for

acetaminophen.

PMID: 17884974

http://www.ncbi.nlm.nih.gov/pubmed/17884974

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