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

Burkhard Hinz^*,1, Olga Cheremina and Kay Brune

^* Institute of Toxicology and Pharmacology, University of Rostock, Rostock, Germany; and

Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich Alexander University Erlangen-Nürnberg, Erlangen, Germany

¹ Correspondence: Institute of Toxicology and Pharmacology, University of Rostock, Schillingallee 70, D-18057 Rostock, Germany. E-mail: burkhard.hinz{at}med.uni-rostock.de

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 B₂ and lipopolysaccharide-induced prostaglandin E₂ 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 (IC₅₀=113.7 µmol/L for COX-1; IC₅₀=25.8 µmol/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 IC₅₀ for COX-2 for at least 5 h postadministration. Ex vivo IC₅₀ values (COX-1: 105.2 µmol/L; COX-2: 26.3 µmol/L) of acetaminophen compared favorably with its in vitro IC₅₀ 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.—Hinz, B., Cheremina, O., Brune, K. Acetaminophen (paracetamol) is a selective cyclooxygenase-2 inhibitor in man.

Key Words: cyclooxygenase isoenzymes • COX-2 selectivity • human whole blood assay • pharmacokinetics