Impact of naproxen sodium at over-the-counter doses on cyclooxygenase isoforms in human volunteers.
OBJECTIVE
Over the last few years, there has been concern regarding the cardiovascular safety of selective cyclooxygenase (COX)-2 inhibitors and high-dose regimens of nonsteroidal anti-inflammatory drugs (NSAIDs). On the other hand, those compounds which elicit an almost complete (> 95%) and continuous suppression of platelet COX-1 may represent an exception. Apart from aspirin, which irreversibly inactivates COX-1, high-dose naproxen causes sustained COX-1 inhibition throughout the dose interval in some individuals. The present study examines whether naproxen sodium after a single dose administration and at steady state using "over-the-counter (OTC) doses" produces sufficient COX-1 inhibition. COX-2 inhibition was assessed concomitantly.


METHODS
Ex vivo inhibition of COX enzymes and the pharmacokinetics of naproxen were assessed in four volunteers receiving 220 mg naproxen sodium b.i.d. for 7 days. Blood samples were obtained pre-dose, at specified time points after the first dose on Day 1, and 12 hours after the previous evening dose on Days 2, 3, 4, 5 and 8. Recovery was assessed up to 36 hours after the last dose. Coagulation-induced thromboxane B2 formation and lipopolysaccharide-induced prostaglandin E2 synthesis were measured ex vivo in human whole blood as indices of COX-1 and COX-2 activity.


RESULTS
Maximal inhibition after a single dose and at steady state were as follows: 94% and 93% (COX-1), and 79% and 85% (COX-2). A greater than 95% COX-1 inhibition was observed transiently in 2 of 4 volunteers at the time of maximal plasma concentration after a single-dose administration and in 1 of 4 volunteers throughout the 12-hour dose interval at steady state. For both isoenzymes, COX inhibition correlated with naproxen plasma levels (ex vivo IC50 values of 35.48 micromol/l (COX-1) and 64.62 micromol/l (COX-2)).


CONCLUSIONS
Administration of naproxen sodium at OTC doses was associated with a profound inhibition of both COX enzymes. Although low-dose naproxen may elicit a virtually complete COX-1 inhibition in some individuals, it does not mimic the reliable, sustained and complete COX-1 blockade produced by aspirin. In conclusion, prolonged treatment with 220 mg naproxen sodium b.i.d. is not expected to provide sufficient cardioprotection in all patients, but may influence platelet function in some.
Hinz
B
B
Institute of Toxicology and Pharmacology, University of Rostock, Schillingallee 70, Rostock, Germany. burkhard.hinz@med.uni-rostock.de
Cheremina
O
O
Besz
D
D
Zlotnick
S
S
Brune
K
K
D000328:Adult; D000368:Aged; D002851:Chromatography, High Pressure Liquid; D051545:Cyclooxygenase 1 / Q000097:blood; D051546:Cyclooxygenase 2 / Q000097:blood; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology*; D015232:Dinoprostone / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004926:Escherichia coli; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000097:blood; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009288:Naproxen / Q000008:administration & dosage* / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects; D013929:Thromboxane B2 / Q000097:blood
D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008070:Lipopolysaccharides; D013929:Thromboxane B2; D009288:Naproxen; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D015232:Dinoprostone