Received for publication March 7, 2007.
Revised April 30, 2007.
Accepted for publication April 30, 2007.

Human pharmacology of naproxen sodium

Abstract

We compared the variability in degree and recovery from steady-state inhibition of cyclooxygenase(COX)-1 and COX-2 ex vivo and in vivo and platelet aggregation by naproxen sodium 220mg BID versus 440mg BID and low-dose aspirin in healthy subjects. Six healthy subjects received consecutively naproxen sodium 220mg BID, 440mg BID and aspirin (100mg daily) for 6 days, separated by washout periods of two weeks. COX-1 and COX-2 inhibition was determined using ex vivo and in vivo indices of enzymatic activity: i) the measurement of serum thromboxane(TX)B₂ levels and whole blood lipopolysaccharide-stimulated prostaglandin(PG)E₂ levels, markers of COX-1 in platelets and COX-2 in monocytes, respectively, ii) the measurement of urinary 11-dehydro-TXB₂ and 2,3-dinor-6-keto-PGF₁ levels, markers of systemic TXA₂ biosynthesis(mostly COX-1 derived) and prostacyclin biosynthesis(mostly COX-2 derived), respectively. Arachidonic acid(AA)-induced platelet aggregation was also studied. The maximal inhibition of platelet COX-1 (95.9±5.1 and 99.2±0.4%) and AA-induced platelet aggregation (92±3.5 and 93.7±1.5%) obtained at 2 h after dosing with naproxen sodium 220 and 440mg BID, respectively, was indistinguishable from aspirin but at 12 and 24 h after dosing, we detected marked variability which was higher with naproxen sodium 220mg than 440mg BID. Assessment of the ratio of inhibition of urinary 11-dehydro-TXB₂ versus 2,3-dinor-6-keto-PGF₁ showed that the treatments caused a more profound inhibition of TXA₂ than prostacyclin biosynthesis in vivo throughout dosing interval. In conclusion, neither of the 2 naproxen doses mimed the persistent and complete inhibition of platelet COX-1 activity obtained by aspirin but marked heterogeneity was mitigated by the higher dose of the drug.

Key words: Aspirin, COX-1, COX-2, Naproxen, PGI2, TXA2