Human Pharmacology of Naproxen Sodium

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 322; no. 2; pp. 453 - 460
• Main Authors: Capone, Marta L, Tacconelli, Stefania, Sciulli, Maria G, Anzellotti, Paola, Di Francesco, Luigia, Merciaro, Gabriele, Di Gregorio, Patrizia, Patrignani, Paola
• Format: Journal Article
• Language: English
• Published: United States American Society for Pharmacology and Experimental Therapeutics 01.08.2007
• Subjects: 6-Ketoprostaglandin F1 alpha - analogs & derivatives; 6-Ketoprostaglandin F1 alpha - urine; Adult; Arachidonic Acid - pharmacology; Aspirin - pharmacology; Blood Platelets - drug effects; Blood Platelets - enzymology; Blood Platelets - metabolism; Cyclooxygenase 1 - blood; Cyclooxygenase 1 - metabolism; Cyclooxygenase 2 - metabolism; Cyclooxygenase Inhibitors - blood; Cyclooxygenase Inhibitors - pharmacology; Dinoprostone - blood; Dinoprostone - metabolism; Dose-Response Relationship, Drug; Epoprostenol - metabolism; Humans; Lipopolysaccharides - pharmacology; Monocytes - drug effects; Monocytes - enzymology; Monocytes - metabolism; Naproxen - blood; Naproxen - pharmacology; Platelet Aggregation - drug effects; Thromboxane B2 - analogs & derivatives; Thromboxane B2 - blood; Thromboxane B2 - urine
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.107.122283

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 at 220 versus 440 mg b.i.d. and low-dose aspirin in healthy subjects. Six healthy subjects received consecutively naproxen sodium (220 and 440 mg b.i.d.) and aspirin (100 mg daily) for 6 days, separated by washout periods of 2 weeks. COX-1 and COX-2 inhibition was determined using ex vivo and in vivo indices of enzymatic activity: 1) the measurement of serum thromboxane (TX)B 2 levels and whole-blood lipopolysaccharide-stimulated prostaglandin (PG)E 2 levels, markers of COX-1 in platelets and COX-2 in monocytes, respectively; 2) the measurement of urinary 11-dehydro-TXB 2 and 2,3-dinor-6-keto-PGF 1α levels, markers of systemic TXA 2 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 at 220 and 440 mg b.i.d., respectively, was indistinguishable from aspirin, but at 12 and 24 h after dosing, we detected marked variability, which was higher with naproxen sodium at 220 mg than at 440 mg b.i.d. Assessment of the ratio of inhibition of urinary 11-dehydro-TXB 2 versus 2,3-dinor-6-keto-PGF 1α showed that the treatments caused a more profound inhibition of TXA 2 than prostacyclin biosynthesis in vivo throughout dosing interval. In conclusion, neither of the two 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.