Human pharmacology of naproxen sodium.
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(1alpha) 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(1alpha) 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.
Capone
Marta L
ML
Department of Medicine and Center of Excellence on Aging, School of Medicine, G. d'Annunzio University, Chieti, Italy. .
Tacconelli
Stefania
S
Sciulli
Maria G
MG
Anzellotti
Paola
P
Di Francesco
Luigia
L
Merciaro
Gabriele
G
Di Gregorio
Patrizia
P
Patrignani
Paola
P
D015121:6-Ketoprostaglandin F1 alpha / Q000031:analogs & derivatives / Q000652:urine; D000328:Adult; D016718:Arachidonic Acid / Q000494:pharmacology; D001241:Aspirin / Q000494:pharmacology*; D001792:Blood Platelets / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D051545:Cyclooxygenase 1 / Q000097:blood / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000097:blood / Q000494:pharmacology; D015232:Dinoprostone / Q000097:blood / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D011464:Epoprostenol / Q000378:metabolism; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D009000:Monocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D009288:Naproxen / Q000097:blood / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects*; D013929:Thromboxane B2 / Q000031:analogs & derivatives / Q000097:blood / Q000652:urine
D016861:Cyclooxygenase Inhibitors; D008070:Lipopolysaccharides; C081960:11-dehydro-2,3-dinor-thromboxane B2; D016718:Arachidonic Acid; D013929:Thromboxane B2; D009288:Naproxen; D015121:6-Ketoprostaglandin F1 alpha; C028290:2,3-dinor-6-ketoprostaglandin F1alpha; D011464:Epoprostenol; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D015232:Dinoprostone; D001241:Aspirin