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 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 1␣ 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 Ϯ 5.1 and 99.2 Ϯ 0.4%) and AA-induced platelet aggregation (92 Ϯ 3.5 and 93.7 Ϯ 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 1␣ 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.

Nonsteroidal Anti-Inflammatory Drugs and the Heart

“…37,38 The increased risk of coronary events associated with vascular COX-2 inhibition is mechanistically consistent with the pattern of cardioprotection associated with platelet COX-1 inhibition by low-dose aspirin in low-risk subjects, that is, a clear decrease in coronary risk. 45 These findings suggest an important role of PGI 2 and TXA 2 in modulating platelet activation and its contribution to coronary atherothrombosis.…”

“…11,12 Naproxen, when taken regularly at high doses and an adequate dosing interval (ie, 500 mg twice daily), is the only traditional NSAID that has been reported to inhibit platelet COX-1 activity by >95% throughout the dosing interval and to suppress TXA 2 biosynthesis in vivo to the same extent as low-dose aspirin. 37,38 Lower doses and less frequent dosing of naproxen are not expected to reproduce this aspirin-like antiplatelet effect. 38 Some NSAIDs favoring COX-1 versus COX-2 inhibition such as ibuprofen and naproxen (Figure 3) may interfere with the antiplatelet effect of low-dose aspirin by competing with acetylsalicylic acid for a common docking site (arginine 120) within the COX-1 channel.…”

“…37,38 Lower doses and less frequent dosing of naproxen are not expected to reproduce this aspirin-like antiplatelet effect. 38 Some NSAIDs favoring COX-1 versus COX-2 inhibition such as ibuprofen and naproxen (Figure 3) may interfere with the antiplatelet effect of low-dose aspirin by competing with acetylsalicylic acid for a common docking site (arginine 120) within the COX-1 channel. 39 Prior occupancy of arginine 120 by an NSAID will prevent aspirin from acetylating a serine residue (Ser-529) just below the COX catalytic site of the enzyme, which forms the basis of the unique mechanism of action of aspirin, resulting in permanent inactivation of platelet COX-1.…”

“…37 Second, the cardiovascular effects of lower naproxen doses such as those typically used in over-the-counter preparations (eg, 220 mg twice daily) are uncertain because a lower-dose regimen does not mimic the aspirin-like effect of 500 mg twice daily. 38 Third, the apparent safety advantage of high-dose naproxen regimens over other traditional NSAIDs may not be preserved after long-term use because of substantially similar untoward hemodynamic and renal effects that may increase the risk of heart failure (see above) and possibly ischemic stroke.…”

Adverse Effects and Drug Interactions of the Non‐Steroidal Anti‐Inflammatory Drugs

“…However, with the exception of naproxen, neither of the non-selective NSAIDs (apart from aspirin) could afect platelet COX-1 in such a signiicant manner necessary for a platelet inhibitory efect [15].…”