Pharmacokinetics of aspirin and salicylate in relation to inhibition of arachidonate cyclooxygenase and antiinflammatory activity.

Abstract

Among the nonsteroid antiinflammatory drugs there is generally a close correlation between the potency of their inhibition of arachidonate cyclooxygenase, and thus prostaglandin production, and their antiinflammatory activity.One anomaly in this generalization is that whereas aspirin and salicylate are equipotent as antiinflammatory agents, salicylate is less active than aspirin in inhibiting prostaglandin production in vitro. Using rats, we have now measured the concentrations of aspirin and salicylate in plasma and in inflammatory exudates after their oral administration and determined their effects on thromboxane B2 production in clotting blood and prostaglandin (PG) E2 concentrations in the exudates. We have also investigated the effects of both drugs, at concentrations achieved in the exudates, on PGE2 production by nonproliferative explants of acutely inflamed tissues. Aspirin is rapidly metabolized, resulting in peak concentrations of salicylate in the plasma and exudate that exceeded peak concentrations of aspirin by 30-to 50-fold. Furthermore, concentrations of aspirin rapidly declined, whereas high concentrations of salicylate persisted in the plasma and in the exudate for up to 6 hr after a single administration of aspirin. Both drugs reduced PGE2 concentrations in inflammatory exudates by 50-70%, but aspirin was considerably more potent than salicylate in inhibiting thromboxane B2 production in clotting blood. The concentration of salicylate found in inflammatory exudates 6 hr after the administration of aspirin was sufficient to reduce PGE2 production in explants by more than 50%. We conclude that the antiinflammatory action of both drugs depends on the inhibition of PGE2 synthesis by salicylate.The discovery that aspirin, indomethacin, and salicylate inhibit the synthesis of prostaglandins (1-3) provided the first comprehensive explanation of the mechanism of action of these drugs. Subsequent studies have shown that the broad group of nonsteroid antiinflammatory drugs inhibits arachidonate cyclooxygenase, the enzyme that converts arachidonic acid to prostaglandin endoperoxides (for review see ref. 4). However, anomalies exist in the potencies of these drugs with respect to their antiinflammatory activities and to their ability to inhibit cyclooxygenase; of particular interest has been the disparity between the potency of aspirin and salicylate in inhibiting cyclooxygenase. Aspirin and salicylate are equipotent as antiinflammatory agents, but aspirin is some 20 times more potent than salicylate in inhibiting an enzyme preparation from guinea pig lung in vitro (1). Furthermore, it has been reported that oral administration of aspirin (10 mg/kg) inhibited thromboxane (TX) production by rat platelets but 20 times this dose of salicylate had no effect (5). These findings led to speculation that the antiinflammatory activity of these drugs was not related to inhibition of prostaglandin (PG) synthesis (5, 6).We have now (i) measured the concentrations of aspirin and salicylate in plasma and inflam...

Selectivity of nonsteroidal antiinflammatory drugs as inhibitors of constitutive and inducible cyclooxygenase.

“…Here we show that aspirin is =100 times more potent than salicylate as an inhibitor of COX-1 in intact cells but only twice as potent as an inhibitor of COX-2. These observations may explain those of Higgs et al (30) showing that salicylate and aspirin were approximately equipotent inhibitors of COX activity in explants of acutely inflamed tissue (COX-2?). However, aspirin was found to be considerably more potent than salicylate as an inhibitor of PGs in the serum (COX-1?).…”

Acetylation of prostaglandin H2 synthases by aspirin is inhibited by redox cycling of the peroxidase

“…Subsequently, we used aspirin at the final concentration of 20 μM because it inhibited PGE 2 synthesis by ~80% in our experimental conditions. As aspirin can be deacetylated in these cells to form salicylic acid [22], we performed the same experiment with equivalent concentrations of salicylic acid and demonstrated that the inhibition observed with aspirin was not due to its deacetylated product. A range of concentrations of 12-HPETE was added to IL-1β activated A549 cells that immediately were exposed to 20 μM aspirin.…”

Identification and determination of salicylic acid and salicyluric acid in urine of people not taking salicylate drugs

“…After administration, aspirin undergoes rapid hydrolysis to generate salicylic acid (SA), and it is this phenolic acid that may be responsible for the persistence of the anti-in£ammatory e¡ect of aspirin. 2 Paterson et al, 3 using high-performance liquid chromatography (HPLC), gas chromatography^mass spectrometry (GCMS) and salicylate hydroxylase, demonstrated that SA and two of its hydroxylated metabolites were present in the serum of people who had not taken salicylate drugs, and they suggested that these phenolic acids may have had a dietary origin. Swain et al 4 determined SA in foodstu¡s using HPLC with UV detection and estimated that the dietary intake of SA was in the range 70^1100 mol per person per 24 h. Janssen et al 5 examined acid-treated urine using HPLC with £uorescence detection, and suggested that the dietary intake of SA was about 10 mol per person per 24 h. However, neither Swain et al nor Janssen et al had characterized the compound(s) they had determined.…”