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Pharmacokinetics of Aspirin and Salicylate in Relation to Inhibition

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Pharmacokinetics of Aspirin and Salicylate in Relation to Inhibition Proc. Natl. Acad. Sci. USA Vol. 84, pp. 1417-1420, March 1987 Medical Sciences Pharmacokinetics of aspirin and salicylate in relation to inhibition of arachidonate cyclooxygenase and antiinflammatory activity (inflammation/thromboxane/prostaglandins) GERALD A. HIGGS, JOHN A. SALMON, BRIAN HENDERSON, AND JOHN R. VANE* Department of Mediator Pharmacology, Wellcome Research Laboratories, Langley Court, Beckenham, Kent BR3 3BS, United Kingdom Contributed by John R. Vane, October 27, 1986 ABSTRACT Among the nonsteroid antiinflammatory We have now (i) measured the concentrations of aspirin drugs there is generally a close correlation between the potency and salicylate in plasma and inflammatory exudates collected of their inhibition of arachidonate cyclooxygenase, and thus from rats 5 min to 6 hr after a single oral administration of prostaglandin production, and their antiinflammatory activity. either aspirin or salicylate; (ii) measured the effects on serum One anomaly in this generalization is that whereas aspirin and TXB2 concentrations and concentrations of PGE2 in the salicylate are equipotent as antiinflammatory agents, salicylate exudates; and (iii) compared the effects of aspirin and is less active than aspirin in inhibiting prostaglandin produc- salicylate, at a range of concentrations achieved in inflam- tion in vitro. Using rats, we have now measured the concen- matory exudates, on the production ofPGE2 by nonprolifera- trations of aspirin and salicylate in plasma and in inflammatory tive explants of acutely inflamed tissue. Some of these data exudates after their oral administration and determined their have been presented elsewhere (7). 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 MATERIALS AND METHODS achieved in the exudates, on PGE2 production by nonprolifera- tive explants of acutely inflamed tissues. Aspirin is rapidly Groups of five male Wistar rats (190-210 g) were subcuta- metabolized, resulting in peak concentrations of salicylate in neously implanted with polyester sponges soaked in 1% the plasma and exudate that exceeded peak concentrations of carrageenan (Sigma), in sterile saline (8). Aspirin (Wellcome; aspirin by 30- to 50-fold. Furthermore, concentrations of 200 mg/kg) or salicylate (Wellcome; 200 mg/kg) was admin- aspirin rapidly declined, whereas high concentrations of sali- istered orally in aqueous solution 5 min to 6 hr before sponge cylate persisted in the plasma and in the exudate for up to 6 hr removal, whereas control animals received the vehicle alone. after a single administration of aspirin. Both drugs reduced After 6 hr, the rats were anesthetized, 5 ml of blood was PGE2 concentrations in inflammatory exudates by 50-70%, withdrawn from the abdominal aorta, and the sponges were but aspirin was considerably more potent than salicylate in removed. Blood (1 ml) was allowed to clot in glass test tubes inhibiting thromboxane B2 production in clotting blood. The at 37°C for 45 min, and the resulting serum was collected after concentration ofsalicylate found in inflammatory exudates 6 hr centrifugation. The remaining 4 ml of blood was added to after the administration of aspirin was sufficient to reduce tubes containing lithium heparin (Sarstedt, UK) to prevent PGE2 production in explants by more than 50%. We conclude coagulation, plus aqueous potassium fluoride (10 ,ul/ml; 50% that the antiinflammatory action of both drugs depends on the wt/vol), to limit enzymic hydrolysis of aspirin. The sponge inhibition of PGE2 synthesis by salicylate. exudates were squeezed into plastic tubes containing 50 ,ul of the potassium fluoride solution and were centrifuged to yield The discovery that aspirin, indomethacin, and salicylate a cell-free supernatant. Aspirin and salicylate concentrations inhibit the synthesis ofprostaglandins (1-3) provided the first in plasma and exudates were measured using reversed-phase comprehensive explanation of the mechanism of action of HPLC (9). Briefly, internal standard (3,4-dimethylbenzoic these drugs. Subsequent studies have shown that the broad acid; 3 ,g) was added to the sample that was then acidified group of nonsteroid antiinflammatory drugs inhibits arachi- with orthophosphoric acid and extracted with chloroform. donate cyclooxygenase, the enzyme that converts arachi- The chloroform was removed under nitrogen, and the residue donic acid to prostaglandin endoperoxides (for review see was reconstituted in HPLC mobile phase [methanol: 0.072% ref. 4). However, anomalies exist in the potencies of these orthophosphoric acid, 55:45 (vol/vol)]. An aliquot was in- drugs with respect to their antiinflammatory activities and to jected onto a 5-Am Spherisorb ODS reversed-phase HPLC their ability to inhibit cyclooxygenase; of particular interest column. The compounds were eluted by pumping mobile has been the between the phase through the column at 1 ml/min and were detected at disparity potency of aspirin and 234 nm. salicylate in inhibiting cyclooxygenase. Aspirin and salicy- The concentrations of aspirin and salicylic acid in plasma late are equipotent as antiinflammatory agents, but aspirin is and inflammatory exudate were subjected to pharmacokinet- some 20 times more potent than salicylate in inhibiting an ic analysis using a model similar to that described by Rowland enzyme preparation from guinea pig lung in vitro (1). Fur- et al. (10). The data points were fitted by nonlinear least thermore, it has been reported that oral administration of squares to a two-compartment model for both aspirin and its aspirin (10 mg/kg) inhibited thromboxane (TX) production by metabolite salicylic acid using a computer package (11). The rat platelets but 20 times this dose of salicylate had no effect concentration of the compounds in the plasma was assumed (5). These findings led to speculation that the antiinflamma- to represent the central compartment from which elimination tory activity of these drugs was not related to inhibition of occurred. The concentration of the compounds in the inflam- prostaglandin (PG) synthesis (5, 6). Abbreviations: PG, prostaglandin; TX, thromboxane. The publication costs of this article were defrayed in part by page charge *Present address: The William Harvey Research Institute, St. payment. This article must therefore be hereby marked "advertisement" Bartholomew's Hospital Medical College, Charterhouse Square, in accordance with 18 U.S.C. §1734 solely to indicate this fact. London EC1M 6BQ, United Kingdom. Downloaded by guest on October 2, 2021 1417 1418 Medical Sciences: Higgs et al. Proc. Natl. Acad. Sci. USA 84 (1987) matory exudate was considered to reflect another compart- achieved about 1 min after administration ofthe drug (Fig. 1). ment linked to the central compartment. The rate constants After attaining a maximum concentration, the levels of for tissue distribution and elimination found to define the aspirin in plasma rapidly decreased to 10% ofthe peak values pharmacokinetics of salicylic acid after oral administration after 1 hr and to an undetectable level after 6 hr. were used in the evaluation of the pharmacokinetics of Salicylate was detected in all the plasma samples taken up aspirin and its major metabolite (salicylic acid). The rate to 6 hr after administration of aspirin. After 5 min, salicylate constants for absorption, tissue distribution, and elimination concentrations in the' plasma were 20 times higher than of aspirin and salicylic acid obtained by Rowland et al. (10) aspirin; the concentrations of salicylate reached a peak 30 provided a guide to these parameters for the present evalu- min to 2 hr after administration. At 6 hr, plasma salicylate ation. The only significant difference between the model concentrations had fallen but were still 20-30 times higher described by Rowland et al. (10) and that used in the present than peak aspirin concentrations (Fig. 1). study was that we had to assume that elimination of salicylic Aspirin was also detected in the inflammatory exudate, in acid from the central compartment occurred by a zero-order which the highest concentrations were reached after 30 min. process. 'All other rate constants were first order. Peak aspirin concentrations in plasma and exudates were TXB2 concentrations in the serum and in exudates and similar but aspirin remained in the exudate for longer than in PGE2 concentrations in the exudates were determined by the plasma (Fig. 2). Aspirin could not be detected in the specific radioimmunoassays (8). exudate 6 hr after administration. Salicylate concentrations In a separate series of experiments, sponges were implant- increased in the exudate after aspirin administration and ed in groups offive rats 24 hr before the animals were killed, reached concentrations at 2 hr 30-40 times higher than the and the inflamed tissue around the implant was dissected out. highest aspirin concentrations (Fig. 2). After 6 hr, salicylate The'tissue was cut into segments weighing 30-60 mg that was still present in the exudate at near maximal concentra- were then maintained individually in Trowell's nonprolifera- tions. tive adult organ maintenance culture under an atmosphere of Effects of Aspirin on Cyclooxygenase Activity. Serum from 95% 02/5% CO2 at 37TC for 24 hr (12). Aspirin (0.25-25 control animals contained TXB2 at 332.4 ± 65.7 ng/ml (mean ,ug/ml) or salicylate (2.5-100 Ag/ml) was added to the culture ± SEM, n = 5). Serum collected from rats 5 min to 6 hr after medium and at the end of the incubation period the concen- aspirin administration did not contain any detectable TXB2 tration of PGE2 was assayed by radioimmunoassay. (<0.5 ng/ml; Fig. 3). Inflammatory exudates collected from control animals 6 hr after sponge implantation contained TXB2 at 42.6 ± 4.1 ng/ml and PGE2 at 19.5 ± 2.4 ng/ml. The RESULTS administration ofaspirin 5-20 min before sponge removal had variable effects on TXB2 and PGE2 concentrations, but 30 Concentrations of Aspirin and Salicylate after Administra- min to 6 hr after aspirin administration PGE2 was reduced by tion ofAspirin. The highest concentration (2.28 ± 1.09 kkg/ml) 45-60% (Fig.
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