Pharmacology of platelet inhibition in humans: implications of the salicylate-aspirin interaction.

Abstract

The current dispute over the effects of "low" vs "high"doses of aspirin should take into consideration the pharmacokinetics of this drug. In fact, different pharmaceutical formulations of aspirin may deliver little or no aspirin to the systemic blood. This was the case, for instance, in healthy volunteers taking 320 mg of compressed aspirin or 800 mg of enteric-coated aspirin. In all instances thromboxane B2 generation in serum was fully inhibited. Platelet cyclooxygenase might therefore be effectively acetylated by exposure to aspirin in the portal circulation, whereas vascular cyclooxygenase could be spared. Thus aspirin formulations ensuring complete first-pass deacetylation should be sought rather than "low" or "high" doses of unspecified aspirin formulations. Regardless of the type and dose of aspirin administered, salicylate is formed and accumulates in the circulation. It may antagonize the effects of aspirin on cyclooxygenase, at least in acute conditions. As an example, after administration of 1 g of salicylate to healthy volunteers, when plasma levels of the drug were about 75 ,ug/ml, the effect of 40 mg iv aspirin (given 40 min later) on platelet cyclooxygenase and aggregation was significantly diminished. In contrast, in patients undergoing saphenectomy, the same dose of salicylate (1 g) gave plasma drug levels of about 25 ,ug/ml; salicylate was unable to prevent the inhibitory effect on platelets of 40 mg iv aspirin (given 1 hr later) but did act on vascular prostacyclin. Thus the combination of salicylate with aspirin at an appropriate dose and blood level ratio may result in almost complete dissociation of the drug's effect on platelets and vessels in man. Because the studies outlined in this review address only the short-term outcome of the salicylate-aspirin interaction, the possibility should be tested that inactivation of cyclooxygenase would occur after long-term administration of salicylate-aspirin. A pharmacokinetic approach to the "aspirin dilemma" should also consider the possibility that salicylate and/or its metabolites (e.g., gentisic acid) may interfere with lipoxygenase activity, synthesis of the prothrombin complex coagulation factors, and fibrinolysis. Circulation 72, No. 6, 1185No. 6, -1193No. 6, , 1985 Aspirin, salicylate, and inhibition of platelet aggregation and cyclooxygenase activity. Aspirin inhibits platelet aggregation and the concomitant release reaction.I4 This exciting discovery, made more than 15 years ago, was characterized by three main facts: (1) aspirin was active in man at oral doses as low as 150 mg (about 2 mg/kg), (2) its effects were long lasting (at least 24 to 48 hr), and (3) salicylate, the main metabolite of aspirin, was virtually inactive. The last two observations suggested that the effect of aspirin on platelets was the result of irreversible acetylation. Consequently, the salicylate moiety of aspirin was considered irrelevant for the drug's action on platelets.

Increased Proinflammatory Cytokines in Patients With Chronic Stable Angina and Their Reduction By Aspirin

“…Aspirin may prevent cyclooxygenase-mediated cell activation and proliferation and reduce the release of these cytokines in blood by acetylating cyclooxygenase. 45 Aspirin administration in patients with chronic stable angina has been associated with increased plasma levels of the antiproliferative cytokine, transforming growth factor-b (TGF-b). 46 Interestingly, an inverse relation between TGF-b and MCSF blood levels has been found.…”

Biochemical selectivity of oral versus intravenous aspirin in rats. Inhibition by oral aspirin of cyclooxygenase activity in platelets and presystemic but not systemic vessels.

“…Presystemic deacetylation of aspirin after oral administration is responsible for reduced peripheral drug levels. Consequently, after oral aspirin peripheral vascular cyclooxygenase might be exposed to lower concentrations of the drug and/or its inactive metabolite, salicylate (20). In contrast, platelets passing through the gut capillaries during absorption could be effectively acetylated by the drug.…”

Effect of Single Oral Dose of Aspirin on Human Platelet Functions and Plasma Plasminogen Activator Inhibitor-1

“…In the endothelium, the formation of the antiaggregatory prosta noid prostacyclin is mediated by cyclo-oxy genase and is therefore also inhibited, but at relatively higher dose levels [7], Although as pirin's antiplatelet and antithrombotic effects have been attributed to its inhibition of plate let cyclo-oxygenase, its salicylate moiety may exert additional antithrombotic effects. Aspi rin has been shown to inhibit the synthesis of vitamin K-dependent clotting factors, stimu late fibrinolysis, and antagonize the lipoxy genase pathway of arachidonate metabolism when given to experimental animals and hu mans at large doses [8]. These studies suggest ed that the clinically impressive performance of aspirin cannot be simply explained on the basis of inhibition of platelet cyclo-oxygenase activity.…”