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

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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 circulations. 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 μg/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 μg/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.

Original languageEnglish
Pages (from-to)1185-1193
Number of pages9
JournalCirculation
Volume72
Issue number6
Publication statusPublished - 1985

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ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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