Novel Aspects of Aspirin Action
Aspirin acetylates and irreversibly inhibits the enzyme cyclooxygenase (Roth and Majerus, 1975). Recent studies (Patrignani et al., 1982; FitzGerald et al., 1983; Weksler et al., 1983) have clarified the dose-response relationships between aspirin and the production of prostacyclin (PGl2) and thromboxane (Tx)A2, the predominant cyclooxygenase products formed by vascular endothelium and platelets, respectively and indicate that doses of aspirin less than 100 mg have a more pronounced effect on Tx formation both in vivo (Patrignani et al., 1982; FitzGerald et al., 1983) and ex vivo (Weksler et al., 1983). Possible explanations for such “biochemical selectivity” have included differential tissue sensitivity to enzyme inhibition by aspirin and/or accelerated recovery of PGl2 formation by nucleated endothelial cells, a phenomenon demonstrable in culture (Jaffe and Weksler, 1979). To address the possibility that pharmacokinetic variables might also contribute to such dose-related pharmacodynamic effects of aspirin, we have characterized the dose-related kinetics of aspirin and identified a selective mode of drug delivery that relies on platelet acetylation in the presystemic circulation, sparing systemic vascular endothelium from drug exposure.
KeywordsSelective Mode Stable Isotope Dilution Assay Platelet Thromboxane Serum TxB2 Aspirin Concentration
Unable to display preview. Download preview PDF.
- Lewis, H.D., Davis, J.W., Archibald, D.G., Steinke, W.E., Smitherman, T.C., Docherty, J.E., Schnaper, H.W., LeWinter, M.M., Linares, E., Pouget, J.M., Sabharwal, S.C., Chester, E., and DeMots, H., 1983, Protective effects of aspirin against acute myocardial infarction and death in men with unstable angina, N. Engl. J. Med. 309:396–403.PubMedCrossRefGoogle Scholar
- Reilly, I. A. G., and FitzGerald, G. A., 1984, Presystemic inhibition of platelet thromboxane formation by simulated slow release, low dose aspirin in man, Clin. Res. 32:320A.Google Scholar