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. 1986 Jul;78(1):323–326. doi: 10.1172/JCI112569

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

C Cerletti, M C Gambino, S Garattini, G de Gaetano
PMCID: PMC329565  PMID: 3088044

Abstract

In rats intravenous aspirin was only slightly more effective an inhibitor of platelet thromboxane B2 (TxB2) than of aorta 6-keto-prostaglandin (PGF)1 alpha generation (1.9 versus 2.1 mg/kg). In contrast, oral aspirin was about five times more effective on platelet than on aorta cyclooxygenase activity. The "biochemical selectivity" of aspirin as an inhibitor of platelet and vascular cyclooxygenase thus was not apparent after intravenous administration of the drug. However, this could be achieved by relatively low doses of oral (or intraduodenal) aspirin, on account of "presystemic" acetylation of platelet cyclooxygenase. Even in this condition, though, aspirin selectivity was relative to "systemic" peripheral vessels but not to the vessels of the enterohepatic circulation. Indeed after an oral or intraduodenal dose of 5 mg/kg aspirin, generation of portal vein 6-keto-PGF1 alpha was inhibited to much the same extent as platelet TxB2, while inferior vena cava 6-keto-PGF1 alpha formation was spared.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Ali M., McDonald J. W., Thiessen J. J., Coates P. E. Plasma acetylsalicylate and salicylate and platelet cyclooxygenase activity following plain and enteric-coated aspirin. Stroke. 1980 Jan-Feb;11(1):9–13. doi: 10.1161/01.str.11.1.9. [DOI] [PubMed] [Google Scholar]
  2. Baenziger N. L., Dillender M. J., Majerus P. W. Cultured human skin fibroblasts and arterial cells produce a labile platelet-inhibitory prostaglandin. Biochem Biophys Res Commun. 1977 Sep 9;78(1):294–301. doi: 10.1016/0006-291x(77)91253-0. [DOI] [PubMed] [Google Scholar]
  3. Brantmark B., Wåhlin-Boll E., Melander A. Bioavailability of acetylsalicylic acid and salicylic acid from rapid-and slow-release formulations, and in combination with dipyridamol. Eur J Clin Pharmacol. 1982;22(4):309–314. doi: 10.1007/BF00548398. [DOI] [PubMed] [Google Scholar]
  4. Burch J. W., Baenziger N. L., Stanford N., Majerus P. W. Sensitivity of fatty acid cyclooxygenase from human aorta to acetylation by aspirin. Proc Natl Acad Sci U S A. 1978 Oct;75(10):5181–5184. doi: 10.1073/pnas.75.10.5181. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Burch J. W., Stanford N., Majerus P. W. Inhibition of platelet prostaglandin synthetase by oral aspirin. J Clin Invest. 1978 Feb;61(2):314–319. doi: 10.1172/JCI108941. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Cerletti C., Latini R., Dejana E., Tognoni G., Garattini S., de Gaetano G. Inhibition of human platelet thromboxane generation by aspirin in the absence of measurable drug levels in peripheral blood. Biochem Pharmacol. 1985 May 15;34(10):1839–1841. doi: 10.1016/0006-2952(85)90658-6. [DOI] [PubMed] [Google Scholar]
  7. Dejana E., Cerletti C., de Castellarnau C., Livio M., Galletti F., Latini R., de Gaetano G. Salicylate-aspirin interaction in the rat. Evidence that salicylate accumulating during aspirin administration may protect vascular prostacyclin from aspirin-induced inhibition. J Clin Invest. 1981 Oct;68(4):1108–1112. doi: 10.1172/JCI110336. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Fiocchi R., Bianchi G., Petrillo P., Tavani A., Manara L. Morphine inhibits gastrointestinal transit in the rat primarily by impairing propulsive activity of the small intestine. Life Sci. 1982 Nov 15;31(20-21):2221–2223. doi: 10.1016/0024-3205(82)90123-0. [DOI] [PubMed] [Google Scholar]
  9. FitzGerald G. A., Brash A. R., Oates J. A., Pedersen A. K. Endogenous prostacyclin biosynthesis and platelet function during selective inhibition of thromboxane synthase in man. J Clin Invest. 1983 Oct;72(4):1336–1343. doi: 10.1172/JCI111089. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Hamberg M., Svensson J., Wakabayashi T., Samuelsson B. Isolation and structure of two prostaglandin endoperoxides that cause platelet aggregation. Proc Natl Acad Sci U S A. 1974 Feb;71(2):345–349. doi: 10.1073/pnas.71.2.345. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Hanley S. P., Bevan J., Cockbill S. R., Heptinstall S. Differential inhibition by low-dose aspirin of human venous prostacyclin synthesis and platelet thromboxane synthesis. Lancet. 1981 May 2;1(8227):969–971. doi: 10.1016/s0140-6736(81)91733-5. [DOI] [PubMed] [Google Scholar]
  12. Hanley S. P., Bevan J. Inhibition by aspirin of human arterial and venous prostacyclin synthesis. Prostaglandins Leukot Med. 1985 Nov;20(2):141–149. doi: 10.1016/0262-1746(85)90005-8. [DOI] [PubMed] [Google Scholar]
  13. Hatori A., Shigematsu A., Tsuya A. The metabolism of aspirin in rats; localization, absorption, distribution and excretion. Eur J Drug Metab Pharmacokinet. 1984 Jul-Sep;9(3):205–214. doi: 10.1007/BF03189643. [DOI] [PubMed] [Google Scholar]
  14. Iwamoto K., Takei M., Watanabe J. Gastrointestinal and hepatic first-pass metabolism of aspirin in rats. J Pharm Pharmacol. 1982 Mar;34(3):176–180. doi: 10.1111/j.2042-7158.1982.tb04216.x. [DOI] [PubMed] [Google Scholar]
  15. Jaffe E. A., Weksler B. B. Recovery of endothelial cell prostacyclin production after inhibition by low doses of aspirin. J Clin Invest. 1979 Mar;63(3):532–535. doi: 10.1172/JCI109332. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Levy G., Angelino N. J. Hydrolysis of aspirin by rat small intestine. J Pharm Sci. 1968 Aug;57(8):1449–1450. doi: 10.1002/jps.2600570843. [DOI] [PubMed] [Google Scholar]
  17. Masotti G., Galanti G., Poggesi L., Abbate R., Neri Serneri G. G. Differential inhibition of prostacyclin production and platelet aggregation by aspirin. Lancet. 1979 Dec 8;2(8154):1213–1217. doi: 10.1016/s0140-6736(79)92334-1. [DOI] [PubMed] [Google Scholar]
  18. Moncada S., Vane J. R. Pharmacology and endogenous roles of prostaglandin endoperoxides, thromboxane A2, and prostacyclin. Pharmacol Rev. 1978 Sep;30(3):293–331. [PubMed] [Google Scholar]
  19. Patrignani P., Filabozzi P., Patrono C. Selective cumulative inhibition of platelet thromboxane production by low-dose aspirin in healthy subjects. J Clin Invest. 1982 Jun;69(6):1366–1372. doi: 10.1172/JCI110576. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Patrono C., Ciabattoni G., Pinca E., Pugliese F., Castrucci G., De Salvo A., Satta M. A., Peskar B. A. Low dose aspirin and inhibition of thromboxane B2 production in healthy subjects. Thromb Res. 1980 Feb 1;17(3-4):317–327. doi: 10.1016/0049-3848(80)90066-3. [DOI] [PubMed] [Google Scholar]
  21. Pedersen A. K., FitzGerald G. A. Dose-related kinetics of aspirin. Presystemic acetylation of platelet cyclooxygenase. N Engl J Med. 1984 Nov 8;311(19):1206–1211. doi: 10.1056/NEJM198411083111902. [DOI] [PubMed] [Google Scholar]
  22. Preston F. E., Greaves M., Jackson C. A., Stoddard C. J. Low-dose aspirin inhibits platelet and venous cyclo-oxygenase in man. Thromb Res. 1982 Aug 15;27(4):477–484. doi: 10.1016/0049-3848(82)90065-2. [DOI] [PubMed] [Google Scholar]
  23. Preston F. E., Whipps S., Jackson C. A., French A. J., Wyld P. J., Stoddard C. J. Inhibition of prostacyclin and platelet thromboxane A2 after low-dose aspirin. N Engl J Med. 1981 Jan 8;304(2):76–79. doi: 10.1056/NEJM198101083040203. [DOI] [PubMed] [Google Scholar]
  24. Prosdocimi M., Finesso M., Gorio A., Languino L. R., Del Maschio A., Castagnoli M. N., De Gaetano G., Dejana E. Coronary and systemic 6-ketoprostaglandin F1 alpha and thromboxane B2 during myocardial ischemia in dog. Am J Physiol. 1985 Apr;248(4 Pt 2):H493–H499. doi: 10.1152/ajpheart.1985.248.4.H493. [DOI] [PubMed] [Google Scholar]
  25. Ross-Lee L. M., Elms M. J., Cham B. E., Bochner F., Bunce I. H., Eadie M. J. Plasma levels of aspirin following effervescent and enteric coated tablets, and their effect on platelet function. Eur J Clin Pharmacol. 1982;23(6):545–551. doi: 10.1007/BF00637504. [DOI] [PubMed] [Google Scholar]
  26. Roth G. J., Stanford N., Majerus P. W. Acetylation of prostaglandin synthase by aspirin. Proc Natl Acad Sci U S A. 1975 Aug;72(8):3073–3076. doi: 10.1073/pnas.72.8.3073. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Siebert D. J., Bochner F., Imhoff D. M., Watts S., Lloyd J. V., Field J., Gabb B. W. Aspirin kinetics and platelet aggregation in man. Clin Pharmacol Ther. 1983 Mar;33(3):367–374. doi: 10.1038/clpt.1983.47. [DOI] [PubMed] [Google Scholar]
  28. Weksler B. B., Pett S. B., Alonso D., Richter R. C., Stelzer P., Subramanian V., Tack-Goldman K., Gay W. A., Jr Differential inhibition by aspirin of vascular and platelet prostaglandin synthesis in atherosclerotic patients. N Engl J Med. 1983 Apr 7;308(14):800–805. doi: 10.1056/NEJM198304073081402. [DOI] [PubMed] [Google Scholar]
  29. Weksler B. B., Tack-Goldman K., Subramanian V. A., Gay W. A., Jr Cumulative inhibitory effect of low-dose aspirin on vascular prostacyclin and platelet thromboxane production in patients with atherosclerosis. Circulation. 1985 Feb;71(2):332–340. doi: 10.1161/01.cir.71.2.332. [DOI] [PubMed] [Google Scholar]
  30. de Gaetano G., Cerletti C., Dejana E., Latini R. Pharmacology of platelet inhibition in humans: implications of the salicylate-aspirin interaction. Circulation. 1985 Dec;72(6):1185–1193. doi: 10.1161/01.cir.72.6.1185. [DOI] [PubMed] [Google Scholar]

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