Aspirin Kinetics and Inhibition of Platelet Thromboxane Generation-Relevance for a Solution of the “Aspirin Dilemma”

Summary

Six healthy male volunteers received aspirin (ASA) in a compressed (320 mg) and an enteric-coated (800 mg) formulation as single oral doses ten days apart. Ten plasma samples were obtained from each volunteer between 5 and 120 min after compressed ASA, and seven between 10 and 240 min after enteric-coated ASA.

ASA was undetectable (less than 100 ng/ml) in plasma from three subjects receiving compressed ASA and two receiving the enteric-coated preparation. Plasma levels and kinetic parameters of salicylate were the same in subjects with undetectable and detectable ASA plasma levels.

More than 98% inhibition of pre-drug serum TXB₂ was noted in all samples collected one and four hours after either ASA preparation. TXB₂ generation recovered on average by 3.5% at 24 hr with both preparations.

Thus inhibition of platelet TXB₂ generation occurred independently of the amount of ASA reaching the peripheral circulation.

If this is due to inhibition of platelet function in the enterohepatic circulation followed by extensive first-pass deacetylation of ASA, vascular PGI₂ synthesis could be spared.

A better knowledge of the kinetic parameters of ASA for each of the formulations used in thrombosis prevention trials might help in solving the “aspirin dilemma”.

Keywords

Aspirin - Thromboxane - Pharmacokinetic

• References

• 1 de Gaetano G, Cerletti C, Bertelé V. Pharmacology of antiplatelet drugs and clinical trials on thrombosis prevention: A difficult link. Lancet 1982; 2: 974-977
• 2 Majerus PW. Arachidonate metabolism in vascular disorders. J Clin Invest 1983; 72: 1521-1525
• 3 Marcus AJ. Aspirin as an antithrombotic medication. N Engl J Med 1983; 309: 1515-1517
• 4 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 (in press)
• 5 Patrignani P, Filabozzi P, Patrono C. Selective cumulative inhibition of platelet thromboxane production by low-dose aspirin in healthy subjects. J Clin Invest 1982; 69: 1366-1372
• 6 Peng GW, Gadalla MA, Smith V, Peng A, Chiou WL. Simple and rapid high-pressure liquid chromatographic simultaneous determination of aspirin, salicylic acid, and salicyluric acid in plasma. J Pharm Sci 1978; 67: 710-712
• 7 Bonati M, Castelli D, Latini R, Garattini S. Comparison of gas-liquid chromatography with nitrogen-phosphorus selective detection and high-performance liquid chromatography methods for caffeine determination in plasma and tissues. J Chromatogr 1979; 164: 109-113
• 8 Sacchi Landriani G, Guardabasso V, Rocchetti M. NL-FIT: A microcomputer program for non-linear fitting. Comput Programs Biomed 1983; 16: 35-42
• 9 Ingerman-Wojenski C, Silver MJ, Smith JB, Macarak E. Bovine endothelial cells in culture produce thromboxane as well as prostacyclin. J Clin Invest 1981; 67: 1292-1296
• 10 Ali M, McDonald JW, Thiessen JJ, Coates PE. Plasma acetylsalicylate and salicylate and platelet cyclo-oxygenase activity following plain and enteric-coated aspirin. Stroke 1980; 11: 9-13
• 11 Brantmark B, Wahlin-Boll E, Melander A. Bioavailability of acetyl- salicylic acid and salicylic acid from rapid- and slow-release formulations, and in combination with dipyridamol. Eur J Clin Pharmacol 1982; 22: 309-314
• 12 Ross-Lee LM, Elms MJ, Cham BE, Bochner F, Bunce IH, Eadie MJ. Plasma levels of aspirin following effervescent and enteric coated tablets, and their effect on platelet function. Eur J Clin Pharmacol 1982; 23: 545-551
• 13 Siebert DJ, Bochner F, Imhoff DM, Watts S, Lloyd JV, Field J, Gabb BW. Aspirin kinetics and platelet aggregation in man. Clin Pharmacol Ther 1983; 33: 367-374
• 14 Rowland M, Riegelman S, Harris PA, Sholkoff SD. Absorption kinetics of aspirin in man following oral administration of an aqueous solution. J Pharm Sci 1972; 61: 379-385
• 15 Masotti G, Galanti G, Poggesi L, Abbate R, Neri Serneri G. Differential inhibition of prostacyclin production and platelet aggregation by aspirin. Lancet 1979; 2: 1213-1216
• 16 Weksler BB, Pett SB, Alonso D, Richter RC, Stelzer P, Subramanian V, Tack-Goldman K, Gay Jr WA. Differential inhibition by aspirin of vascular and platelet prostaglandin synthesis in atherosclerotic patients. N Engl J Med 1983; 308: 800-805
• 17 Fitgerald GA, Brash AR, Oates JA, Pedersen AK. Endogenous prostacyclin biosynthesis and platelet function during selective inhibition of thromboxane synthase in man. J Clin Invest 1983; 72: 1336-1347
• 18 Bertelé V, Falanga A, Tomasiak M, Dejana E, Cerletti C, de GaetanoG. Platelet thromboxane synthetase inhibitors with low doses of aspirin: Possible resolution of the “aspirin dilemma”. Science 1983; 220: 517-519
• 19 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; 68: 1108-1112
• 20 Cerletti C, Bonati M, Del Maschio A, Galletti F, Dejana E, Tognoni G, de Gaetano G. Plasma levels of salicylate and aspirin in healthy subjects: Relevance to drug interaction on platelet function. J Lab Clin Med, 1984; 103: 869-877
• 21 O’Brien JR. Effect of anti-inflammatory agents on platelets. Lancet 1968; 1: 894-895
• 22 Kocsis JJ, Hemandovich J, Silver MJ, Smith JB, Ingerman C. Duration of inhibition of platelet prostaglandin formation and aggregation by ingested aspirin or indomethacin. Prostaglandins 1973; 3: 141-144
• 23 Burch JW, Stanford N, Majerus PW. Inhibition of platelet prostaglandin synthetase by oral aspirin. J Clin Invest 1978; 61: 314-319
• 24 Catalano PM, Smith JB, Murphy S. Platelet recovery from aspirin inhibition in vivo; differing patterns under various assay conditions. Blood 1981; 57: 99-105
• 25 Rao GH R, Johnson GJ, White JG. Influence of epinephrine on the aggregation response of aspirin-treated platelets. Prostaglandins Med 1980; 5: 45-58
• 26 Di MinnoG, Silver MJ, Murphy S. Monitoring the entry of new platelets into the circulation after ingestion of aspirin. Blood 1983; 61: 1081-1085
• 27 Dejana E, Barbieri B, Cerletti C, Livio M, de Gaetano G. Impaired thromboxane production by newly formed platelets after aspirin administration to thrombocytopenic rats. Br J Haematol 1980; 46: 465-469
• 28 Cerskus AL, Ali M, Davies BJ, McDonald JW D. Possible significance of small numbers of functional platelets in a population of aspirin-treated platelets in vitro and in vivo. Thromb Res 1980; 18: 389-397
• 29 Pedersen AK, FitzGerald GA. Dose-related kinetics of aspirin. Presystemic acetylation of platelet cyclo-oxygenase N Engl J Med 1984; 311: 1206-1211