PLATELETS AND VASCULAR OCCLUSION Clinical pharmacology of platelet cyclooxygenase inhibition

Nonsteroidal anti-inflammatory drugs and sulfinpyrazone compete dose-dependently with arachidonate for binding to platelet cyclooxygenase. Such a process closely follows systemic plasma drug concentrations and is reversible as a function of drug elimination. Peak inhibition and extent of its reversibility at 24 hr varies consistently with individual pharmacokinetic profile. Inhibition of platelet cyclooxygenase activity by these agents is associated with variable effects on prostaglandin (PG) synthesis in the gastric mucosa and the kidney. Aspirin acetylates platelet cyclooxygenase and permanently inhibits thromboxane (TX) A2 production in a dose-dependent fashion when single doses of 0. 1 to 2.0 mg/kg are given. Acetylation of the enzyme by low-dose aspirin is cumulative on repeated dosing. The fractional dose of aspirin necessary to achieve a given level of acetylation by virtue of cumulative effects approximately equals the fractional daily platelet turnover. Serum TXB2 measurements obtained during long-term dosing with 0.11, 0.22, and 0.44 mg/kg aspirin in four healthy subjects could be fitted by a theoretical model assuming identical acetylation of platelet (irreversible) and megakaryocyte (reversible) cyclooxygenase. For a given dose within this range, both the rate at which cumulative acetylation occurs and its maximal extent largely depend upon the rate of platelet turnover. Continuous administration of low-dose aspirin (20 to 40 mg/day) has no statistically significant effect on urinary excretion of either 6-keto-PGFl,a or 2,3-dinor-6-keto-PGF ,t, i.e., indexes of renal and extrarenal PGI2 biosynthesis in vivo. Whether a selective sparing of extraplatelet cyclooxygenase activity by low-dose aspirin will result in increased antithrombotic efficacy, fewer toxic reactions, or both remains to be established in prospective clinical trials. Circulation 72, No. 6, 1177-1184, 1985. PLATELET CYCLOOXYGENASE or prostaglandin (PG) H synthase (i.e., the enzyme that converts arachidonate released from membrane phospholipids into PG endoperoxides) is the target of several antiplatelet agents that can reversibly or irreversibly block the activity of the enzyme by competing with the substrate or permanently altering the active site, respectively.' Such drugs belong to the class of so-called nonsteroidal anti-inflammatory agents (e.g., indomethacin, aspirin), but also include a uricosuric agent, i.e., sulfinpyrazone. This article will review the available information on platelet cyclooxygenase inhibition, as derived from human studies in health and disease, and present novel findings related to the mechanism of and variables affecting cumulative inhibition of the enzyme by low-dose aspirin. From the Department of Pharmacology, Catholic University School of Medicine, Rome. Supported by grants from Consiglio Nazionale delle Ricerche (82.00389.96 and 83.02535.04) and Ministero della Pubblica Istruzione (60/82, 60/83). Address for correspondence: Dr. Carlo Patrono, Department of Pharmacology, Catholic University School of Medicine, Largo Francesco Vito 1, 00168 Rome, Italy. Vol. 72, No. 6, December 1985 Assessment of human platelet cyclooxygenase activity. Platelet PGH synthase levels can be determined with an immunoradiometric assay.2 However, PGH synthase immunoreactivity is not influenced by inactivation of the enzyme with aspirin.2 Similarly, a dissociation between platelet PGH synthase concentration and activity has been shown in uremic patients.3 Also, the enzyme can be measured by its ability to interact selectively with (acetyl-3H) aspirin and undergo a site-specific acetylation reaction, giving rise to (acetyl-3H) PGH synthase.4 Inactivation of platelet cyclooxygenase by aspirin in vivo can be measured as a reduction in the ability of (acetyl-3H) aspirin to acetylate the enzyme in washed platelets in vitro.5 In the vast majority of studies assessing pharmacologic inhibition of platelet cyclooxygenase enzyme activity was measured ex vivo by quantitative analysis of the main product(s). These analyses may include measurement of (1) thromboxane (TX) A2-like biological activity released by exogenous arachidonate in platelet-rich plasma (PRP),6 (2) malondialdehyde (MDA) production in PRP stimulated with N-ethyl-malei1177 by gest on A ril 9, 2017 http://ciajournals.org/ D ow nladed from