Abstract
Background and aims : Therapy with NSAIDs may interfere with antiplatelet activity of aspirin. The mechanism of this drug-drug interaction has not yet been established on the level of enzyme kinetics and quantitative structure-activity relationship (QSAR). Methods: Time-dependent kinetics (log K) for the onset of COX-1 inhibition was measured for 17 common NSAIDs using arachidonic acid-induced COX-1 activity (human platelet microsomes, bioluminescence). IC50 values of all NSAIDs were determined by arachidonic acid-induced platelet thromboxane (TX) formation in platelet rich plasma, as well as the in vitro interaction with aspirin. Dragon and SYSTAT softwares served to develop QSAR models in which dependent parameters were log K and IC50 and independent parameters were structural/physico-chemical parameters (MoR32m, G2v, L3S, representing the shape, size and polarizibility). Results: All NSAIDs could be classified into a time-dependent (slow onset) or a time-independent (fast onset) mode of inhibition. Time-dependent NSAIDs included diclofenac, flurbiprofen, indomethacin, ketoprofen and ketorolac. These NSAIDs did not decrease TX inhibition by aspirin. In contrast, all other studied NSAIDs were time-independent inhibitors and prevented inhibiton by aspirin. The inhibition kinetics (log K) and IC50 were correlated with MoR32m, G2v and L3S (equations 1 and 2). eq.1: -log IC50 = 4.54 (±0.99) MoR32m - 64.62 (±12.58) G2v + 3.41 (±0.56) L3S + 8.59; r = 0.91; r2 = 0.84; s = 0.41; F = 22.81; PRESS = 5.00. eq.2: -log K = 2.35 (±0.69) MoR32m - 16.50 (±8.68) G2v + 1.18 (±0.39) L3S + 1.61; r = 0.74; r2 = 0.55; s = 0.29; F = 5.49, PRESS= 3.01; r, correlation coefficient; s, standard deviation; F, Fisher’s test; PRESS, sum of square differences. Conclusions: NSAIDs decrease the antiplatelet activity of aspirin. This is highly dependent on the inhibition kinetics of platelet COX-1, whereas the inhibition kinetics and IC50 values for TX inhibition further depends on MoR32m, G2v and L3S of a particular NSAID. Time-independent NSAIDs decrease the anti-platelet activity of aspirin. Therefore, time-dependent NSAIDs should be preferred in patients on antiplatelet treatment with aspirin. The QSAR models may predict the kinetics and enzyme inhibition by NSAIDs.
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