A high level of cyclooxygenase-2 inhibitor selectivity is associated with a reduced interference of platelet cyclooxygenase-1 inactivation by aspirin

Both nonsteroidal anti-inflammatory drugs, such as ibuprofen, and the proto typical selective cyclooxygenase (Cox)-2 inhibitors DuP-697 and NS-398 bloc k the inhibition of Cox-1 by aspirin in vitro. However, clinical studies ha ve shown that the Cox-2 selective drugs (or coxibs) rofecoxib and etoricoxi b, at therapeutic doses, do not interfere with the antiplatelet effect of a spirin, in contrast to ibuprofen. Here, we have evaluated the relative pote ntial of ibuprofen and various coxibs to interfere with the inactivation of Cox-1 by aspirin by using purified enzyme and calcium ionophore-activated human platelets. The irreversible inactivation of Cox-1 by aspirin can be a ntagonized by ibuprofen and coxibs, albeit with widely different potencies. The rank order of potencies for this process (ibuprofen > celecoxib > vald ecoxib > rofecoxib > etoricoxib) parallels that obtained for the inhibition of Cox-1-mediated thromboxane B-2 production by calcium ionophore-stimulat ed platelets. The antagonism of aspirin therefore likely involves a competi tion at the enzyme active site. The EC50 value for the antagonism against 1 0 muM aspirin for each drug is approximate to 10- to 40-fold lower than the corresponding IC50 value for inhibition of platelet Cox-1 activity, consis tent with the much weaker initial binding of aspirin to Cox-1 as compared w ith arachidonic acid. These results show that a low affinity for Cox-1 and a high degree of Cox-2 selectivity confers a low potential to block aspirin inhibition of platelet Cox-1, consistent with the results of clinical stud ies.