CONCOMITANT ETODOLAC AFFECTS NEITHER THE UNBOUND CLEARANCE NOR THE PHARMACOLOGICAL EFFECT OF WARFARIN

Potential interactions between the nonsteroidal anti-inflammatory etod olac and the anticoagulant warfarin were studied in 18 healthy subject s by use of a randomized, three-period crossover design. Each treatmen t lasted 2 1/2 days and consisted of warfarin, etodolac, or both drugs . Prothrombin time was determined daily during each warfarin period to measure pharmacologic effect. Total serum concentration and unbound f raction of both drugs were determined over the dose interval after the last dose of the study drug(s). Concomitant etodolac did not affect t he prothrombin time response or the unbound clearance of warfarin. Dur ing concomitant etodolac administration, the median peak concentration of total warfarin was significantly decreased by 19% (p = 0.005), med ian total clearance was significantly increased by 13% (p = 0.0123), a nd the unbound fraction tended to increase (median unbound fraction of warfarin, 1.245% with etodolac and 1.045% without etodolac; p = 0.097 9; not statistically significant). These observations suggest a small displacement of warfarin from serum protein by etodolac or a metabolit e of etodolac. No etodolac pharmacokinetic parameter was significantly affected by concomitant warfarin administration. Thus etodolac does n ot appear to alter the unbound clearance of warfarin or augment its ph armacologic effect. Nevertheless, it is prudent that clinical monitori ng be done for individuals taking these two compounds concomitantly.