Interaction of Naproxen and Aspirin in the Rat and in Man

Abstract

Pharmacokinetic interactions between aspirin and other nonsteroidal anti-inflammatory agents (NSAI), particularly indomethacin, have been documented in many species, including man. Since aspirin and other NSAI's are commonly coadministered, such interactions may be clinically relevant. In fact, it has been suggested that they are responsible for the failure of many clinical trials to demonstrate that indomethacin is more effective than placebo. We have, therefore, performed a series of studies to determine if naproxen and aspirin interact and to explore the significance of such interactions. In rats administration of aspirin significantly decreases the plasma level resulting from coadministration of naproxen. This effect is dose-related, is seen regardless of the route of naproxen administration and is apparently due to an off-loading of naproxen from its binding sites on serum albumina by the salicylate. When therapeutic doses of naproxen and aspirin are coadministered to man, naproxen plasma levels are also lower than would be seen with naproxen alone but the differences are relatively small. Dissection of the kinetics of the interaction by administration of ³H naproxen shows that the decrease in plasma levels is due to the acceleration of naproxen metabolism and renal clearance by aspirin. Coadministration of the two drugs in a controlled clinical trial, however, demonstrates an additive effect. We, therefore, conclude that the metabolic interaction, although real, results in changes of such small magnitude as to be of no clinical significance.