Copper(II) interactions with nonsteroidal antiinflammatory agents. II. Anthranilic acid as a potential. OH-inactivating ligand.

It has long been established that copper complexes of inactive substances exert antiinflammatory activity and that copper complexes of nonsteroidal antiinflammatory drugs (NSAIDs) are more active than these drugs by themselves. Based on these observations, it was proposed that copper complexes of NAIDs are their active metabolites. This hypothesis was not confirmed for salicylic acid, however, as computer-aided speciation studies have shown that no copper-salicylate complex can reach significant levels in blood plasma. In view of this result, it was of interest to test with the same technique the influence on copper metabolism of an inactive substance known to be activated by copper. Anthranilic acid was chosen for this test in the present work. First, copper(II)-anthranilate interactions have been investigated by glass electrode potentiometry under physiological conditions. Given the key role of histidine as copper(II) ligand in blood plasma, copper(II)-histidine-anthranilate ternary equilibra have also been determined. Computer simulations of copper distribution have then been run relative to the two main biofluids in respect of global metabolism, i.e., gastrointestinal (g.i.) fluid and blood plasma. Like salicylic acid, anthranilic acid is expected to favor copper g.i. absorption, but cannot either exert any significant influence on plasma copper distribution. Clearly, the fact that anthranilate becomes antiinflammatory when administered with copper cannot originate in any effect of anthranilate on copper global metabolism. Speciation investigations have then been extended to the synovial fluid. Whereas salicylate does not appear to be a better ligand of copper in this medium than in blood plasma at any pH between 7.4 and 5.5, anthranilate on the contrary can mobilize increasing fractions of copper as the pH decreases, i.e., the more inflammation, the more copper is bound to anthranilate. This is in line with the recent observation that salicylate inactivates copper-induced .OH radicals through its bulk scavenging properties whereas .OH inactivation by anthranilate under the same conditions is a direct function of the copper-anthranilate binding. Anthranilate thus seems to correspond to the recently defined notion of .OH-inactivating ligand (OIL). More generally, these results provide a beginning of rationale for the antiinflammatory properties of copper complexes with substances that are active or inactive against inflammation by themselves. The extra antiinflammatory activity induced by copper on NSAIDs appears to be independent of any Cu(II)-NSAID association in vivo. On the contrary, the binding of inactive substances with copper(II) at inflammatory sites seems to be essential to their activation by copper.