EFFECT OF LEFLUNOMIDE ON CONSTITUTIVE AND INDUCIBLE PATHWAYS OF CELLULAR EICOSANOID GENERATION

Leflunomide exerts its effects primarily via the immunomodulating and antiphlogistic activities of its major metabolite A 77 1726. Our inves tigation in several eicosanoid forming systems revealed that in human white blood cells the metabolite did not cause any alteration on Ca-io nophore stimulated metabolism of membrane bound arachidonic acid to ci s-, trans- and epi-LTB(4). Thus, the involved enzyme systems phospholi pase Az, 5-lipoxygenase and LTA(4)-hydrolase can be ruled out as a tar get of the drug. However, in several cellular systems the drug weakly inhibited the generation of 5-HETE and LTB(4) from exogenous arachidon ic acid, possibly by interfering with the exogenous substrate's access to the 5-lipoxygenase. In order to get information about the cyclooxy genase (COX-2) which is inducible in human PMNL by inflammatory mediat ors via de novo protein biosynthesis, we activated the cells with LPS for 18 h. A 77 1726 and indomethacin had no influence on the enzyme ac tivity of the newly induced COX-2. However, both drugs in low concentr ations were able to blunt the long term activation process resulting i n PGE(2) generation. In contrast, the prostaglandins generated by cons titutive enzymes (COX-1) are probably involved in maintaining vital fu nctions, and their inhibition by indomethacin and other nonsteroidal a ntiinffammatory drugs (NSAIDs) account for numerous adverse effects, f or instance gastric erosion. Our study revealed that leflunomide and A 77 1726 are not to be regarded as COX-1-inhibitors, and thus cannot b e associated with the typical adverse effects of the NSAIDs.