MECHANISM OF ACTION OF LEFLUNOMIDE IN RHEUMATOID-ARTHRITIS

Leflunomide, a novel drug with proven efficacy in rheumatoid arthritis , is an isoxazol derivative structurally unrelated to other immunomodu latory drugs. Leflunomide is rapidly metabolized to its active form, A 77 1726. Two mechanisms of action have been identified for A77 1726: i nhibition of dihydroorotate dehydrogenase (DHODH) and inhibition of ty rosine kinases. DHODH inhibition occurs at lower concentrations of A77 1726 than that of tyrosine kinases and is currently considered the ma jor mode of action. Stimulated lymphocytes must increase ribonucleotid e levels from 8 to 16-fold before proceeding from the G(1) into the S phase. Increased levels of ribonucleotides can only be met by de novo ribonucleotide synthesis. At low levels of ribonucleotides, p53, a ''s ensor'' molecule, gets activated and prevents progression through the cell cycle. Therefore, an inhibitor of de novo uridine monophosphate s ynthesis would predictably arrest stimulated cells at the G(1) phase. In support of this mechanism of action, in vitro mitogen stimulated hu man peripheral blood lymphocytes treated with A77 1726 undergo arrest at the G(1) phase; this inhibition is reversed by uridine. (J Rheumato l 1998;25 Suppl 53:20-26).