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Leflunomide
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Leflunomide (Arava) May Act By Interrupting Pyrimidine Synthesis Annals of the Rheumatic Diseases 11/20/2000 By David Loshak The primary mode of action of the new disease-modifying anti-rheumatic drug, leflunomide, may be its interruption of de novo pyrimidine synthesis. In phase II and phase III clinical trials, leflunomide has been shown to improve primary and secondary outcome measures in patients with active rheumatoid arthritis. Leflunomide has also demonstrated a satisfactory safety profile. At low, therapeutically applicable doses, the active metabolite of leflunomide, A77 1726, reversibly inhibits dihydroorotate dehydrogenase (DHODH). This is the rate limiting step in the de novo synthesis of pyrimidines. Unlike other cells, activated lymphocytes expand their pyrimidine pool by about eight times during proliferation, while purine pools are only doubled. To meet this demand, lymphocytes must use both salvage and de novo synthesis pathways. The inhibition of DHODH by A77 1726 thus prevents lymphocytes from accumulating enough pyrimidines to support DNA synthesis. At higher doses, A77 1726 inhibits tyrosine kinases responsible for early T cell and B cell signalling in the G0/G1 phase of the cell cycle. It is because the immunoregulatory effects of A77 1726 occur at doses that inhibit DHODH but not tyrosine kinases that the interruption of de novo pyrimidine synthesis may be the primary mode of action. Recent evidence suggests that the anti-inflammatory effects of A77 1726 may relate to its ability to suppress interleukin 1 and tumour necrosis factor selectively over their inhibitors in T lymphocyte/monocyte contact activation. A77 1726 has also been shown to suppress the activation of nuclear factor B, a potent mediator of inflammation when stimulated by inflammatory agents. Continuing research indicates that A77 1726 may down-regulate the glycosylation of adhesion molecules. This effectively reduces cell-cell contact activation during inflammation. |
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