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Teratogen Update: Reproductive Risks of Leflunomide (Arava™); a Pyrimidine Synthesis - page 5 / 21





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in vivo. Leflunomide has demonstrated prophylactic and therapeutic effects in animal models of autoimmune disease. In preclinical models of chronic graft versus host disease (GvHD) and solid organ graft rejection, it has prolonged the time to rejection and/or reversed ongoing rejection. In addition, leflunomide has exhibited mild antiinflammatory and weak analgesic and antipyretic activity. In a model of experimental septicemia, leflunomide did not alter the resistance of mice to bacterial pathogens.

In vitro, after mitogen stimulation, the active metabolite of leflunomide, inhibits T cell proliferation, DNA synthesis, and expression of certain cell surface and nuclear antigens directly involved in T cell activation and proliferation. It inhibits mitogen-stimulated proliferation of human peripheral blood mononuclear cells (PBMCs) and proliferation in transformed murine and human cell lines, in a dose-dependent fashion. This antiproliferative activity is reversed by the addition of uridine to the cell culture, indicating that the active metabolite acts at the level of de novo pyrimidine biosynthesis. Leflunomide inhibition of GvHD (graft versus host disease) in vivo is also reversed by feeding uridine, further indicating that the active metabolite acts at the level of the de novo pyrimidine biosynthesis pathway.

It has been demonstrated that the active metabolite binds to, and is a potent inhibitor of, dihydroorotate dehydrogenase (DHODH), an enzyme in the de novo pyrimidine synthesis pathway important for DNA synthesis.  In vitro, incubation of PHA/IL-2 stimulated human peripheral T cells with the active metabolite of leflunomide, triggered cell cycle arrest at the G1 phase or, in those cells undergoing DNA synthesis, at the S phase.

Together, these data suggest that, in vivo at concentrations achievable in patients, leflunomide inhibits de novo pyrimidine synthesis in activated lymphocytes and other rapidly dividing cell populations resulting in reversible cell cycle arrest.

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