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Leflunomide, another nonbiologic DMARD, undergoes rapid conversion, both in the intestine and in the plasma, to its active metabolite, A77-1726. This metabolite inhibits dihydroorotate dehydrogenase, leading to a decrease in ribonucleotide synthesis and the arrest of stimulated cells in the G1 phase of cell growth. Consequently, leflunomide inhibits T-cell proliferation and pro-duction of autoantibodies by B cells. Secondary effects include increases of interleukin-10 receptor mRNA, decreased interleu-kin-8 receptor type A mRNA, and decreased TNF-α-dependent nuclear factor kappa B (NF-κB) activation.
Leflunomide is completely absorbed and has a mean plasma half-life of 19 days. Its active metabolite, A77-1726, is thought to have approximately the same half-life and is subject to enterohepatic recirculation. Cholestyramine can enhance leflunomide excretion and increases total clearance by approximately 50%.
Leflunomide is as effective as methotrexate in rheumatoid arthri-tis, including inhibition of bony damage. In one study, combined treatment with methotrexate and leflunomide resulted in a 46.2% ACR20 response compared with 19.5% in patients receiving methotrexate alone.
Diarrhea occurs in approximately 25% of patients given lefluno-mide, although only about 3–5% discontinue the drug because of this side effect. Elevation in liver enzymes can occur. Both effects can be reduced by decreasing the dose of leflunomide. Other adverse effects associated with leflunomide are mild alopecia, weight gain, and increased blood pressure. Leukopenia and thrombocy-topenia occur rarely. This drug is contraindicated in pregnancy.
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