LEFLUNOMIDE
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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