| Indication |
For the management of the signs and symptoms of active rheumatoid
arthritis (RA) to improve physical function and to slow the progression
of structural damage associated with the disease. Has also been used for
the prevention of acute and chronic rejection in recipients of solid
organ trasnplants and is designated by the FDA as an orphan drug for
this use. |
| Pharmacodynamics |
Leflunomide is a pyrimidine synthesis inhibitor indicated in
adults for the treatment of active rheumatoid arthritis (RA). RA is an
auto-immune disease characterized by high T-cell activity. T cells have
two pathways to synthesize pyrimidines: the salvage pathways and the de
novo synthesis. At rest, T lymphocytes meet their metabolic requirements
by the salvage pathway. Activated lymphocytes need to expand their
pyrimidine pool 7- to 8-fold, while the purine pool is expanded only 2-
to 3-fold. To meet the need for more pyrimidines, activated T cells use
the de novo pathway for pyrimidine synthesis. Therefore, activated T
cells, which are dependent on de novo pyrimidine synthesis, will be more
affected by leflunomide's inhibition of dihydroorotate dehydrogenase
than other cell types that use the salvage pathway of pyrimidine
synthesis. |
| Mechanism of action |
Leflunomide is a prodrug that is rapidly and almost completely
metabolized following oral administration to its pharmacologically
active metabolite, A77 1726. This metabolite is responsible for
essentially all of the drug's activity in-vivo. The mechanism of action
of leflunomide has not been fully determined, but appears to primarily
involve regulation of autoimmune lymphocytes. It has been suggested that
leflunomide exerts its immunomodulating effects by preventing the
expansion of activated autoimmune lymphocytes via interferences with
cell cycle progression. In-vitro data indicates that leflunomide
interferes with cell cycle progression by inhibiting dihydroorotate
dehydrogenase (a mitochondrial enzyme involved in de novo pyrimidine
ribonucleotide uridine monophosphate (rUMP)synthesis) and has
antiproliferative activity. Human dihydroorotate dehydrogenase consists
of 2 domains: an α/β-barrel domain containing the active site and an
α-helical domain that forms a tunnel leading to the active site. A77
1726 binds to the hydrophobic tunnel at a site near the flavin
mononucleotide. Inhibition of dihydroorotate dehydrogenase by A77 1726
prevents production of rUMP by the de novo pathway; such inhibition
leads to decreased rUMP levels, decreased DNA and RNA synthesis,
inhibition of cell proliferation, and G1 cell cycle arrest. It is
through this action that leflunomide inhibits autoimmune T-cell
proliferation and production of autoantibodies by B cells. Since salvage
pathways are expected to sustain cells arrested in the G1 phase, the
activity of leflunomide is cytostatic rather than cytotoxic. Other
effects that result from reduced rUMP levels include interference with
adhesion of activated lymphocytes to the synovial vascular endothelial
cells, and increased synthesis of immunosuppressive cytokines such as
transforming growth factor-β (TGF-β). Leflunomide is also a tyrosine
kinase inhibitor. Tyrosine kinases activate signalling pathways leading
to DNA repair, apoptosis and cell proliferation. Inhibition of tyrosine
kinases can help to treating cancer by preventing repair of tumor cells.
|
| Absorption |
Well absorbed, peak plasma concentrations appear 6-12 hours after dosing |
| Volume of distribution |
|
| Protein binding |
>99.3% |
| Metabolism |
Primarily hepatic. Leflunomide is converted to its active form following oral intake. |
| Route of elimination |
The active metabolite is eliminated by further metabolism and
subsequent renal excretion as well as by direct biliary excretion. In a
28 day study of drug elimination (n=3) using a single dose of
radiolabeled compound, approximately 43% of the total radioactivity was
eliminated in the urine and 48% was eliminated in the feces. It is not
known whether leflunomide is excreted in human milk.
Many drugs are excreted in human milk, and there is a potential for
serious adverse reactions in nursing infants from leflunomide. |
| Half life |
2 weeks |
| Clearance |
Not Available |
| Toxicity |
LD50=100-250 mg/kg (acute oral toxicity) |
