INTRODUCTION
LEF (5-methyl-N-[4-Triflueromethylphenyl]-5-methylisoxazole- 4-carboxamide) is an immuno-modulatory agent which belongs to the DMARD (Disease Modifying Anti-rheumatic Drug) class of drugs.1-4 LEF is converted to its primary metabolite “teriflunomideâ€, which inhibits dihydro-orotate dehydrogenase (DHODH).1 DHODH is an essential mitochondrial enzyme in the de- novo pyrimidine biosynthesis pathway.1,5,6 With DHODH inhibition there is accumulation of pyrimidine precursors inhibiting T and B cell proliferation with induction of apoptosis.1,3,5 The DHODH inhibitory effects of teriflunomide are completely rescued by supplementation with exogenous uridine leading to generation of uridine monophosphate (UMP) by uridine kinase.4
The oral bioavailability of LEF is 80-90% and is highly protein bound.1,5 Teriflunomide undergoes enterohepatic circulation and biliary recycling, which contributes to its long half-life of greater than two weeks with predominantly renal excretion.1,5 Although hepatoxicity is rare, LEF does have a black box warning for potential hepatotoxicity.6
LEF is a teratogen, and contraception for both men and women is recommended.1,4-8 The inhibition of DHODH is felt to be responsible for the teratogenicity of LEF, and in animal models supplementation with exogenous uridine is protective.6 In women considering pregnancy, rapid elimination of LEF with cholestryramine 8 grams three times daily or 50 grams of activated charcoal for 11 days can be done.5 This is followed by two separate measurements showing plasma concentrations below 0.02 μg/ml.5 There has not been shown to be a substantial increased risk of adverse pregnancy outcomes due to LEF exposure among women who undergo cholestyramine elimination procedure early in pregnancy.5
In addition to its inhibition of DHODH, additional molecular targets of teriflunomide include a number tyrosine kinases, and this effect is not rescued by uridine.1-4 LEF is currently administered orally with a loading dose of 100 mg tablets X 3 day for rheumatoid arthritis, usually followed by 20 mg daily.1-4 The main toxicity of LEF below 25mg daily are diarrhea, dyspepsia, abdominal pain, nausea, and oral ulcerations.1-4 Weight loss is also report, as well as reversible alopecia and hypetension.4 In approximately 2-4% patients with initially normal liver functions, an increase transaminase is seen within 6 months, but with discontinuation of LEF this normalizes.9 Significant liver necrosis in individuals with evidence of liver compromise prior to therapy has been reported, and LEF is contraindicated in patients with abnormal liver functions, hepatitis, and/or heavy alcohol intake.4,6,8,9 Rarely interstitial and hypersensitivity pneumonitis, neuropathy, and delayed wound healing have been reported.8-12 Increased infections usually occur only when this LEF is used in combination with other immunosuppressive medications.1,3,8,9
There is one common missense mutation in the DHODH gene that appears to affect response to LEF therapy, however, it may
