Dihydroorotate dehydrogenase is a mitochondrial enzyme which catalyses the conversion of dihydroorotate into orotate, step necessary for the biosynthesis of uridine monophosphate (UMP).
Leflunomide (Arava*), by opening isoxazole ring, is converted into an active metabolite which inhibits dihydrofolate dehydrogenase and the synthesis of UMP. Deficiency in UMP activates the P53 protein expression which leads to the discontinuation of cell division. Leflunomide particularly affects the activated lymphocytes and little the quiescent lymphocytes. In vitro the activity of leflunomide is reversed by the supply of uridine. The elimination of the main active metabolite of leflunomide is slow, its half-life being about 2 weeks; thus it remains present in the body a long time after the discontinuation of its administration and can be at the origin of drug interactions. It is indicated for the treatment of rheumatoid arthritis and psoriatic arthritis. Among its many adverse effects, one can underline its hepatic toxicity.