Mechanism of action of leflunomide in rheumatoid arthritis.

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Fox RI

Mechanism of action of leflunomide in rheumatoid arthritis.

J Rheumatol Suppl. 1998 Jul;53:20-6.

PubMed ID

9666414 [ View in PubMed

]

Abstract

Leflunomide, a novel drug with proven efficacy in rheumatoid arthritis, is an isoxazol derivative structurally unrelated to other immunomodulatory drugs. Leflunomide is rapidly metabolized to its active form, A77 1726. Two mechanisms of action have been identified for A77 1726: inhibition of dihydroorotate dehydrogenase (DHODH) and inhibition of tyrosine kinases. DHODH inhibition occurs at lower concentrations of A77 1726 than that of tyrosine kinases and is currently considered the major mode of action. Stimulated lymphocytes must increase ribonucleotide levels from 8 to 16-fold before proceeding from the G1 into the S phase. Increased levels of ribonucleotides can only be met by de novo ribonucleotide synthesis. At low levels of ribonucleotides, p53, a "sensor" molecule, gets activated and prevents progression through the cell cycle. Therefore, an inhibitor of de novo uridine monophosphate synthesis would predictably arrest stimulated cells at the G1 phase. In support of this mechanism of action, in vitro mitogen stimulated human peripheral blood lymphocytes treated with A77 1726 undergo arrest at the G1 phase; this inhibition is reversed by uridine.

DrugBank Data that Cites this Article

Drugs

Leflunomide

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Leflunomide	Dihydroorotate dehydrogenase (quinone), mitochondrial	Protein	Humans	Yes	Inhibitor	Details