Evaluation of mechanism of hepatotoxicity of leflunomide using albino wistar rats

Leflunomide (LEF) is used for the treatment of rheumatoid arthritis via inhibition of dihydroorotate dehydrogenase and tyrosine kinase enzymes. It is metabolised by cytochrome 2C9 enzyme to active form A771726 (melononitrilamide) which is responsible for both its pharmacological and toxicological responses. Food and Drug Administration (FDA) gave black box warning in 2010 due to acute liver failure in humans. While the exact mechanism of its toxicity remains unknown, it has been postulated that the formation of toxic reactive metabolites and elevation of serum transaminase level may be responsible for its toxicity. The purpose of this study is to investigate whether oxidative stress has any role in inducing hepatotoxicity of this drug. LEF was administered orally in 10 mg/kg body weight to albino wistar rats. Then, liver and blood were collected at 4, 8, 12 and 16 h intervals. Liver glutathione (GSH), oxidized lipid (malonaldehyde MDA), superoxide dismutase (SOD), catalase (CAT) and plasma alanine transaminase (ALT), aspartate transaminase (AST) levels were measured to determine the level of toxicity. GSH, CAT and SOD levels were found to be decreased with respect to control at all time points, whereas MDA level was significantly increased which signified liver cell injury after drug administration. The plasma ALT and AST levels were also increased at the same time, denoting liver tissue damage. Our result collectively indicated that oxidative stress might be responsible for LEF inducing hepatotoxicity.   Key words: Leflunomide, A771726 metabolite, hepatotoxicity, oxidative stress.