English

Lal Lodhi

doi:10.5897/ajpp2013.3517

Abstract

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.

Highlights

Leflunomide (LEF, Figure 1) is used for the treatment of rheumatoid arthritis since 1998 and this action is mediated through inhibition of dihydroorotate dehydrogenase and tyrosine kinase enzymes (Alcorn et al, 2009; Fox 1998)
Significant differences were observed between control and 4, 8, 12, 16 h LEF treated rats
LEF is converted to A771726 via fast pass metabolism after oral administration in both rats and human

Summary

Introduction

Leflunomide (LEF, Figure 1) is used for the treatment of rheumatoid arthritis since 1998 and this action is mediated through inhibition of dihydroorotate dehydrogenase and tyrosine kinase enzymes (Alcorn et al, 2009; Fox 1998). This action is triggered through inhibition of T- and B-lymphocytes proliferation in vitro (Cutolo et al, 2009). Researcher proposed that LEF induces tumor necrosis factors-α and interleukin-1β factors during its pharmacological response (Déage et al, 1998). Cytochrome 2C9 is the key enzyme which metabolized LEF to its active form A771726 (melononitrilamide, major), 4-trifluoroaniline and other minor metabolites (Rozman, 2002). Food and Drug Administration (FDA) categorised this drug through black box warning in 2010 due to its acute liver failure in humans (FDA Drug Safety Communication, 2010).

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