The pathogenesis of diclofenac induced immunoallergic hepatitis in a canine model of liver injury

Diclofenac is a non-steroidal anti-inflammatory drug (NSAID) commonly used for the treatment of arthritis and chronic pain associated with musculoskeletal injuries. However, its use is associated with a variety of adverse drug reaction, including rare but severe hepato- and nephrotoxicity. The molecular mechanism leading to diclofenac induced immunoallergic hepatitis is unknown. The objective of this study is to identify the molecular mechanisms involving immune mediated inflammatory reactions and its link to DILI through whole genome gene expression profiling. Beagle dogs were given 1 (LD, N=3) or 3 mg/kg/day (HD, N=3) oral diclofenac for 28 days. Control animals (N=3) received empty gelatine capsules. Clinical signs, serum biochemistry, blood smear and serum/urinary electrolytes were determined on day 1, 15 and 28. Histo- and immunopathology revealed causes of allergic hepatitis. The whole genome gene expression profiling of liver and kidney were examined to define the molecular mechanism of diclofenac induced immune mediated organ toxicity.