Nimesulide and hepatic adverse effects: roles of reactive metabolites and host factors

Nimesulide, similar to other nonsteroidal anti-inflammatory drugs (NSAIDs), has been associated with rare and unpredictable but serious hepatic adverse reactions. The low incidence (about 0.1 case per 100,000 treated patients, no more than with most other NSAIDs), estimated from the total number of reported cases relative to the unit sales, plus the fact that the time to onset of liver reactions varied from several days to almost 1 year, suggest that the rare cases of liver injury may be caused by a metabolic idiosyncrasy. This implies that multiple individual host factors affect the toxic potential of nimesulide and/or its metabolites. At the molecular level, reductive bioactivation of the aromatic nitro group might cause oxidoreductive stress and induce covalent binding of, reactive intermediates to proteins. Nimesulide can cause toxicity to mitochondria in vitro, although it is unlikely that the high concentrations required are therapeutically relevant. The mitochondrial toxicity at these supratherapeutic concentrations of nimesulide is characterised by uncoupling of oxidative phosphorylation and opening of the membrane permeability transition pore. Because severe hepatic damage is very rare, and because normally reactive metabolites are readily inactivated or their deleterious effects antagonised, perhaps genetically or environmentally determined alterations in these pathways account for the rare individual susceptibility.