There is evidence that the interaction between LPS-induced cytokines and drugs or their metabolites plays an important role in the LPS-drug interaction (Zou et al., 2009a) . Tumor necrosis factor-alpha (TNF) is a proximal mediator of the inflammatory cascade induced by LPS (Beutler and Kruys, 1995) and is critically involved in many models of liver injury, such as ischemia/reperfusion (Teoh et al., 2004) , alcoholic liver disease (Yin et al., 1999) and some drug/LPS-induced liver injury models (Shaw et al., 2009b; Tukov et al., 2007; Zou et al., 2009a) . As an example, TNF selectively augmented the cytotoxicity of sulindac sulfide, which is the major toxic metabolite of sulindac (Zou et al., 2009a) . In the case of amiodarone, the major metabolite of AMD is mono-N-desethylamiodarone (DEA), which shares similar pharmacological (Talajic et al., 1987) and pharmacokinetic (Shayeganpour et al., 2008) characteristics with AMD. DEA has antiarrhythmic properties, a very long half-life, and accumulates in the liver and many other tissues. In primary hepatocytes, HepG2 cells and other cell types, DEA is much more cytotoxic than AMD (Waldhauser et al., 2006) . The plasma concentration of DEA is greater in cases of AMD-associated IADRs (O'Sullivan et al., 1995) , suggesting a possible role for this metabolite in AMD toxicity.