The timing of AMD and LPS dosing in this model was important for the development of severe liver damage. A minimal interval of 16 h was required for AMD and LPS to interact to induce liver injury. When LPS was injected within 16 h after AMD, no liver injury was observed. Absorption, distribution, metabolism, and clearance as well as toxicological actions could contribute to this timing requirement. The elimination of AMD is primarily through hepatic metabolism and biliary excretion, and its half-life in plasma is very long (55 days in humans) (Pollak et al., 2000) . Accordingly, the loss of AMD due to elimination within 16 h is minimal. AMD has a dose-dependent effect on the respiratory chain and b-oxidation in the mitochondria (Fromenty et al., 1990a, b) , and it can also affect the function of lysosomes and other acidic organelles (Stadler et al., 2008) . The 16-h interval may be required for AMD to distribute into the liver, accumulate in organelles, and sensitize hepatocytes to interact with LPS or its downstream cytokines.