Redox-silent vitamin E analogues, represented by alpha-tocopheryl succinate, are potent anti-cancer drugs with potential secondary bioactivity due to their processing in vivo. Here we verified the hypothesis that hepatic processing of these agents determines the secondary effect. Mice were repeatedly injected with alpha-tocopheryl succinate, and their systemic and hepatic vein blood was assessed for alpha-tocopheryl succinate and its hydrolysis product, vitamin E (alpha-tocopherol). While levels of alpha-tocopherol doubled compared to control mice and alpha-tocopheryl succinate accumulated in the systemic blood, no alpha-tocopheryl succinate was detected in blood draining the liver. We conclude that hepatic processing endows compounds like alpha-tocopheryl succinate with a secondary, anti-oxidant/anti-inflammatory activity due to converting it to the redox-active alpha-tocopherol. Our finding epitomises a novel, general paradigm, according to which a drug can be converted in the liver into a product that has a different beneficial bioactivity. (C) 2004 Elsevier Inc. All rights reserved.