Time development of distribution and toxicity following single toxic APAP doses in male BOM:NMRI mice

The time development of the biodistribution and the hepatotoxicity following peroral administration of 14C-acetaminophen (APAP 400 or 800 mg.kg-'; 1 pCi) was characterized in a trial procedure using male Bom:NMRI mice. APAP (400 mg.kg-') caused a transitory hepatic glutathione (GSH) depletion while APAP 800 mg.kg-' maximally depleted hepatic GSH throughout the 12 h trial period. A lag time between the initial GSH depletion and the ensuing hepatic necrosis was seen. From 8 h post dosing a decrease of I4C-APAP or its metabolites coincided with recovery of the hepatic GSH level and the regeneration of the hepatic cells caused by APAP 400 mg.kg-'. Hepatic glycogen depletion preceded centrilobular necrosis, and irrespective of APAP dose definite kidney damage was absent. Irrespective of APAP dose the hiodistribution of 14C-APAP or its metabolites was predominantly in organs associated with metabolism and excretion. After APAP (800 mg.kg-') significant amounts of 14C-APAP or its metabolites were present up to 24 h post dosing. The operative status of the hepatic GSH conjugative system has an important influence on the rate of elimination of toxic APAP doses. Hepatic cell necrosis with a possible effect on the circulation may play an important secondary role in the elimination of toxic APAP doses. Factors which may influence the status of the hepatic GSH conjugative system and toxicokinetics of perorally administered APAP doses are discussed.