Pathways of disposition of acetaminophen conjugates in the mouse

After a single dose of [14C]acetaminophen (50 mg/kg) was administered orally to bile duct cannulated mice, 13.9% of the radioactivity was recovered in the bile while 41.2% was found in the urine in the first 3 h after administration. Analyses of biles revealed that the major biliary metabolite was acetaminophen glutathione (AG) conjugate which was derived from the hepatotoxic acetaminophen intermediate. Examination of urines showed that they contained mostly glucuronide and sulfate conjugates with no AG or its degradation products (cysteine and mercapturate). Analysis of urines collected from non-cannulated animals at 4 h showed that they contained glucuronide, sulfate, cysteine and mercapturate metabolites. Our results suggest that after formation in the liver, the majority of the glucuronide and sulfate conjugates were directly eliminated by the kidney. On the other hand, the pathway for the disposition of the glutathione conjugate was first into the bile, then reabsorption, and finally disposition into the urine as cysteine and mercapturate metabolites.