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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

Altered hepatobiliary disposition of acetaminophen metabolites after phenobarbital pretreatment and renal ligation: evidence for impaired biliary excretion and a diffusional barrier.

The effects of phenobarbital (Pb)-pretreatment and bilateral renal ligation on the disposition of acetaminophen, acetaminophen glucuronide (AG) and acetaminophen sulfate (AS) were examined in serum, bile and urine of rats. Pb-pretreatment significantly decreased the percentage of the acetaminophen dose (100 mg/kg) excreted in bile as the glucuronide and sulfate conjugates in rats with intact kidneys [AG (0.94% vs. 6.49%); AS (1.41% vs. 4.19%)] and in renal-ligated rats [AG (2.22% vs. 7.71%); AS (6.12% vs. 9.13%)], compared to vehicle-pretreated controls. Decreased biliary recovery of AG occurred despite a Pb-induced increase in the fraction of the acetaminophen dose converted to AG. Similarly, biliary recovery of AS was reduced further than expected based on Pb-associated decreases in the fraction of the acetaminophen dose converted to AS. These observations suggest that the hepatobiliary disposition of AG and AS was altered at multiple sites due to 1) direct interactions with Pb (or a Pb metabolite) and/or 2) metabolic induction by Pb. Renal ligation shifted the metabolic pathway toward sulfation, with a subsequent increase in biliary recovery of AS. However, renal ligation did not alter the percentage of the dose excreted as AG in bile despite a marked elevation in AG serum concentrations. Furthermore, biliary excretion rate vs. time profiles of AG and AS in renal-ligated rats exhibited a terminal half-life exceeding that of acetaminophen in serum. These data provide evidence that diffusional barriers between blood and hepatocytes influence the hepatic disposition and routes of elimination of polar metabolites such as AG and AS.[1]


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