Glucuronidation and biliary excretion of acetaminophen in rats

Dose-dependent acetaminophen pharmacokinetics is thought to be due to saturation of sulfation and glucuronidation, although its glucuronidation has not been thoroughly examined. Because many drug-glucuronides are extensively excreted into bile, the excretion of acetaminophen metabolites in bile was examined in urethane-anesthetized rats which received 37.5, 75, 150, 300 or 600 mg/kg of acetaminophen i.v. Disappearance of acetaminophen from plasma exhibited clear dose-dependency as determined by prolongation of T 1/2 and decreases in total body clearance at 150 mg/kg or higher. Biliary excretion of the various metabolites of acetaminophen increased from 20 to 49% as the dosage was increased from 37.5 to 600 mg/kg. The glucuronide conjugate was the major form of acetaminophen in bile at all dosages. Biliary excretion of the glucuronide conjugate increased from 10.5 to 40.2% of the recovered dose as the amount administered was increased to 600 mg/kg, whereas urinary excretion of the glucuronide conjugate remained relatively constant at approximately 20% of that recovered. Although the fraction of acetaminophen excreted as the glucuronide conjugate increased to over 70% of that recovered at the highest dose, a significant decline in the rate constant for glucuronide formation was noted at 300 mg/kg and higher. Likewise, the rate for glutathione conjugation was also lower at 300 mg/kg, whereas the formation of the sulfate conjugate was decreased at lower dosages (75 mg/kg). The results of the present study show that glucuronidation is a high-capacity, high-dose saturable pathway of acetaminophen biotransformation whose product is preferentially eliminated in bile after high dosages.(ABSTRACT TRUNCATED AT 250 WORDS)