Effect of experimental renal failure on sulfate retention and acetaminophen pharmacokinetics in rats

The investigation was designed to determine the effect of experimental renal failure on the retention of free (inorganic) sulfate and on the pharmacokinetics of acetaminophen in rats. Adult male Sprague-Dawley rats with renal failure produced by uranyl nitrate treatment or ligation of ureters had much higher serum free sulfate concentrations (about 2 and 5 mM, respectively) than normal animals (about 1 mM). The time-averaged total clearance of a 100-mg/kg dose of acetaminophen was higher in animals with renal failure than in normal rats and was positively correlated with serum free sulfate concentration (r = 0.76, P less than .001). Renal failure had no effect on the total clearance of a 15-mg/kg dose of acetaminophen, apparently because free sulfate was not appreciably depleted by this small dose. A 6-hr infusion of acetaminophen, at 36 mg/kg/hr, produced steady-state plasma concentrations of about 20 micrograms/ml within 2 hr in renal failure (ureter-ligated) animals, whereas in normal animals the plasma concentrations increased continuously to about 100 micrograms/ml at 6 hr. Free sulfate concentrations in serum at the end of the infusion were about 0.2 mM in normal animals and generally greater than 1 mM in the renal failure animals. The rats with renal failure converted most of the administered dose to acetaminophen sulfate, whereas normal animals metabolized much of the drug to acetaminophen glucuronide. These observations demonstrate the important effect of the endogenous free sulfate level in the body on the elimination kinetics and metabolic fate of a drug that is subject to conjugation with sulfate.