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.