Acetaminophen sulfation deficit in obese rats overfed an energy-dense cafeteria diet

The current studies examine acetaminophen pharmacokinetics and biotransformation in obese animals for possible shifts in metabolic conjugation reactions. Obesity was produced in Sprague-Dawley rats with an energy-dense cafeteria feeding regimen. Acetaminophen half-life remained unchanged and apparent volume of distribution increased slightly in obese versus pellet-fed control rats following an ip dose of 287 mg/kg. However, obese animals exhibited lower plasma concentrations of acetaminophen sulfate and excreted less sulfate conjugate but more glucuronide conjugate in urine. Absolute clearance of acetaminophen from plasma was similar for both groups of rats but formation clearance of acetaminophen sulfate was lower and formation clearance of acetaminophen glucuronide and was higher than control in obese rats. Renal clearance of unchanged drug and both conjugated metabolites appeared to rise with the degree of obesity. The many parallels in acetaminophen disposition shared with the obese human show the overfed rat to be a promising model for metabolic and physiologic changes associated with human obesity.