Disposition of acetaminophen in protein-calorie malnutrition

The influence of dietary protein deficiency on the pharmacokinetics, metabolism and disposition of acetaminophen was investigated in male Sprague-Dawley rats fed for 4 weeks on a 23% (control) or a 5% (low) protein diet ad libitum. Acetaminophen and its two major metabolites, acetaminophen glucuronide and acetaminophen sulfate in plasma and urine, were determined by a sensitive and specific high-performance liquid chromatography assay. After an i.v. dose of 100 mg/kg of acetaminophen, the average mean residence time was 40% higher in the protein-deficient rats, whereas the total plasma clearance per kilogram of body weight and elimination rate constant were both decreased by approximately 36% when compared to rats on a normal protein diet. No significant differences were found in the two groups of animals with respect to the apparent steady-state volume of distribution. Rats on a low protein diet excreted a larger percentage of the administered dose as the glucuronide conjugate (34.6 vs. 12.3%) and a smaller percentage as acetaminophen sulfate (41.0 vs. 70.1%). In addition, there was a reduction in the partial metabolic clearance to acetaminophen sulfate and a concomitant 2-fold increase in the partial metabolic clearance to acetaminophen glucuronide.