An overfed rat model that reproduces acetaminophen disposition in obese humans

This disposition of acetaminophen was examined in an overfed rat model of human obesity following iv administration of a subtoxic 303 +/- 5 mg/kg dose based upon ideal body weight. Weanling Sprague-Dawley rats were maintained on a nutritionally complete semisynthetic diet containing 60% vegetable shortening and were compared to animals given a standard laboratory diet over the same 22-week period. At the time of study obese rats outweighed controls by 42% (637 +/- 32 g vs. 450 +/- 7 g, respectively). The absolute clearance of acetaminophen from plasma increased by 27% in obese rats. Higher partial formation clearance to acetaminophen glucuronide and sulfate conjugates accounted for most of this increase. Clearance by sulfhydryl conjugation was also substantially increased (56%), indicating that metabolism via toxic oxidation also occurred at a greater rate in obese animals. Absolute renal clearance of the glucuronide and sulfate conjugates but not acetaminophen increased with obesity, whereas parent volume of distribution remained unchanged. Some rats raised on the energy-dense diet remained lean and were examined separately as a dietary control group. Acetaminophen disposition in these animals was indistinguishable from pellet-fed controls, suggesting that acetaminophen elimination changes in overweight animals resulted from obesity itself and not from the obesity inducing energy-dense diet. Although animals placed on the energy-dense diet ate fewer grams of food per day, their caloric intake was similar to that of pellet-fed animals when adjusted for differences in body weight and caloric content of the diets.(ABSTRACT TRUNCATED AT 250 WORDS)