Abstract

A dietary-induced animal model of obesity was examined to assess the mechanisms of obesity-altered changes in theophylline clearance and distribution. Obesity was induced over several months in Sprague-Dawley rats by feeding a palatable "cafeteria" diet containing approximately 60% fat in addition to normal chow (6% fat). Body composition (fat volume and fat-free mass) was measured by a standard tritium dilution method. Obese male rats achieved body weights up to 55% larger than normal controls. Theophylline disposition was not affected by the cafeteria diet or ages of the animals. Theophylline was measured in serum by high-performance liquid chromatography after a 20-mg/kg i.v. dose of drug, and total clearance and steady-state volume of distribution (Vss) were calculated. Absolute clearance (uncorrected for body size parameters) was similar in normal (26.8 +/- 5.4 ml/h) and obese (22.5 +/- 3.6 ml/h) male rats, indicating that total metabolic function remained constant in spite of increased body and liver weights. The Vss increased proportionally with total body weight (0.42-0.48 ml/g). Analysis of drug in fat (partition coefficient = 0.091) indicated limited fat uptake of theophylline. The increase of fat-free mass in obesity was found to account for similar Vss per gram values between normal and obese animals. The diet failed to induce obesity in female rats and the latter exhibited lower drug clearances, even upon adjustment for body weight. The dietary obese male rat resembles the human with respect to theophylline pharmacokinetics and allows demonstration of appropriate normalization of parameters for abnormal body weights under controlled experimental conditions.