Verofylline pharmacokinetics in dietary-induced obese rats: Role of fat mass and protein binding in determining volume of distribution

Abstract

1. Verofylline, a lipophilic polysubstituted methylxanthine, was utilized to examine how severely altered body composition in obesity affects drug disposition; the role of fat-free mass, fat mass and protein binding in determining the volume of distribution (Vss) was investigated. Obesity was induced by feeding Sprague-Dawley rats for 8 months with a calorie-dense diet; the obese rats showed increases of 50% in total body mass and 150% in body fat. 2. Both the absolute Vss and the clearance (Cl) in the obese rats increased 2-fold over control. Since Cl and Vss increased similarly, the half-life of verofylline in obese rats did not change. 3. The increase of Cl in obese rats can be accounted for by metabolic function related to fat-free mass and decreased serum binding. Similarly, an increase in fraction unbound and in total body mass accounted for the increase in Vss. 4. Based on in vitro measurements of muscle and fat tissue uptake of verofylline, and the assumed body space (from tritium dilution method), the predicted values for Vss closely approximated those of observed values. The semi-physiological model proposed here appears adequate to relate changes of body composition and serum protein binding in obesity to Vss.