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 (V_ss) 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 V_ss and the clearance (Cl) in the obese rats increased 2-fold over control. Since Cl and V_ss 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 V_ss.

4. Based on in vitro measurements of muscle and fat tissue uptake of verofylline, and the assumed body spaces (from tritium dilution method), the predicted values for V_ss 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 V_ss.