Pharmacokinetic characteristics of the obese overfed rat

The present study was undertaken to examine the appropriateness of the obese overfed rat and the obese Zucker rat as animal models for evaluating drug disposition changes in human obesity. It was found that 11 of 12 characteristics that control or influence drug clearance and volume of drug distribution in obese humans were qualitatively reproduced in the obese overfed rat. In contrast, existing literature shows that the obese Zucker rat resembles the obese human in only five of 12 characteristics, with meaningful discrepancies in fat-free mass, creatinine clearance, and thyroid function. Perhaps of greatest significance were changes in hepatic cytochrome P-450, which increased in proportion to total body mass in the obese overfed rat but remain unchanged in the Zucker rat. Although P-450 status in human obesity is unknown, the overfed rat model provides an opportunity for examining increased oxidative drug elimination that appears as an established feature of human obesity. In conclusion, the obese overfed rat appears to be superior to the obese Zucker rat as an animal model for evaluating the pharmacological consequences of human obesity, particularly those in which reproducing drug pharmacokinetics is an important consideration.