Pharmacokinetics and dynamics of (±)-verapamil in lean and obese Zucker rats

To evaluate the mechanism of obesity-induced changes in pharmacokinetics and pharmacodynamics of verapamil observed in humans, single-dose and steady-state kinetic/dynamic studies in obese Zucker rats were done. Seven lean and five obese Zucker rats received a single dose of verapamil (2 mg/kg) and plasma samples were obtained for verapamil concentrations over the following 7 hr. Terminal elimination half-life was significantly prolonged in obese animals compared to lean (mean ± S.D., 2.68 ± 0.87 hr obese vs. 1.39 ± 0.35 hr lean; P < .01) due to the significantly increased total volume of distribution observed in the obese animals (1.62 ± 0.28 liters obese vs. 0.83 ± 0.14 liters lean; P < .001). There was no significant difference in the total clearance (0.45 ± 0.16 liters/hr obese vs. 0.43 ± 0.10 liters/hr lean; NS) between lean and obese animals. A physiological explanation for the increased volume of distribution was evaluated by determining actual distribution of verapamil into tissue during steady-state infusion. Six lean and six obese animals received a loading infusion of verapamil (25 μg/min) for 1.2 hr in lean and 1.6 hr in obese rats followed by a constant infusion of 5 μg/min for the next 2.5 to 3 hr. Steady-state clearance was similar between groups (0.349 ± 0.095 liters/hr obese vs. 0.244 ± 0.066 liters/hr lean; NS). Plasma verapamil concentration at the termination of steady-state infusion was similar between lean and obese rats (0.91 ± 0.24 μg/ml obese vs. 1.26 ± 0.33 μg/ml lean). When total body burden of verapamil was estimated, the absolute amount of verapamil in the various tissues was significantly increased in the obese rats (205 ± 39 μg obese vs. 133 ± 26 μg lean; P < .01), due primarily to the increased tissue burden of verapamil in fat of the obese rats (165 ± 34 μg obese vs. 69 ± 24 μg lean; P < .001). The marked increase of drug in fat of obese rats with similar steady-state plasma concentrations and calculated clearance between obese and lean rats suggests this is the physiological basis for the observed increase in volume of distribution determined after single dose administration in the obese rats.