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 less than .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 less than .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 micrograms/min) for 1.2 hr in lean and 1.6 hr in obese rats followed by a constant infusion of 5 micrograms/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 microgram/ml obese vs. 1.26 +/- 0.33 microgram/ml lean).(ABSTRACT TRUNCATED AT 250 WORDS)
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001798:Blood Proteins / Q000378:metabolism; D001835:Body Weight; D004195:Disease Models, Animal; D005260:Female; D007700:Kinetics; D009765:Obesity / Q000378:metabolism*; D011485:Protein Binding; D051381:Rats; D011924:Rats, Zucker; D014700:Verapamil / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology
D001798:Blood Proteins; C016904:norverapamil; D014700:Verapamil