Vol. 290, Issue 2, 664-671, August 1999

Mechanism-Based Modeling of Rebound Tachycardia after Chronic l-Propranolol Infusion in Spontaneous Hypertensive Rats¹

Lena Brynne, Lennart K. Paalzow and Mats O. Karlsson

Department of Pharmacy, Division of Biopharmaceutics and Pharmacokinetics, Uppsala University, Uppsala, Sweden

The aims of the study were to characterize the rate and extent of the rebound effect after abrupt cessation of a chronic exposure of l-propranolol in spontaneous hypertensive rats, using exercise-induced tachycardia as a pharmacodynamic endpoint. Thirty-two spontaneous hypertensive rats were randomized to receive either placebo or 4 or 8 mg/kg/day s.c. infusion of l-propranolol for 11 days using osmotic minipumps. The heart rate was measured after standardized physical exercise before and during drug exposure and over 12 days after cessation, using a computerized tail-cuff method. Blood samples were collected after each effect measurement during the infusion. A similar reduction in exercise tachycardia was registered for the two doses. No apparent tolerance development was found, but both doses showed a clear rebound effect of similar extent and intensity. The maximal rebound effect was observed on the second day after cessation and was found to have a duration of about 6 days. A mechanism-based model was developed to describe the rate and extent of changes in -adrenoceptor up- and down-regulation with increased sensitivity of the transducer complex. The half-life of disappearance of up-regulated -adrenoceptors was estimated to be 2.0 days (1.0-3.9 days). The effect-versus-time data was analyzed by nonlinear mixed-effect modeling with the program NONMEM. A dose-dependent reduction in the growth of body weight was observed during drug treatment, which was reversible. A dose- and time-dependent increase in the ₁-acid glycoprotein concentration was also observed.