Abstract
The aims of the study were to characterize the rate and extent of the rebound effect after abrupt cessation of a chronic exposure ofl-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 β-adrenoceptor up- and down-regulation with increased sensitivity of the transducer complex. The half-life of disappearance of up-regulated β-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 α1-acid glycoprotein concentration was also observed.
Footnotes
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Send reprint requests to: Dr. Lena Brynne, Department of Pharmacy, Division of Biopharmaceutics and Pharmacokinetics, Box 580, SE-751 23 Uppsala, Sweden. E-mail: lena.brynne{at}biof.uu.se
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↵1 This work was supported in part by the Swedish Pharmaceutical Society. This study has been presented in reduced form at the meeting of the 3rd Jerusalem Conference on Pharmaceutical Sciences and Clinical Pharmacology in conjunction with the Pharmacy World Congress, 56th International Congress of FIP, September 1–6, 1996, and at the 3rd International Symposium on Measurement and Kinetics of In Vivo Drug Effects, the Netherlands, May 27–30, 1998.
- Abbreviation:
- AGP
- α1-acid glycoprotein
- Received July 6, 1998.
- Accepted April 29, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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