Abstract
The concentration-effect relationship of l-propranolol anddl-metoprolol were investigated in spontaneous hypertensive rats using reduction in exercise-induced tachycardia as a pharmacodynamic endpoint. The influence of protein binding on the effect relationship was also assessed. The rats were assigned to treatment or placebo groups, where each group received three randomly selected consecutively increasing steady-state infusions. Different pharmacodynamic effect models were fitted to the data, using nonlinear mixed effect modeling. The data were best described by a combined effect model, with a sum of an ordinary Imax and a linear model. At the lower concentration range, the ordinary Imaxmodel dominated, although at higher concentrations, the effect was linearly related to the antagonist concentration. The Imaxwere 83 ± 6 and 103 ± 6 beats · min−1and the IC50 were 18.1 ± 4.3 and 50.6 ± 15.2 ng/ml for l-propranolol and dl-metoprolol, respectively. The slope in the linear model was steeper forl-propranolol than for dl-metoprolol, 28.9 ± 2.8 and 4.48 ± 0.39 beats · ml · (min · μg)−1, respectively. Plasma protein binding ofl-propranolol was saturable. The unbound IC50for l-propranolol was 1.14 ± 0.27 ng/ml. The concentration-effect relationship of l-propranolol was altered at higher plasma concentrations, due to saturable protein binding. The Imax and the linear concentration-effect relationship may be interpreted as a specific β-antagonist effect and a membrane-stabilizing effect, respectively. Using exercise-induced tachycardia as a pharmacodynamic endpoint, to study the effect of β-antagonists in spontaneous hypertensive rats, seems to give reliable results and can be a useful model to extrapolate to humans.
Footnotes
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Send reprint requests to: Dr. Lena Brynne, Department of Pharmacy, Division of Biopharmaceutics and Pharmacokinetics, Box 580, S-751 23 Uppsala, Sweden.
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↵1 This study was supported in part by the Swedish Pharmaceutical Society, Sweden. This study has been presented at the meeting of the Annual American Pharmaceutical Society (AAPS), Boston, 1997.
- Abbreviations:
- AGP
- α1-acid glycoprotein
- SHR
- spontaneous hypertensive rat
- Received December 22, 1997.
- Accepted April 24, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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