In an attempt to evaluate the propranolol (P) concentration-effect relationship, percentage reduction in exercise heart rate was modeled as a function of unbound and total P concentrations using the linear, Emax, and sigmoid Emaxmodels. Nine volunteers underwent repeated treadmill exercise tests over 48 hr during a control period, after receiving 160 mg of P orally and again after receiving 160 mg once daily for 7 days. Beta blockade was assessed as the percentage reduction in exercise heart rate compared to control. Total serum P concentrations were determined by HPLC and unbound fractions by equilibrium dialysis. Using nonlinear least-squares regression, the Emaxmodel was best in describing the concentration-effect relationship in each subject. Mean parameters for combined single dose and steady state were Emax33.6±4.5% and EC5018.2±15.6ng/ml for total P and Emax33.5±4.3% and EC501.66±1.56 for unbound P. Model fits were not significantly better for unbound versus total P and EC50values showed similar intersubject variability. The observed unbound EC50values are consistent with reported receptor dissociation constants. Therefore the large intersubject variability in EC50could not be accounted for by variability in P protein binding.
- exercise heart rate
- pharmacodynamic modeling
- unbound and total concentration