Propranolol pharmacodynamic modeling using unbound and total concentrations in healthy volunteers

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, E_max, and sigmoid E_maxmodels. 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 E_maxmodel was best in describing the concentration-effect relationship in each subject. Mean parameters for combined single dose and steady state were E_max33.6±4.5% and EC₅₀18.2±15.6ng/ml for total P and E_max33.5±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.