The disposition of propranolol. 3. Decreased half-life and volume of distribution as a result of plasma binding in man, monkey, dog and rat.

The binding of propranolol to plasma has been determined at therapeutic concentrations by equilibrium dialysis in man (93.2%), monkey (99.2%), dog (96.6%) and rat (92.2%) and correlated with its kinetics of disposition after intravenous administration. In nine human subjects the clearance of propranolol from the blood was high and relatively constant at 1.05 liters/min. The apparent volume of distribution (V dβ) which varied 2-fold was proportional to the disposition rate constant, β. In all the species examined Vdβ increased as free drug concentration increased in the order monkey:dog:man:rat, such that the volume of distribution of free drug was constant. This occurred despite large variations in drug clearance among the species (14-92 ml/kg/min), which resulted from differences in hepatic extraction ratio, relative magnitude of liver blood flow and extrahepatic metabolism. When the influence of a variable drug clearance was taken into account, increased drug binding was associated with a decrease in drug half-life. Such differences in binding account in part for species differences in half-life and are entirely responsible for interindividual variation in half-life in man after intravenous administration. These data are consistent with the hypothesis that plasma binding decreases the half-life of propranolol by increasing the rate of drug delivery to its site of elimination. This results because only volume of distribution is dependent on the free drug in the circulation, whereas more than the free fraction of the drug in the circulation is available for clearance by the organs of elimination.