Propranolol: Pooled Michaelis-Menten parameters and the effect of input rate on bioavailability

Average steady-state propranolol plasma concentration (Css) were calculated from published steady-state propranolol clearance data for dose rates (Ro) of 40, 80, 160, 240, and 320 mg/ day in divided doses every 6 hours. The Css-Ro data for each of four subjects were fit essentially perfectly by the equation: Css = KmRo/ (Vm-Ro). Very similar Vm and Km values were obtained with the Vmi and Kmi values for four parallel Michaelis-Menten pathways of propranolol metabolism. It is shown by use of the mean Vm and Km values that the propranolol input rate profoundly affects its bioavailability, which is expected for a first-pass drug that follows Michaelis-Menten elimination kinetics after oral dosing. This most likely explains the poor bioavailability of propranolol after a sustained-release formulation. The decreased bioavailability of propranolol when the number of subdivisions of the daily dose is increased is also explained.