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

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Abstract
Average steady-state propranolol plasma concentration (.hivin.Css) were calculated from published steady-state propranolol [antiarrhythmic drug] clearance data for dose rates (R0) of 40, 80, 160, 240 and 320 mg/day in divided doses every 6 h. The .hivin.Css-R0 data for each of 4 subjects were fit essentially perfectly by the equation: .hivin.Css = KmR0/(Vm - R0). Very similar Vm and Km values were obtained with the Vmi and Kmi values for 4 parallel Michaelis-Menten pathways of propranolol metabolism. It was shown by use of the mean Vm and Km values that the propranolol input rate profoundly affects its bioavailability, which is expected for a 1st-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.

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