Analysis of hepatic metabolism affecting pharmacokinetics of propranolol in humans.

We examined the metabolic kinetics of propranolol, constructed from saturable and non-saturable components, using liver microsomes. The metabolic activity in rat microsomes was much higher than that in human microsomes within the clinically observed plasma range. Using the physiologically based pharmacokinetic (PBPK) model incorporating the obtained metabolic parameters, the plasma kinetics of propranolol was well correlated with reported values, and then used to analyze the effect of hepatic first-pass metabolism on propranolol plasma pharmacokinetics in clinical doses. The simulated plasma concentrations and AUC values of propranolol increased proportionally to its dose; these levels were almost equivalent to intrinsic clearance (CLint1), presumed to be non-saturable. When Michaelis-Menten parameters were decreased to one twentieth, plasma concentrations slightly increased after 160 mg dosing. A similar result was obtained with steady-state plasma levels after repeated administration. On the other hand, the first-order absorption rate constant of propranolol did not affect AUC values. The dose-normalized AUC value started to increase about 10(3)mg dosing. When the dose exceed 10(6)mg dose, the CLint1 component hardly contributed to propranolol pharmacokinetics. Accordingly, under the conditions of the PBPK model, propranolol pharmacokinetics was considered to be dose-independent within the clinical dose range.