Nonlinear pharmacokinetics of unbound propranolol after oral administration

After multiple oral doses, propranolol has been reported to accumulate to a greater degree than expected based on its terminal elimination rate constant and dosage interval. To determine whether the decrease in presystemic elimination can be attributed solely to a decrease in unbound intrinsic clearance or possibly a decrease in unbound fraction, we studied the pharmacokinetics of unbound propranolol in nine healthy subjects who were given 160 mg of regular or sustained‐release propranolol orally as single doses, and once daily for 7 d. Unbound propranolol concentrations were calculated by HPLC and equilibrium dialysis on each serum sample. With regular propranolol, the mean unbound oral clearance (CL_orat) decreased 29%, from 503 ± 281 after a single dose to 359 ± 143 mL/min/kg at steady state (p < 0.05). Similarly, CL_oral decreased 33% with sustained‐release propranolol from 1077 ± 514 to 721 ± 385 mL/min/kg (NS). The corresponding accumulation ratios for regular and sustained‐release propranolol were 1.39 ± 0.49 and 1.61 ± 0.81, respectively (NS). Therefore, the mean bioavailability of sustained‐release relative to that of regular propranolol was 0.52 ± 0.23 and 0.54 ± 0.17 for single doses and at steady‐state, respectively. The percent unbound of propranolol ranged from 6.8 to 14.0 with an average of 10.1. Neither the percent unbound nor α₁‐acid glycoprotein (AAG) serum concentrations were statistically different between single and multiple doses. The binding ratio was significantly correlated to AAG concentration (r = 0.776, p < 0.05). The data support a decrease in unbound intrinsic clearance of propranolol with no change in unbound fraction, leading to an increase in bioavailability at steady state.