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 (CLoral) decreased 29%, from 503 +/- 281 after a single dose to 359 +/- 143 mL/min/kg at steady state (p less than 0.05). Similarly, CLoral 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 alpha 1-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 less than 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.
Straka
R J
RJ
Department of Clinical Pharmacy, College of Pharmacy, University of Tennessee, Memphis 38163.
Lalonde
R L
RL
Pieper
J A
JA
Bottorff
M B
MB
Mirvis
D M
DM
D000284:Administration, Oral; D000328:Adult; D001682:Biological Availability; D003692:Delayed-Action Preparations; D006801:Humans; D007700:Kinetics; D008297:Male; D008657:Metabolic Clearance Rate; D009961:Orosomucoid / Q000378:metabolism; D011433:Propranolol / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*
D003692:Delayed-Action Preparations; D009961:Orosomucoid; D011433:Propranolol