Disposition of propranolol V. Drug accumulation and steady‐state concentrations during chronic oral administration in man

In 6 normal volunteers, a twofold accumulation of propranolol in the blood was observed during chronic oral administration of 80 mg every 6 hours that was unpredicted on the basis of the drug's half‐life. No accumulation occurred in 2 subjects given 20 mg intravenously every 6 hours. The observed drug accumulation resulted from two mechanisms. During administration of the first dose an avid hepatic extraction process became saturated after removal of about 30 mg and remained saturated during the dosage interval. This resulted in a 60% increase in the amount of drug reaching the systemic circulation at steady state compared to that after a single dose. It is suggested that the avid hepatic extraction is a result of high‐affinity drug binding and that the increase in availability is due to saturation of this binding site. In addition, the increase in drug availability was sufficient to partially saturate drug metabolism and decrease systemiC drug clearance, resulting in a 44% increase in drug half‐life. These data were supported by the finding that during steady state folloWing 6 hourly oral propranolol administration to 7 subjects, plasma levels were proportional to the dose up to 160 mg per day, suggesting first‐order drug elimination in the presence of a saturated high affinity binding site in the liver. An average of between 160 and 320 mg per day metabolism becomes nonlinear, resulting in a disproportionate increase in plasma concentrations. These studies indicate that saturable hepatic tissue binding, as well as safurable metabolism, can result in nonlinear kinetics of drug disposition.