Variable first-pass elimination of propranolol following single and multiple oral doses in hypertensive patients

Abstract

The disposition of orally administered propranolol has been studied in twelve patients with mild to moderate hypertension. Each patient received single doses of 40, 80, and 160 mg. Serial blood samples were obtained and quantitated using a sensitive gas chromatographic analytical technique. Ten of the twelve patients received 40 mg doses of propranolol every 6 hours for 5 doses. Blood samples were obtained after administration of the first, second, third, and fifth doses. Substantial intersubject variability in the areas under the bloodconcentration-time profiles (AUC) was observed. Evidence for a nonlinear first-pass effect was not obtained in all patients. The patients displaying a nonlinear relationship between dose and AUC for single propranolol doses consistently showed a similar relationship during multiple dosing. Blood levels obtained following the evening dose (08h00 to 14h00) appeared to be lower than expected based on multiple-dosing pharmacokinetic principles. These findings suggest that monitoring propranolol blood levels is the most viable way to ascertain therapeutic concentrations of this drug.

Pharmacokinetics of single oral and multiple intravenous and oral administration of acebutolol enantiomers in a rat model

“…Such behavior could be a source of variability in drug response. There are numerous examples in the literature describing the time-dependent pharmacokinetics of drugs [13,14]. The most common cause of time-dependent kinetics are variations in enzyme induction, diurnal variations in renal function, urine pH, h 1 -acid glycoprotein concentration, gastrointestinal physiology, cardiac output and regional blood flow [15].…”