Kinetics and cardiac effects of propranolol in humans

Six healthy volunteers received single 20-mg intravenous (IV) and 80-mg oral doses of propranolol on two occasions in random sequence. Serum propranolol concentrations were determined by gas chromatography in multiple samples drawn during 24 h after each dose. Mean (+/- SE) kinetic variables for IV propranolol were: elimination half-life (t 1/2 beta), 5.3 (+/- 0.6) h; volume of distribution, 2.3 (+/- 0.3) l/kg; total clearance, 4.9 (+/- 0.3) ml/min/kg; predicted extraction ratio, 0.23 (+/- 0.02). After single oral doses, t 1/2 beta (3.8 +/- 0.2 h) tended to be smaller than after the IV dose, and actual systemic availability (0.60 +/- 0.07) was less than that based on the predicted extraction ratio. During multiple oral dosage (80 mg every 12 h), observed steady state serum levels (47 +/- 5 ng/ml) tended to be less than those predicted based on the single oral dose (61 +/- 5 ng/ml), thus providing no evidence for reduced propranolol clearance at steady-state. Echocardiographic measurements of left ventricular performance (posterior wall velocity, diastolic dimensions) made during the single-dose oral study indicated significant impairment of function; impairment was maximal at 3 h post-dosage, and corresponded to the time of the peak serum propranolol concentration (341 ng/ml).