Biological determinants of propranolol disposition in man

Abstract

Propranolol disposition has been investigated in 15 normal subjects with the use of a protocol which allowed simultaneous determination of the kinetics of the drug after both intravenous and oral administration by giving H 3 ‐propranolol intravenously and native drug orally. In addition, plasma propranolol binding and the bloodlplasma propranolol concentration ratio (B/P) were measured. The data were used to calculate hepatic blood flow as well as systemic drug clearance from the blood and intrinsic clearance, which is an estimate of the activity of the drug‐metabolizing enzymes. Under the steady‐state conditions used, the hepatic extraction ratio was found to be 64% ± 2.5% (mean ± SE) resulting in a bioavailability of 36% ± 2.6%. Calculated liver blood flow varied from 778 to 2,162 ml/min, and, as predicted, the systemic clearance of propranolol (0.61 to 1.52 L/min) was correlated with both liver blood flow and intrinsic drug clearance (1.16 to 5.08 L/min). Variations in plasma drug binding had no effect on systemic clearance. Because of presystemic or “first‐pass” elimination, the variation in both free and total propranolol levels was greater after oral (5‐fold) than intravenous administration (2.5‐fold). We conclude that the approach described allows quantification of all of the biological determinants of propranolol disposition in subjects with normal hepatic vasculature.