Prodrug strategies for bypassing the first-pass metabolism of propranolol

Propranolol is a nonspecific beta-adrenergic antagonist used for the treatment of cardiac arrhythmias, angina pectoris and hypertension. A significant problem in propranolol therapy is that it undergoes extensive presystemic metabolism after oral administration leading to reduced bioavailability and significantly greater inter-subject variability in blood levels after oral than after intravenous administration. In previous studies, Gareceau et al. demonstrated that the hemisucciante ester of propranolol, when administered orally to beagle dogs, yields propranolol levels eight times higher than an equivalent dose of propranolol hydrochloride, suggesting that the prodrug approach may be an effective means of avoiding first -pass metabolism of drugs which undergo extensive first-pass elimination. The purpose of this study is to obtain preliminary information to be used in subsequent mechanistic studies of the avoidance of first-pass metabolism by prodrugs. The results conclude that O-acyl ester prodrugs of propranolol are suitable as model compounds for mechanistic studies focusing of the use of the prodrug approach to bypass first-pass metabolism by the live. The Spraque Dawley rat has also been identified as a suitable animal model for such studies. However, since both the acetate and succinate ester were similar in bioavailability in the current study, both being higher than propranolol, lipophilicity alone may not be the determining factor in these results.