PROD RUG STRATEGIES FOR BYPASSING THE FIRST·PASS METABOLISM OF PROPRANOLOL by

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 intersubject variability in blood levels after oral than after intravenous administration. In previous studies, Garceau et al. demonstrated that the hemisuccinate 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 ~e 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 focussing on the use of the prodrug approach to bypass first-pass metabolism by the liver. The Spraque Dawley rat has also been identified as a suitable animal model for such studies. However, since both the acetate and succinate esters were similar in bioavailability in the current study, both being higher than propranolol, lipophilicity alone may not be the determinig factor in these results.