ROLE OF LUNG AND SMALL INTESTINE ON THE FIRST-PASS METABOLISM OF ESTER DERIVATIVES OF PROPRANOLOL

Abstract

The species difference for disposition of propranolol (PL) drivatives between rat and dog was investigated. In the intravenous administration, the total clearances of butyryl PL were 1.5 fold and 30 fold greater than hepatic blood flow in rat and dog, respectively. In vitro hydrolysis experiments showed that hepatic hydrolytic clearances of rat and dog were equivalent to hepatic blood flow, indicating that butyryl PL was mainly hydrolyzed in liver for rat. On the other hand, dog showed markedly high hydrolytic activity in lung, and it was demonstrated from an artery injection experiment that butyryl PL recieved the first-pass metabolism in lung. In the oral administration, we found that ester derivatives of PL improved the oral bioavailability of PL in dogs according to the following mechanism; increases of absorption rate and hepatic uptake rate and rapid hepatic hydrolysis lead to metabolic saturation of PL with increase of hepatic PL concentration. However, unfortunately, ester derivatives did not improve oral bioavailability of PL in rats due to almost complete hydrolysis of ester derivatives in small intestine.