1. A 50 microL bolus dose containing (+/-)-propranolol hydrochloride (200 microg) and [14C]-sucrose, or antipyrine (2 mg) and [14C]-sucrose, or [14C]-taurocholate sodium was injected into the portal vein of the isolated perfused rat liver preparation and perfusate outflow samples were collected frequently for the next 30 min. After a 20 min washout period this procedure was repeated. 2. [14C]-Sucrose, antipyrine and [14C]-taurocholate each eluted as a single peak at 18, 31 and 28 s, respectively, after each dose. In contrast, propranolol eluted with two peaks at approximately 18 and 128 s after dosing. 3. There was no significant difference in dose-corrected area under the outflow curve (AUC) for [14C]-sucrose, antipyrine or [14C]-taurocholate between the first and second doses whereas the mean propranolol AUC for the second dose was only 0.577+/-0.439 that for the first dose (P<0.05). 4. Unmetabolized propranolol accounted for more than 80% of the drug in hepatic tissue for the first and second doses at 18 s and greater than 50% at 128 s, and there was no significant difference in these values at each time between the first and second doses. 5. These findings suggest that for an avidly extracted drug, such as propranolol, systemic availability of orally administered drug will be highly dependent on factors that influence the hepatic tissue binding of the drug.