A PRIMING DOSE OF PROPRANOLOL REDUCES THE AVAILABILITY OF A SUBSEQUENT DOSE IN THE ISOLATED-PERFUSED RAT-LIVER PREPARATION

1, A 50 mu L bolus dose containing (+/-)-propranolol hydrochloride (20 0 mu g) and [C-14]-sucrose, or antipyrine (2mg and [C-14]sucrose, or [ C-14]-taurocholate sodium was injected into tile portal vein of the is olated perfused rat liver preparation and perfusate outflow samples we re collected frequently for the next 30 min. After a 20 min washout pe riod this procedure mas repeated. 2, [C-14]-Sucrose, antipyrine and [C -14]-taurocholate each eluted as a single peak at IS, 31 and 28 s, res pectively, after each dose, In contrast, propranolol eluted with two p eaks at approximately 18 and 128 s after dosing, 3, There was no signi ficant difference in dose-corrected area under the outflow curve (AT;C ) for [C-14]-sucrose, antipyrine: or [C-14]-taurocholate between the f irst and second doses whereas the mean propanolol AUC for the second d ose tvas only 0.577+/-0.439, that for the first dose P<0.05). 4. Unmet abolized propranolol accounted for more than 80% of the drug in hepati c tissue for the first and second doses at 18 s and greater than 50% a t 128s, and there was no significant difference in these values at eac h time between the first and second doses, 5, These findings suggest t hat fur an avidly extracted drug, such as propranolol, systemic availa bility of ur orally administered drug will be highly dependent on fact ors that influence the hepatic tissue binding of tile drug.