PRODUCT INHIBITION AND DOSE-DEPENDENT BIOAVAILABILITY OF PROPRANOLOL IN THE ISOLATED-PERFUSED RAT-LIVER PREPARATION

We investigated in the isolated perfused rat liver (IPRL) whether prod uct inhibition of metabolism contributes to the dose-dependent bioavai lability of propranolol, a drug with a high, but saturable, hepatic fi rst-pass effect. (+/-)-Propranolol was infused in the IPRL, using a re circulating design, for three 36-min periods (n = 9). Mean steady-stat e reservoir, i.e. hepatic inflow concentrations (C-in), were 4.97, 10. 4, and 20.4 mu M, respectively. Mean reservoir concentrations of the m etabolites 4'-hydroxypropranolol, 5'-hydroxypropranolol, N-desisopropy lpropranolol, and naphthoxylactic acid (NLA), a major side-chain-oxida tion metabolite, increased disproportionately with propranolol dose, b ut their production rate did not reach steady state. In separate exper iments (n = 4), perfusate containing 7.1, 12.8, and 21.6 mu M (+/-)-pr opranolol, corresponding to administration rates of 114, 205, and 346 nmol/min, respectively, was passed through the liver for 30 min each u sing a single-pass design. The bioavailability (hepatic outflow concen tration/C-in) of propranolol increased with C-in from 0.012 to 0.150 t o 0.288 in the recirculating IPRL. In the single-pass IPRL the increas e (0.0077 in 0.0669 to 0.136) was significantly less (P < 0.001). The greater bioavailability of propranolol in recirculating experiments wa s attributed to product inhibition since metabolites do not accumulate with the single-pass design. NLA did not appear to be the inhibiting metabolite because in further single-pass experiments with propranolol C-in of 21.6 mu M the presence of NLA (21.6 mu M) in perfusate had no eff act on propranolol bioavailability (n = 7) compared with control experiments (n = 5). These data suggest that, with the recirculating I PRL, dose-dependent bioavailability of propranolol is due to Competiti ve inhibition of propranolol metabolism by propranolol metabolites, wh ich is distinct from the noncompetitive product inhibition that has be en reported to accompany chronic propranolol administration.