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 product inhibition of metabolism contributes to the dose-dependent bioavailability of propranolol, a drug with a high, but saturable, hepatic first-pass effect. (+/-)-Propranolol was infused in the IPRL, using a recirculating design, for three 36-min periods (n = 9). Mean steady-state reservoir, i.e. hepatic inflow concentrations (Cin), were 4.97, 10.4, and 20.4 microM, respectively. Mean reservoir concentrations of the metabolites 4'-hydroxypropranolol, 5'-hydroxypropranolol, N-desisopropylpropranolol, and naphthoxylactic acid (NLA), a major side-chain-oxidation metabolite, increased disproportionately with propranolol dose, but their production rate did not reach steady state. In separate experiments (n = 4), perfusate containing 7.1, 12.8, and 21.6 microM (+/-)-propranolol, corresponding to administration rates of 114, 205, and 346 nmol/min, respectively, was passed through the liver for 30 min each using a single-pass design. The bioavailability (hepatic outflow concentration/Cin) of propranolol increased with Cin from 0.012 to 0.150 to 0.288 in the recirculating IPRL. In the single-pass IPRL the increase (0.0077 in 0.0669 to 0.136) was significantly less (P < 0.001). The greater bioavailability of propranolol in recirculating experiments was 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 Cin of 21.6 microM the presence of NLA (21.6 microM) in perfusate had no effect on propranolol bioavailability (n = 7) compared with control experiments (n = 5).(ABSTRACT TRUNCATED AT 250 WORDS)