Metabolic disposition of tacrine in primary suspensions of rat hepatocyte and in single-pass perfused liver: in vitro/in vivo comparisons.

1. Incubations of tacrine (1,2,3,4-tetrahydro-9-acridinamine monohydrochloride monohydrate, THA) with a primary suspension of rat hepatocytes for 2 min resulted in formation of the 1-hydroxy derivative as the major metabolite with smaller amounts of the 2- and 4-hydroxy metabolites. 2. Apparent Vmax and Km for THA metabolism were 12.4 +/- 3.3 nmol/min/g liver and 0.98 +/- 0.34 microM respectively. 3. Incubations of THA for longer time-periods (> 10 min) resulted in irreversible binding of THA-derived radioactivity to hepatocellular protein. The apparent maximal rate of irreversible binding (Bmax) was 76.7 +/- 30.5 pmol equivalents bound/h/mg cell protein, whereas the apparent Kb for binding was 2.8 +/- 1.4 microM. 4. The kinetic parameters, Vmax and Km, were used to predict steady-state extraction ratios (ERSS) for various THA input concentrations (Cin) in single-pass perfused rat liver. At low input concentrations (0.72-0.85 microM; Cin < Km), ERSS of THA was approximately 1. For higher Cin (14.05, 20.72, 20.88 microM; Cin >> Km), the calculated ERSS was markedly decreased with 0.300, 0.296 and 0.261, respectively. 5. The intrinsic clearance of THA (Cli) estimated from in vitro hepatocyte data was 6.7 ml/min/g liver while the apparent oral THA clearance (Cloral) calculated from in vivo rat data was 6.6 ml/min/g liver.