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

Abstract

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 V_max and K_m for THA metabolism were 12·4 ± 3·3 nmol/min/g liver and 0·98 ± 0·34 μm 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 (B_max) was 76·7 ± 30·5 pmol equivalents bound/h/mg cell protein, whereas the apparent K_b for binding was 2·8 ± 1·4μm.

4. The kinetic parameters, V_max and K_m, were used to predict steady-state extraction ratios (ER_ss) for various THA input concentrations (C_in) in single-pass perfused rat liver. At low input concentrations (0·72–0·85 μm; C_in < K_m), ER_ss of THA was approximately 1. For higher C_in (14·05, 20·72, 20·88 μm; C_in), the calculated ER_ss was markedly decreased with 0·300, 0·296 and 0·261, respectively.

5. The intrinsic clearance of THA (Cl_i) estimated from in vitro hepatocyte data was 6·7 ml/min/g liver while the apparent oral THA clearance (Cl_oral) calculated from in vivo rat data was 6·6 ml/min/g liver.