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 monohydro chloride monohydrate, THA) with a primary suspension of rat hepatocyte s for 2 min resulted in formation of the l-hydroxy derivative as the m ajor metabolite with smaller amounts of the 2- and 4-hydroxy metabolit es. 2. Apparent V-max and K-m for THA metabolism were 12.4 +/- 3.3 nmo l/min/g liver and 0.98 +/- 0.34 mu M respectively. 3. Incubations of T HA 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 eq uivalents bound/h/mg cell protein, whereas the apparent K-b for bindin g was 2.8 +/- 1.4 mu M. 4. The kinetic parameters, V-max and K-m, were used to predict steady-state extraction ratios (ER(ss)) for various T HA input concentrations (C-in) in single-pass perfused rat liver. At l ow input concentrations (0.72-0.85 mu M; C-in < K-m), ER(ss) of THA wa s approximately 1. For higher C-in (14.05, 20.72, 20.88 mu M; C-in, mu ch greater than K-m), the calculated ER(ss) was markedly decreased wit h 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 li ver while the apparent oral THA clearance (Cl-oral) calculated from in vivo rat data was 6.6 ml/min/g liver.