The effect of cytochromes P4501A induction and inhibition on the disposition of the cognition activator tacrine in rat hepatic preparations.

1. The disposition of tacrine 1,2,3,4-tetrahydro-9-acridinamine monohydrochloride monohydrate (THA, Cognex), was studied using livers obtained from control, phenobarbital (PB), isosafrole (ISO), and 3-methycholanthrene (3-MC) treated rats. 2. Pretreatment of rats with PB, ISO, and 3-MC reduced AUC(10-120 min) of THA in liver perfusates by 28, 32, and 86% respectively. 3. Elimination of [14C]-THA-derived radioactivity into bile was 7.6 +/- 1.2%, 11.7 +/- 2.9%, 14.8 +/- 2.0%, and 46.3 +/- 9.7% (mean +/- SD) of the infusion dose for control PB, ISO, and 3-MC pretreated isolated perfused rat livers, respectively. 4. In perfusion experiments using 3-MC pretreated livers, a marked increase in irreversible protein binding of 3-, 7-, and 8-fold was observed to microsomal, cytosolic and total liver proteins, respectively, compared to control. Only a slight effect was observed on protein binding in perfusion experiments using PB and ISO pretreated animals. 5. Co-incubations of [14C]-THA with the metabolic inhibitors enoxacin, ethimizol, and furafylline in hepatocyte preparations obtained from 3-MC pretreated rats markedly inhibited THA-derived irreversible protein binding. Furafylline, a specific inhibitor of cytochrome P4501A2, had the greatest inhibitory effect (approximately 70%). 6. These results are consistent with a major role of cytochrome P4501A in the metabolism and irreversible protein binding of THA in rat liver and demonstrate the utility of isolated liver perfusion and hepatocyte models for examining the effect of metabolic modulators.