The effects of lidocaine on hepatic enzyme activity were studied using the isolated perfused rat liver. The in vivo liver activity was examined by infusing lidocaine via the jugular vein, followed by organ isolation and drug perfusion 24 h later. The liver was studied in vitro by perfusing the organ with lidocaine until steady state was reached, then allowing the drug and metabolites to wash out of the organ, followed by a second infusion of lidocaine to probe enzyme activity. In both types of experiments, pretreatment with lidocaine caused a reduction in deethylation, and led to a more rapid attainment of steady state. The experimental concentration-time profiles and literature data were successfully described by a mathematical model.