The steady state kinetics of lidocaine and its metabolites were modeled using nonlinear elimination pathways for multiple enzymes. The main metabolites, monoethylglycinexylidide and 3-hydroxy-lidocaine, were infused in the absence of lidocaine to measure the kinetic parameters for secondary elimination. Data from continuous perfusion of lidocaine in the isolated perfused rat liver at concentrations ranging from 9.6 to 278 microM (N = 16) were used to calculate the kinetic parameters for formation of the main metabolites. The elimination of lidocaine in the liver was approximated by the well stirred model. The whole liver study gave higher elimination rates than were predicted from microsomal studies. The major pathways for elimination of lidocaine in the rat were deethylation and hydroxylation, and subsequent elimination along these pathways accounted for the poor material balance at low dosage levels. The observed competitive inhibition of hydroxylation was in agreement with the predictions of the model.