The mechanisms of time-related reduction in lidocaine clearance were studied using a "one-pass" perfused rat liver system. Lidocaine was infused continuously for a period up to 150 min (concentration ranged from 9.6 to 278 microM). The time required for lidocaine to achieve steady state in the effluent ranged from 20 to 90 min. Analysis of material balance suggested that capacity-limited tissue binding was partially responsible for determining the time to steady state. The characteristic rise of monoethylglycinexylidide to a maximum within 5 min and decline to a stable level during constant lidocaine infusion suggested that the deethylation pathway may be partly deactivated. This observation could be the major determinant for the time-dependent effects of lidocaine elimination. Saturation of metabolism, mainly hydroxylation, and product inhibition by monoethylglycinexylidide did not reduce the extraction of lidocaine significantly. The dose-related reduction in lidocaine elimination is believed to have little contribution to the time effects of lidocaine.