The effects of route of administration and blood flow on the elimination of lidocaine, diphenylhydantoin and propranolol have been investigated in the isolated perfused rat liver. After administration directly into the portal vein, drug concentrations in the reservoir were the same at a given flow rate as concentrations in the hepatic vein after drug was placed directly into the reservoir. The apparent clearance of the drug calculated from these concentrations gave an estimate of intrinsic drug clearance, which is an estimate of the activity of the drug-metabolizing enzymes. Intrinsic clearance is defined as drug clearance when flow is not rate limiting and therefore should be independent of flow. This was confirmed by showing that, at steady state, neither hepatic venous drug concentrations nor concentrations in the reservoir after portal venous administration of lidocaine were affected by altering hepatic blood flow from 10 to 20 ml/min. Propranolol was given as a single dose into the reservoir at flows of 10 and 20 ml/min. The area under the concentration-time curve (AUC) in the reservoir was decreased by increased flow, but AUC for hepatic venous blood was unchanged. Although AUC in hepatic venous blood was unchanged. Although AUC in hepatic venous blood was unchanged, higher peak concentrations and a more rapid half-life was seen in keeping with the clearance of drug from the reservoir. These data suggest that after oral drug administration, steady-state concentrations or AUC in systemic blood is dependent only on the activity of the enzymes involved (i.e., intrinsic clearance) and unaffected by flow, provided drug is completely absorbed and eliminated only by the liver. Furthermore, this will apply even to drugs whose systemic clearance and drug half-life after i.v. administration is profoundly affected by altered hepatic blood flow.