The effect of two antisecretory drugs, omeprazole and cimetidine, on the hepatic extraction of indocyanine green and lidocaine was studied in the isolated perfused rat liver. Both indocyanine green and lidocaine are removed by the liver with high extraction efficiency in a flow-dependent manner. The elimination of lidocaine, but not indocyanine green, involves metabolism by the mixed-function oxidase in the liver. A selective effect on the hepatic extraction of lidocaine, but not indocyanine green, may therefore indicate an inhibition of hepatic mixedfunction oxidase. To test this hypothesis, a nonrecycling system at a fixed perfusion flow rate was used to measure the extraction of lidocaine. Under control conditions, the extraction rate of lidocaine was 83% ± 8%. In the presence of omeprazole at concentrations of 0.9, 2.0, and 4.5μgmL, the extraction rates were 81% ± 9%, 82% ± 7%, and 75% ± 7%, respectively. These changes were not significantly different than control rates. In contrast, the increasing concentrations of cimetidine caused significant decreases in the hepatic extraction of lidocaine to values of 78% ± 8%, 63% ± 14%, and 48% ± 14% at concentrations of 0.25, 0.50 and 1.25 μg/mL, respectively. The hepatic extraction of indocyanine green, 39% ± 6%, was not affected by the administration of either omeprazole or cimetidine. Thus, in the rat, omeprazole seems to be a less potent inhibitor of cytochrome P-450 than cimetidine.