The effect of a variety of chemotherapeutic agents on the hepatic transport of amethopterin was studied in the isolated perfused rat liver. Vincristine (1, 10, and 100 µm), dactinomycin (10 and 50 µm), and cyclophosphamide (1, 2.5, and 5 mm), when added individually to the perfusion medium, produced a dramatic decrease in the rate of amethopterin (1 µm) uptake and biliary excretion during a 2-hr perfusion. The inhibitory effect on uptake and bile excretion of amethopterin increased as the concentration of added drug increased. 5-Fluorouracil (10 mm) and cycloheximide (0.1 mm) had no effect on the uptake or excretion of amethopterin. The hepatic tissue:medium ratio ranged from 1.3 to 15, with the highest concentrations observed in the presence of dactinomycin. Parallel studies on the hepatic synthesis of albumin demonstrated a depression in the rate of albumin synthesis by the presence of vincristine, dactinomycin, cyclophosphamide, or cycloheximide. Bile flow was decreased only in the presence of vincristine and dactinomycin. These studies indicate that hepatic uptake and biliary excretion of amethopterin are inhibited by vincristine, dactinomycin, and cyclophosphamide, that dactinomycin produces a greater than expected degree of intracellular accumulation of amethopterin, and that the mechanism of hepatic amethopterin transport does not appear to be dependent on protein synthesis.
This work was supported by research grants from the National Institutes of Health.