Abstract

Various studies were carried out on the uptake of 14C-labeled warfarin and dicumarol by isolated rat hepatocytes. The uptake was rapid, reaching a steady-state level in the isolated cells in about one-half minute. Concentration studies showed that the uptake of warfarin by the cells approached saturation at about 4.5 nmoles per million cells, whereas the uptake of dicumarol did not approach saturation over the range studied. The effects of the anticoagulants on respiration were complex, having little or no effect on respiration at the lowest concentrations, stimulating respiration at the intermediate levels, and reducing respiration at the highest levels. Metabolic inhibitors such as 2,4-dinitrophenol and antimycin reduced the uptake of warfarin but not that of dicumarol. Serum albumin reduced the uptake of anticoagulants by the hepatocytes and the uptake was reciprocally related to the concentration of serum albumin. Computations showed that most of the binding of the drugs would be at the high-affinity sites on the albumin. The cells metabolized warfarin progressively for at least two hours, and serum albumin reduced the rate of metabolism of the drug. The rate of metabolism was relatively slow compared with the uptake; about 1% of the warfarin taken up by the cells was metabolized per minute.