Pyrimidine bases are degraded by the liver. Degradation of pyrimidines by the isolated perfused rat liver follows apparent Michealis-Menten kinetics. When rats are fasted or pretreated with 5-fluorouracil (5FU), the apparent maximal rate of degradation of 5-FU by the isolated perfused liver is decreased. Uracil degradation as assessed by the appearance of labeled carbon dioxide in the breath following the intraperitoneal injection of labeled substrate also is saturable. Fasting appears to decrese this response as well. In the isolated rat liver and in the intact rat, uracil can be detected in the perfusate and plasma, respectively. After 5-FU administration, uracil levels increase in both situations. The increment in uracil levels appears to depend upon the amount of 5-FU added. These results indicate that endogenous pyrimidines compete with exogenous pyrimidines for degradative pathways, and suggest that the endogenous rate of pyrimidine turnover is one factor regulating the disposition of pyrimidine drugs.