Effect of age on the disposition and tissue clearances of fluorinated pyrimidines in rats

Abstract

The age dependency of the elimination and tissue clearances of 5-fluorouracil (FU) and its nucleoside analog, 5'-deoxy-5-fluorouridine (dFUR), was investigated in 2 to 12 months old female Fischer rats. In all age groups, the blood clearances of dFUR at infusion rates of 500 and 750 mg kg(-1) day(-1) and of FU at 25 and 35 mg kg(-1) day(-1) were independent of the dose; however, the clearance of FU at a higher infusion rate of 50 mg kg(-1) day(-1) was significantly lower than at 25 mg kg(-1) day(-1). An inverse relationship between animal age and clearance was observed for dFUR at both 500 and 750 mg kg(-1) day(-1) doses, and for FU at the 50 mg kg(-1) day(-1) dose. By contrast, the FU clearance at the 25 and 35 mg kg(-1) day(-1) doses was independent of age. To examine the age effect on the metabolic activities of major eliminating organs, the metabolism of dFUR by liver and small intestine in young and old rats was compared using 13,000 × g supernatant fractions of the tissue homogenates. Data were computer-fitted to the Michaelis-Menten equation. The Km for both tissues of both age groups was approximately 120 µg ml(-1). The intrinsic clearance (Vmax/Km) of dFUR was 5 ml kg(-1) min(-1) in the liver and 8 ml kg(-1) min(-1) in the intestine. The intestinal intrinsic clearance was independent of animal age, but the hepatic intrinsic clearance was significantly decreased in the older rats. The blood concentrations of FU derived as a metabolite from dFUR were also dependent on the animal age; an elevated FU concentration was associated with a lower dFUR metabolic clearance in the old rats. These data indicate that the elimination of FU and dFUR in rats is age-dependent, and that the systemic concentration of FU, a determinant of dFUR selectivity, is elevated in older animals.