5-Fluoro-2'-deoxyuridine elimination by the isolated perfused rat liver

The influence of dose and hepatic blood flow on the elimination of 5-fluoro-2'-deoxyuridine (FdUrd) by the isolated perfused rat liver were investigated. FdUrd (1-20 mg; 4-81 mumol) was injected into the perfusion reservoir and serial samples were collected for chromatographic determination of plasma FdUrd and 5-fluorouracil concentrations. The decrease in FdUrd concentration from values above 100 microM was linear with time (apparent zero order); at concentrations below 30-40 microM the decline became exponential (apparent first order). Semilogarithmic plots of FdUrd concentration/dose versus time obtained with different doses were not superposable, indicating Michaelis-Menten elimination. At a perfusion rate of 20 ml/min, the apparent Vmax and Km for FdUrd disappearance were 14-19 nmol/ml/min and 161-194 microM, respectively. FdUrd clearance during first-order elimination was 8-11 ml/min. After FdUrd administration, 5-fluorouracil concentration reached 10-15% of the initial FdUrd concentration, then decreased with a half-life of 4-7 min. Fifty-four % of the dose of [2-14C]FdUrd was converted to 14CO2. At a dose of 20 mg, first-order clearance of FdUrd increased from 7 to 12 ml/min as hepatic flow increased from 10 to 30 ml/min. Less than 1% of the dose of [6-3H]FdUrd was incorporated into macromolecules. It was concluded that hepatic elimination of FdUrd is dependent on both dose and blood flow.