Disposition and availability of 5-fluorouracil prodrug 5'-deoxy-5-fluorouridine after oral administration in rats.

5'-Deoxy-5-fluorouridine (dFUR) is a prodrug of 5-fluorouracil (FU) and requires metabolic activation by enzymes that are abundant in several tumors as well as in some normal tissues. 5'-Deoxy-5-fluorouridine is presently under investigation as an orally administered anticancer drug. This study examines the absorption and disposition of orally administered dFUR and its systemic availability in female Fischer rats. Animals were given an oral dose of unlabeled dFUR solution (500 mg.kg-1) and, 5 min later, an intravenous (i.v.) tracer dose of [6-3H]dFUR over a period of 1 min. The concomitant i.v. dose was given to assess the drug clearance during absorption of the oral dose. The blood concentrations of radiolabeled and unlabeled dFUR and FU were analyzed by high-pressure liquid chromatography and liquid scintillation counting. The clearance of the i.v. tracer dose of [6-3H]dFUR was 18.5 +/- 2.5 mL.kg-1.min-1 (mean +/- SD, n = 5). The oral bioavailability, calculated using the clearance of [6-3H]dFUR and the area under the blood concentration-time curve (AUC) of unlabeled dFUR, was 63.4 +/- 16.9%. Eighty to ninety percent of the absorption was completed by 8 h. The absorption rate of dFUR, analyzed by the Loo-Riegelman method, suggests that drug absorption took place in part by saturable mechanisms. The AUC of FU after the oral dose was 15-35% higher than that after i.v. injections of dFUR at the same dose. Analysis of the FU data indicates that a fraction of the dFUR dose was metabolized to FU during the presystemic first pass.