5-FLUORO-2-PYRIMIDINONE, A LIVER ALDEHYDE OXIDASE-ACTIVATED PRODRUG OF 5-FLUOROURACIL

5-Fluorouracil (5-FU) is an effective antitumor agent used in treating various cancers. Because of its metabolism by intestinal and other ce lls, 5-FU has an inconsistent bioavailability that limits its oral use . 5-Fluoro-2-pyrimidinone (5-FP), a 5-FU prodrug, was synthesized and found to be converted to 5-FU by aldehyde oxidase, an enzyme present i n high concentrations in the livers of mice and humans but not in the gastrointestinal tract. Using BDF1 mice, the pharmacokinetics of 5-FP were studied and compared with those of 5-FU. The bioavailability of 5 -FP given orally was 100% at a dosage of 25 mg/kg and 78% at a dosage of 50 mg/kg. The half-lives of both doses of 5-FP were at least 2-fold longer than the half-lives of the same doses of 5-FU, and the clearan ce rates of 5-FP were 3-fold slower. 5-FP was converted rapidly to 5-F U in vivo. The resulting 5-FU was measured at a steady-state level of 40-70 mu M in plasma, at a dosage of 25 mg/kg, that was sustained for at least 4 hr. Also, when given orally, 5-FP was shown to have potent activity against Colon 38 tumor cells and P388 leukemia cells in mice. The therapeutic index of 5-FP was similar to that of 5-FU in these mo use tumor models. The potential clinical use of 5-FP as a prodrug of 5 -FU should be considered.