5-Fluoro-2-pyrimidinone, a liver aldehyde oxidase-activated prodrug of 5-fluorouracil

Biochem Pharmacol. 1995 Apr 18;49(8):1111-6. doi: 10.1016/0006-2952(95)98508-7.


5-Fluorouracil (5-FU) is an effective antitumor agent used in treating various cancers. Because of its metabolism by intestinal and other cells, 5-FU has an inconsistent bioavailability that limits its oral use. 5-Fluoro-2-pyrimidione (5-FP), a 5-FU prodrug, was synthesized and found to be converted to 5-FU by aldehyde oxidase, an enzyme present in 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 clearance rates of 5-FP were 3-fold slower. 5-FP was converted rapidly to 5-FU, in vivo. The resulting 5-FU was measured at a steady-state level of 40-70 microM 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 mouse tumor models. The potential clinical use of 5-FP as a prodrug of 5-FU should be considered.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Administration, Oral
  • Aldehyde Oxidase
  • Aldehyde Oxidoreductases / metabolism
  • Animals
  • Biological Availability
  • Colonic Neoplasms / drug therapy
  • Colonic Neoplasms / pathology
  • Flucytosine* / pharmacokinetics
  • Flucytosine* / therapeutic use
  • Flucytosine* / toxicity
  • Fluorouracil / chemistry
  • Fluorouracil / pharmacokinetics*
  • Fluorouracil / toxicity
  • Half-Life
  • Kinetics
  • Leukemia P388 / metabolism
  • Liver / metabolism
  • Mice
  • Prodrugs* / pharmacokinetics
  • Prodrugs* / therapeutic use
  • Prodrugs* / toxicity


  • Prodrugs
  • Flucytosine
  • Aldehyde Oxidoreductases
  • Aldehyde Oxidase
  • Fluorouracil