5-Fluoro-2-pyrimidinone, a liver aldehyde oxidase-activated prodrug of 5-fluorouracil.
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| Abstract |
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.
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| Authors | X Guo, M Lerner-Tung, H X Chen, C N Chang, J L Zhu, C P Chang, G Pizzorno, T S Lin, Y C Cheng |
| Journal | Biochemical pharmacology (Biochem Pharmacol) Vol. 49 Issue 8 Pg. 1111-6 (Apr 18 1995) ISSN: 0006-2952 [Print] England |
| PMID | 7748192 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.) |
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