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 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.
Guo
X
X
Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA.
Lerner-Tung
M
M
Chen
H X
HX
Chang
C N
CN
Zhu
J L
JL
Chang
C P
CP
Pizzorno
G
G
Lin
T S
TS
Cheng
Y C
YC
D000284:Administration, Oral; D042931:Aldehyde Oxidase; D000445:Aldehyde Oxidoreductases / Q000378:metabolism; D000818:Animals; D001682:Biological Availability; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000473:pathology; D005437:Flucytosine / Q000493:pharmacokinetics / Q000627:therapeutic use / Q000633:toxicity; D005472:Fluorouracil / Q000737:chemistry / Q000493:pharmacokinetics* / Q000633:toxicity; D006207:Half-Life; D007700:Kinetics; D007941:Leukemia P388 / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D011355:Prodrugs / Q000493:pharmacokinetics / Q000627:therapeutic use / Q000633:toxicity
D011355:Prodrugs; D005437:Flucytosine; D000445:Aldehyde Oxidoreductases; D042931:Aldehyde Oxidase; D005472:Fluorouracil