Chemical formula: C₄H₃FN₂O₂ Molecular mass: 130.077 g/mol PubChem compound: 3385
Fluorouracil is an analogue of uracil, a component of ribonucleic acid. The drug is believed to function as an antimetabolite. After intracellular conversion to the active deoxynucleotide, it interferes with the synthesis of DNA by blocking the conversion of deoxyuridylic acid to thymidylic acid by the cellular enzyme thymidylate synthetase. Fluorouracil may also interfere with RNA synthesis.
After intravenous administration, fluorouracil is distributed through the body water and disappears from the blood within 3 hours. It is preferentially taken up by actively dividing tissues and tumours after conversion to its nucleotide. Fluorouracil readily enters the C.S.F. and brain tissue.
Fluorouracil is minimally systemically absorbed when applied topically to intact skin. When applied to the skin, the skin’s barrier function is pathologically altered (e.g., as in ulceration), and the absorption rate can increase to 60%. In patients with AK, 2.4-6% of the topical dose was absorbed systemically. Similarly, under occlusion, significantly more fluorouracil is absorbed.
Following IV administration, the plasma elimination half-life averages about 16 minutes and is dose dependant. Following a single IV dose of fluorouracil approximately 15% of the dose is excreted unchanged in the urine within 6 hours; over 90% of this is excreted in the first hour. The remainder is mostly metabolised in the liver to inactive metabolites by the usual body mechanisms for uracil. Hepatic impairment may result in slower metabolism of fluorouracil and may require dose adjustment.
5-fluorouracil is catabolised by the enzyme dihydropyrimidine dehydrogenase (DPD) to the much less toxic dihydro-5-fluorouracil (FUH2). Dihydropyrimidinase cleaves the pyrimidine ring to yield 5-fluoro-ureidopropionic acid (FUPA). Finally, β-ureido-propionase cleaves FUPA to α-fluoro-β-alanine (FBAL) which is cleared in the urine. Dihydropyrimidine dehydrogenase (DPD) activity is the rate limiting step. Deficiency of DPD may lead to increased toxicity of 5-fluorouracil.
Preclinical information has not been included, as the clinical toxicity profile of fluorouracil has been established after many years of clinical use.
There is evidence from animal work that fluorouracil is teratogenic.
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