5-Fluorouracil enzyme interactions

A similar model was employed to predict the DDIs between 5-fluorouracil and sorivudine (124). Sorivudine is converted by gut flora to (E)-5-(2-bromovinyl) uracil, which inactivates dihydropyrimidine dehydrogenase and impairs the metabolism of 5-fluorouracil by this enzyme. This interaction led to 15 deaths in Japan from 5-fluorouracil toxicity due to elevated exposure to the drug. Using a fcE of 0.00018 min, a fivefold increase in the AUC of 5-fluorouracil was predicted after administration of sorivudine (150 mg/day for 5 days), which was close to the observed data in patients. 

Sorivudine and 5-fluorouracil (5-FU) interaction, leading to severe or fatal gastrointestinal and bone marrow toxicities. Soruvidine was withdrawn from the market in 1993. Sorivudine inhibits dihydropyrimidine dehydrogenase, an enzyme pathway responsible forfluoropyrimidine metabolism. 48... 

Irinotecan is a DNA topoisomerase inhibitor. Irinotecan is a derivative of camptothecin. Camptothecins interact specifically with the enzyme topoisomerase I, which relieves torsional strain in DNA by inducing reversible single-strand breaks. It is indicated in the metastatic cancer of the colon or rectum after standard treatment with fluorouracil. 

Fluorouracil (5-FU) requires enzymatic conversion to the nucleotide (ribosylation and phosphorylation) in order to exert its cytotoxic activity these reactions are illustrated in Figure 51-5. The interaction between FdUMP and TS blocks the synthesis of thymidine triphosphate (TTP), a necessary constituent of DNA. The folate cofactor, 5,10-methylenetetrahydrofolate, and FdUMP form a covalently bound ternary complex with TS. The transfer of the methylene group and two hydrogen atoms from folate to FdUMP is blocked in the inhibited complex of TS-FdUMP-folate by the stability of the fluorine carbon bond on FdUMP sustained inhibition of the enzyme results. In... 

Sorivudine appears to be converted in the gut into a metabolite (BVU or bromovinyluraeil) that is a potent inhibitor of dihydropyrimidine dehydrogenase (DPD), an enzyme involved in the metabolism of fluorouracil (which is derived from tegafiir and other fluorouracil prodrugs). There is some evidence that DPD activity is genetically determined, and that there are poor fluorouracil metabolisers with low DPD activity, who would be expected to be more susceptible to this interaction. ... 

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