Eniluracil: an irreversible inhibitor of dihydropyrimidine dehydrogenase

Expert Opin Investig Drugs. 2000 Jul;9(7):1635-49. doi: 10.1517/13543784.9.7.1635.


One of the most widely used drugs in cancer chemotherapy is 5-fluorouracil (5-FU). 5-FU is optimally delivered via continuous iv. infusion, which is both cumbersome and expensive. Prolonged oral dosing of 5-FU could mimic continuous infusion with less inconvenience and cost. However, oral administration of 5-FU has been hampered by incomplete and erratic bioavailability due to substantial variability in the activity of dihydropyrimidine dehydrogenase (DPD), the rate-limiting enzyme in 5-FU catabolism. Eniluracil (ethynyluracil, GlaxoWellcome, USA), a uracil analogue, which irreversibly inhibits DPD, increases the oral bioavailability of 5-FU to 100%, facilitating uniform absorption and predictable toxicity. Cytotoxicity is enhanced one- to five-fold in cell lines treated with eniluracil plus 5-FU compared with 5-FU alone. Though eniluracil is neither toxic nor active as a single agent in animals, it improves the antitumour efficacy and therapeutic index of 5-FU. In Phase I trials, eniluracil markedly reduced the maximum tolerated dose of oral 5-FU, increased the half-life 20-fold and decreased the clearance 22-fold. DPD is completely inactivated within 1 h of eniluracil administration. Two dosing schedules have been evaluated in combination with oral 5-FU: a 5-day schedule every 28 days and a 28-day schedule every 35 days. The dose-limiting toxicity on the first schedule is myelosuppression with diarrhoea being dose-limiting on the 28-day schedule. Phase II trials employing the 28-day schedule have been completed in cancers of the colon, breast, liver and pancreas. Phase III trials in colorectal and pancreatic carcinoma have been completed and await analysis. Eniluracil is a promising drug, which permits reliable and safe administration of oral 5-FU and has the potential to overcome 5-FU resistance mediated by overexpression of DPD.

Publication types

  • Review

MeSH terms

  • Animals
  • Antimetabolites, Antineoplastic / adverse effects
  • Antimetabolites, Antineoplastic / pharmacokinetics
  • Antimetabolites, Antineoplastic / pharmacology*
  • Antimetabolites, Antineoplastic / therapeutic use*
  • Clinical Trials as Topic
  • Dihydrouracil Dehydrogenase (NADP)
  • Enzyme Inhibitors / adverse effects
  • Enzyme Inhibitors / pharmacokinetics
  • Enzyme Inhibitors / pharmacology*
  • Enzyme Inhibitors / therapeutic use
  • Fluorouracil / therapeutic use
  • Humans
  • Neoplasms / drug therapy
  • Oxidoreductases / pharmacology*
  • Oxidoreductases / therapeutic use
  • Uracil / adverse effects
  • Uracil / analogs & derivatives*
  • Uracil / pharmacokinetics
  • Uracil / pharmacology
  • Uracil / therapeutic use


  • Antimetabolites, Antineoplastic
  • Enzyme Inhibitors
  • eniluracil
  • Uracil
  • Oxidoreductases
  • Dihydrouracil Dehydrogenase (NADP)
  • Fluorouracil