Modulation of fluorouracil tissue pharmacokinetics by eniluracil: in-vivo imaging of drug action

Lancet. 2000 Jun 17;355(9221):2125-31. doi: 10.1016/s0140-6736(00)02380-1.


Background: Fluorouracil is widely used for chemotherapy of gastrointestinal cancer, but response rates are poor. Eniluracil is being developed as an inactivator of dihydropyrimidine dehydrogenase, the enzyme that brings about first-pass degradation of fluorouracil. We studied the mechanism of action of eniluracil by measuring with positron emission tomography (PET) the effect of eniluracil on tumour and normal-tissue pharmacokinetics of fluorine-18-labelled fluorouracil.

Methods: Six patients with advanced gastrointestinal cancers were studied. PET scanning was done after injection of oxygen-15-labelled water to assess tissue blood flow, followed by 1 mg/m2 18F-fluorouracil. We compared the pharmacokinetics of 18F-fluorouracil when the patients had not received eniluracil, during a 4-day course of oral eniluracil, and during a 28-day course of oral fluorouracil plus eniluracil.

Findings: In eniluracil-naïve patients, 18F-fluorouracil localised more strongly (mean 0.0234% [SE 0.0019] of injected activity per mL tissue at 11 min) in liver than in tumours (0.0032% [0.0004]). There was substantial inhibition, after eniluracil administration, of radiotracer uptake and retention in normal liver (mean area under the time versus radioactivity curve 0.927 [SE 0.086] vs 1.857 [0.169] m2 mL(-1) s) and kidneys (1.096 [0.048] vs 5.043 [0.915] m2 mL(-1) s). There was also an increase in plasma uracil and unmetabolised 18F-fluorouracil and an increase in the radiotracer half-life in tumours (2.3 h to >4.0 h).

Interpretation: Two events strongly suggested increased exposure of 18F-fluorouracil and its anabolites in the tumours, consistent with the inactivation of dihydropyrimidine dehydrogenase: a selective decrease in radiotracer exposure in normal liver and kidneys compared with tumours; and an increase in radiotracer half-life in tumours.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Adult
  • Aged
  • Antimetabolites, Antineoplastic / administration & dosage
  • Antimetabolites, Antineoplastic / pharmacokinetics*
  • Antimetabolites, Antineoplastic / therapeutic use
  • Dihydrouracil Dehydrogenase (NADP)
  • Drug Interactions
  • Enzyme Inhibitors / administration & dosage
  • Enzyme Inhibitors / pharmacology*
  • Female
  • Fluorouracil / administration & dosage
  • Fluorouracil / pharmacokinetics*
  • Fluorouracil / therapeutic use
  • Gastrointestinal Neoplasms / drug therapy
  • Gastrointestinal Neoplasms / metabolism*
  • Half-Life
  • Humans
  • Injections, Intravenous
  • Liver / drug effects
  • Liver / metabolism
  • Male
  • Middle Aged
  • Oxidoreductases / antagonists & inhibitors*
  • Tissue Distribution
  • Tomography, Emission-Computed
  • Uracil / administration & dosage
  • Uracil / analogs & derivatives*
  • Uracil / pharmacology


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