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Pharmacology · Antimetabolites

Fluorouracil !

A fake pyrimidine: cells turn it into FdUMP, which jams thymidylate synthase and starves DNA of thymidine. A backbone of colorectal cancer chemotherapy.

Updated 2026-11-01

  • Class: Antimetabolites
  • Enzyme: Thymidylate synthase
  • ATC code: L01BC02
  • WHO Model List of Essential Medicines

Also called: 5-fluorouracil, 5-FU

The crystal holds FdUMP, the active form that cells make from fluorouracil, not fluorouracil itself.

Target in 3D: Thymidylate synthase. PDB structure 6QXG (RCSB PDB, public domain). View the structure at RCSB PDB

Mechanism of action

Fluorouracil is a prodrug that cells convert into fraudulent nucleotides. The key one, FdUMP, binds thymidylate synthase together with the folate cofactor 5,10-methylene-tetrahydrofolate and blocks it, so dUMP can no longer become dTMP and DNA cannot be copied. Other metabolites are built into RNA and add to the damage. Folinic acid (leucovorin) raises the folate cofactor and makes the block tighter, which is why the two are given together.

  1. Cells convert fluorouracil into FdUMP
  2. FdUMP and the folate cofactor lock thymidylate synthase
  3. No thymidine: DNA cannot be copied
  4. Tumour cells die; leucovorin tightens the lock

Pharmacokinetics

Absorption
Given IV as a bolus or continuous infusion; a cream is used on the skin.
Distribution
Wide, including the cerebrospinal fluid and brain.
Metabolism
Over 80% is broken down by dihydropyrimidine dehydrogenase (DPD), mainly in the liver.
Elimination
A small part unchanged in the urine; the breakdown products (such as α-fluoro-β-alanine and urea) also in the urine.
Half-life
Very short: about 8 to 20 minutes after a bolus, which is why continuous infusions are used.

Indications

  • Colorectal adenocarcinoma, with folinic acid and other drugs. Colorectal cancer →
  • Gastric adenocarcinoma, in combination regimens. Gastric cancer →
  • Pancreatic adenocarcinoma, in combination regimens. Pancreatic cancer →
  • Breast adenocarcinoma, in some combination regimens. Breast cancer →
  • Also used for oesophageal, head and neck, cervical and other cancers; as a cream for some skin lesions.

Adverse effects

Common

  • Mouth sores (mucositis) and diarrhoea
  • Nausea and loss of appetite
  • Hand–foot syndrome (red, painful palms and soles), more with continuous infusion
  • Low blood counts
  • Sun sensitivity and hair loss

Contraindications

  • Known complete DPD deficiency (very high risk of fatal toxicity)
  • Pregnancy and breastfeeding

Key interactions

Folinic acid (leucovorin)
Enhances both the antitumour effect and the toxicity, on purpose.
Warfarin
Coagulation times rise; INR is checked closely.

What is monitored

  • DPYD genetic testing before the first dose, unless treatment is urgent
  • Blood count before each cycle
  • Mucositis, diarrhoea and hand–foot changes
  • Chest pain or palpitations during treatment

Test yourself

Think of the answer, then tap the question to see it.

What is the active metabolite of fluorouracil that inhibits thymidylate synthase, and what does the enzyme stop making?

FdUMP. Thymidylate synthase can no longer convert dUMP into dTMP, so DNA synthesis lacks thymidine.

Why is folinic acid given with fluorouracil, when it is used to rescue patients from methotrexate?

It raises 5,10-methylene-tetrahydrofolate, the cofactor that locks FdUMP onto thymidylate synthase, so inhibition becomes stronger and longer.

A patient has severe mucositis, diarrhoea and neutropenia after the first fluorouracil cycle. Which enzyme deficiency is suspected?

Dihydropyrimidine dehydrogenase (DPD) deficiency, often due to DPYD variants, which prevents breakdown of the drug.

Which cardiac adverse effects are described with fluorouracil?

Angina, myocardial ischaemia or infarction, arrhythmias and heart failure; the risk is higher with continuous infusion and in people with coronary disease.

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Educational content on how drugs work; not a prescribing guide and no substitute for a health professional's advice. No doses are given.

Sources: Fluorouracil Injection: MedlinePlus Drug Information (MedlinePlus (U.S. National Library of Medicine), 2024); DailyMed - FLUOROURACIL injection, solution (DailyMed (U.S. National Library of Medicine), 2026); ATCDDD - ATC/DDD Index (WHO Collaborating Centre for Drug Statistics Methodology, 2026); eEML - Electronic Essential Medicines List (World Health Organization, 2025).

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Representative model, for educational purposes only.