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Pharmacology · Topoisomerase inhibitors

Irinotecan !

A camptothecin prodrug for colorectal cancer. Its active form SN-38 traps topoisomerase I; early and late diarrhoea and neutropenia are the key risks.

Updated 2026-11-01

The figure shows camptothecin, the parent compound of irinotecan's active metabolite SN-38, bound to the human topoisomerase I–DNA complex.

Target in 3D: DNA topoisomerase I. PDB structure 1T8I (RCSB PDB, public domain). View the structure at RCSB PDB

Mechanism of action

Carboxylesterases convert irinotecan into SN-38, which is far more active. SN-38 binds the topoisomerase I–DNA complex and prevents the single-strand nick from being resealed. When a replication fork hits the trapped complex, a double-strand break forms and the cell dies. SN-38 is inactivated by glucuronidation through UGT1A1, so people with low UGT1A1 activity are exposed to more SN-38.

  1. Carboxylesterases turn irinotecan into SN-38
  2. SN-38 traps topoisomerase I on nicked DNA
  3. Replication forks collide: double-strand breaks
  4. UGT1A1 inactivates SN-38; low activity means more toxicity

Pharmacokinetics

Absorption
Intravenous infusion only.
Metabolism
Activated to SN-38 by carboxylesterases; oxidised by CYP3A4 to inactive products; SN-38 is glucuronidated by UGT1A1.

Indications

  • Metastatic colorectal carcinoma: first line with fluorouracil and folinic acid, and after progression on fluorouracil. Colorectal cancer →

Adverse effects

Common

  • Early cholinergic syndrome: runny nose, salivation, small pupils, tearing, sweating, flushing, cramps, slow heart rate
  • Late diarrhoea
  • Neutropenia
  • Nausea, vomiting, fatigue and hair loss

Contraindications

  • Known hypersensitivity to irinotecan or its excipients

Key interactions

Strong CYP3A4 inducers (phenytoin, phenobarbital, carbamazepine, rifampicin, St John's wort)
Substantially lower irinotecan and SN-38 exposure; they are not given together.
Strong CYP3A4 or UGT1A1 inhibitors (e.g. ketoconazole)
Raise exposure to irinotecan and SN-38; not given together.
Diuretics and laxatives
Avoided while the patient has diarrhoea, because they worsen dehydration.

What is monitored

  • Blood count before each dose
  • Number and type of stools, fluids and electrolytes
  • UGT1A1 genotype may be tested before starting
  • Bilirubin and respiratory symptoms

Administration and safety

  • Antiemetic premedication before each dose; atropine is kept ready for early cholinergic symptoms.
  • Extravasation: the site is flushed with sterile water and ice is applied.
  • Hazardous drug: prepared and given following hazardous-drug handling procedures (impervious gloves, no skin contact) and disposed of as cytotoxic waste.

Nursing care

  • Independent double check of drug, patient, route and cycle before giving it (high-alert medicine).
  • During and soon after the infusion, watch for sweating, salivation, cramps or early diarrhoea and give atropine as ordered.
  • Teaching: start the prescribed antidiarrhoeal at the first loose stool after leaving, drink plenty of fluids, and call if diarrhoea persists or comes with fever or dizziness.
  • Blood count before each cycle; fever with neutropenia is treated as an emergency.

Pregnancy and breastfeeding

Can cause fetal harm; effective contraception is used during treatment by women and by men with female partners.

Test yourself

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

What are the two types of diarrhoea caused by irinotecan, and how is each managed?

Early cholinergic diarrhoea, which responds to atropine; late diarrhoea, which can be life-threatening and is treated promptly with loperamide and fluids.

Which enzyme converts irinotecan into its active form, and which enzyme inactivates that form?

Carboxylesterases form SN-38; UGT1A1 glucuronidates and inactivates it.

Why might a patient with Gilbert syndrome have more neutropenia on irinotecan?

Reduced UGT1A1 glucuronidation leaves more active SN-38 in the body.

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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: DailyMed - IRINOTECAN HYDROCHLORIDE injection, solution (DailyMed (U.S. National Library of Medicine), 2025); Goodman & Gilman's The Pharmacological Basis of Therapeutics, 14th ed., ch. 70 (McGraw Hill, 2023); 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.