Mercaptopurine

Mechanism of action

Mercaptopurine is a thiol version of hypoxanthine. The salvage enzyme HGPRT converts it into thioinosine monophosphate, which is turned into thioguanine nucleotides (TGNs). TGNs are built into DNA and RNA and cause cell-cycle arrest and death; other metabolites inhibit the first steps of de novo purine synthesis. It is inactivated by two routes: methylation by thiopurine S-methyltransferase (TPMT) and oxidation by xanthine oxidase. NUDT15 also breaks down the active nucleotides.

1. HGPRT converts mercaptopurine into thioinosine monophosphate
2. Thioguanine nucleotides are built into DNA and RNA
3. Metabolites also block de novo purine synthesis
4. TPMT, NUDT15 and xanthine oxidase limit its activity

Indications

• Acute lymphoblastic leukaemia: maintenance phase of combination chemotherapy (children and adults). Acute leukaemia (AML and ALL) →

Adverse effects

Common

• Myelosuppression
• Nausea, vomiting, loss of appetite
• Liver enzyme and bilirubin rises
• Increased infections

Contraindications

• The label lists no absolute contraindications; it is avoided after previous severe hypersensitivity

Key interactions

Allopurinol (xanthine oxidase inhibitor)

Blocks the oxidation of mercaptopurine: much higher exposure and severe myelosuppression unless the dose is reduced.

Warfarin

Weaker anticoagulant effect; INR is monitored.

Other myelosuppressive drugs, such as trimethoprim-sulfamethoxazole

Additive bone marrow suppression.

What is monitored

• Complete blood count regularly
• Liver tests (transaminases, alkaline phosphatase, bilirubin)
• TPMT and NUDT15 testing, especially after severe or repeated myelosuppression

Administration and safety

• Hazardous drug: tablets and oral suspension are handled with gloves.
• Taken consistently with respect to food and time of day, because food lowers exposure.
• Maintenance regimens combine it with other oral drugs such as methotrexate on different schedules: each drug and day is double-checked.

Pregnancy and breastfeeding

Can cause fetal harm; effective contraception is advised. It is stopped if intrahepatic cholestasis of pregnancy develops.

Nursing care

• Ask about allopurinol or febuxostat use before every dispensing.
• Check counts and liver tests; report fever, jaundice or dark urine.
• Support adherence: missed maintenance doses raise the risk of relapse.
• Teaching: avoid live vaccines; contraception during treatment.

Pharmacokinetics

Absorption

Oral; food lowers exposure.

Distribution

Little entry into cerebrospinal fluid.

Metabolism

Inactivated by TPMT (methylation) and xanthine oxidase (oxidation); people with low TPMT or NUDT15 activity build up active nucleotides.

Half-life

Under 2 hours for the parent drug after an oral dose (label); its active nucleotides last much longer in cells.

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Connections

← Back to the class: Antimetabolites

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 - MERCAPTOPURINE tablet (DailyMed (U.S. National Library of Medicine), 2026); Mercaptopurine: MedlinePlus Drug Information (MedlinePlus (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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