Mercaptopurine

Pharmacological Class

• Antimetabolite (purine analogue, thiopurine)
• Cell cycle specific: S-phase

Mechanism of Action

• 6-MP is a prodrug, activated by hypoxanthine-guanine phosphoribosyltransferase (HGPRT) → thioinosine monophosphate (T-IMP).
• T-IMP:
  • Inhibits de novo purine synthesis (blocks AMP and GMP synthesis).
  • Incorporates into DNA and RNA → faulty nucleic acids.
• Result: inhibition of cell replication, especially in rapidly dividing lymphoblasts.

Indications

• Acute lymphoblastic leukemia (ALL) – maintenance therapy (commonly with methotrexate, vincristine, steroids)
• Occasionally in AML protocols (less common)
• Off-label: Crohn’s disease, ulcerative colitis (as immunosuppressant, though azathioprine more common)

Dosing (Oncology Use)

• Adults/Pediatrics (ALL maintenance):
  • 50–75 mg/m² PO once daily (sometimes flat dosing ~50 mg/m² daily in peds).
  • Administer consistently at the same time daily, usually in the evening.
  • Often combined with methotrexate (synergy).

Do not administer with milk or dairy (xanthine oxidase in milk can degrade the drug).

Pharmacogenomics

• Metabolized by TPMT (thiopurine methyltransferase) and NUDT15.
• Genetic polymorphisms (low or absent enzyme activity) → ↑ risk of life-threatening myelosuppression.
• Guidelines recommend TPMT and/or NUDT15 testing before therapy.

Drug Interactions

• Allopurinol / febuxostat (xanthine oxidase inhibitors):
  • Inhibit 6-MP metabolism → ↑ toxicity.
  • Must reduce 6-MP dose to ~25–33% if used with allopurinol.
• Avoid concomitant azathioprine (metabolized to 6-MP).
• Warfarin (↓ anticoagulant effect).

Toxicities / Adverse Effects

Dose-limiting:

• Myelosuppression (neutropenia, anemia, thrombocytopenia)

Other important toxicities:

• Hepatotoxicity (cholestasis, ↑ bilirubin, transaminases, veno-occlusive disease in rare cases)
• GI: nausea, vomiting, anorexia, diarrhea, mucositis
• Rare: pancreatitis, rash

Monitoring

• CBC with differential (weekly initially, then monthly during maintenance)
• LFTs (weekly–monthly)
• TPMT/NUDT15 genotyping or phenotyping before therapy if available
• Signs of infection or bleeding

Clinical Pearls

• Take consistently on an empty stomach (1 hr before or 2 hrs after meals; food can reduce absorption).
• Evening dosing improves efficacy in ALL maintenance (circadian biology of DNA repair).
• Adjust dose in TPMT or NUDT15 deficiency (start at 10% of dose or avoid in homozygous deficient).
• Combination with methotrexate is synergistic in ALL maintenance.
• Counsel patients on strict adherence — noncompliance is a major cause of relapse in ALL.

Summary for practice:

6-MP is a purine analogue antimetabolite, used mainly in ALL maintenance. Activated by HGPRT → blocks purine synthesis & incorporates into DNA/RNA. Myelosuppression is dose-limiting, hepatotoxicity is common, and pharmacogenomics (TPMT, NUDT15) strongly influence safety. Requires CBC/LFT monitoring, dose reduction with xanthine oxidase inhibitors, and patient education on adherence + timing.