6-mercaptopurine
Summary
6-Mercaptopurine (6-MP) is a purine analog chemotherapy and immunosuppressive agent used primarily for acute lymphoblastic leukemia (ALL) maintenance therapy and inflammatory bowel disease (IBD). It requires metabolic activation by HGPRT and is inactivated by xanthine oxidase and TPMT, leading to critical drug interactions and genetic variability in toxicity.
Detail
Mechanism: 6-MP is a prodrug that is converted by hypoxanthine-guanine phosphoribosyltransferase (HGPRT) into active thioguanine nucleotides (6-TGNs), which are incorporated into DNA/RNA, inhibiting de novo purine synthesis and causing cell cycle arrest (S-phase specific) in rapidly dividing cells, particularly lymphoid cells.
Metabolism: 6-MP is metabolized via two competing pathways - (1) xanthine oxidase converts it to inactive 6-thiouric acid, and (2) thiopurine methyltransferase (TPMT) methylates it to inactive metabolites. Patients with TPMT polymorphisms (reduced enzyme activity) accumulate toxic levels of active thioguanine nucleotides, risking severe myelosuppression. TPMT genotyping/phenotyping is recommended before starting therapy.
Key Drug Interaction: Allopurinol (xanthine oxidase inhibitor, used for gout/tumor lysis syndrome prevention) blocks 6-MP degradation, dramatically increasing toxicity. If co-administered, 6-MP dose must be reduced by 60-75%.
Clinical Uses: Maintenance therapy for ALL (often with methotrexate), Crohn's disease, ulcerative colitis, and as a steroid-sparing agent in autoimmune conditions.
Adverse Effects: Myelosuppression (leukopenia, anemia, thrombocytopenia), hepatotoxicity, pancreatitis (especially in IBD patients), and increased risk of infections due to immunosuppression. Long-term use may increase risk of secondary malignancies (lymphoma).
Monitoring: CBC, liver function tests regularly; TPMT activity testing before initiation.
Related Drug: Azathioprine is a prodrug of 6-MP, also used in IBD, autoimmune diseases, and post-transplant immunosuppression.
Sources
- Katzung's Basic & Clinical Pharmacology
- First Aid for the USMLE Step 1
- Goodman & Gilman's The Pharmacological Basis of Therapeutics
- UpToDate: Thiopurine therapy in IBD
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