Mercaptopurine

Approved Indications:

• Acute Lymphoblastic Leukemia (ALL):
• Used as part of a combination chemotherapy regimen for the maintenance treatment of ALL in both pediatric and adult patients.

Important Off-Label or Clinically Accepted Uses:

• Acute Myeloid Leukemia (AML): Occasionally used in selected protocols.
• Inflammatory Bowel Disease (IBD):
• Maintenance therapy in Crohn’s disease and ulcerative colitis, especially when steroid-sparing therapy is needed.
• Autoimmune Hepatitis: Off-label use in patients intolerant to azathioprine.
• Chronic Myelogenous Leukemia (CML): Previously used; now largely replaced by targeted therapies.

Route of Administration: Oral (tablet)

Acute Lymphoblastic Leukemia (ALL):

• Adults & Pediatrics:
• Usual dose: 1.5 to 2.5 mg/kg orally once daily
• Dosage adjusted based on blood counts and response
• Treatment duration: maintenance phase of ALL (typically 2–3 years)

Inflammatory Bowel Disease (Off-label):

• Adults:
• Starting dose: 50 mg once daily, titrated up to 1–1.5 mg/kg/day
• Maintenance dose often 50–100 mg/day
• Adjustments based on thiopurine methyltransferase (TPMT) activity, clinical response, and tolerance

Pediatric IBD:

• Starting dose: 0.5–1 mg/kg/day, adjusted gradually

Special Populations:

• Renal Impairment:
• Use cautiously; dose reduction may be needed
• Hepatic Impairment:
• Use with caution; monitor liver enzymes regularly
• Elderly:
• Start at the lower end of dosing range; monitor for myelosuppression

Mercaptopurine is a purine antimetabolite that interferes with nucleic acid synthesis. It is converted intracellularly into active thioguanine nucleotides (TGNs), which are incorporated into DNA and RNA, causing cytotoxicity and inhibition of purine nucleotide synthesis. This leads to cell cycle arrest and apoptosis, particularly in rapidly dividing cells like leukemic blasts. In autoimmune conditions, it suppresses lymphocyte proliferation and dampens immune-mediated inflammation.

• Absorption: Oral bioavailability varies (approximately 16–50%) due to first-pass metabolism and food effect
• Distribution: Widely distributed; not bound extensively to plasma proteins
• Metabolism:
• Primarily metabolized in the liver by:
• Thiopurine methyltransferase (TPMT)
• Xanthine oxidase (XO)
• Hypoxanthine-guanine phosphoribosyltransferase (HGPRT)
• Half-life: Plasma half-life ~1 hour; intracellular active metabolites have a longer duration
• Excretion: Primarily renal (metabolites in urine)
• Onset of Action (in IBD): May take 8–12 weeks to observe clinical improvement

Pregnancy:

• FDA Pregnancy Category: D (based on older classification)
• Summary: Evidence of fetal harm (teratogenicity and myelosuppression) in humans. Should be avoided unless benefits outweigh risks.

Lactation:

• Excreted in breast milk in small amounts
• Breastfeeding is generally not recommended during therapy due to potential risk of infant bone marrow suppression
• If used, advise close infant monitoring or consider alternate feeding methods

• Primary Class: Antimetabolite
• Subclass: Purine antagonist; Thiopurine derivative
• Pharmacologic Category: Immunosuppressant / Antineoplastic agent

• Known hypersensitivity to mercaptopurine or any component of the formulation
• Patients with TPMT deficiency (homozygous) due to risk of life-threatening myelotoxicity
• Concomitant use with febuxostat (potent xanthine oxidase inhibitor)
• Pregnancy (unless clearly indicated and no alternatives)

• Myelosuppression: Risk of severe leukopenia, thrombocytopenia, and anemia; monitor CBC frequently
• Hepatotoxicity: Risk of liver enzyme elevation and cholestatic jaundice; monitor LFTs regularly
• Immunosuppression: Increased risk of infections and secondary malignancies, including lymphoma
• TPMT & NUDT15 Genetic Variants: Patients with reduced enzyme activity are at increased risk of toxicity; testing recommended before starting
• Drug Interactions with XO inhibitors: Allopurinol or febuxostat increases mercaptopurine levels—reduce dose to 25–33% if used concurrently
• Malignancy: Long-term use associated with increased risk of hepatosplenic T-cell lymphoma, especially in young males with IBD

Hematologic:

• Leukopenia
• Thrombocytopenia
• Anemia
• Bone marrow suppression (dose-dependent)

Hepatic:

• Elevated liver enzymes
• Cholestatic jaundice
• Hepatotoxicity

Gastrointestinal:

• Nausea
• Vomiting
• Anorexia
• Pancreatitis (rare)

Dermatologic:

• Rash
• Hyperpigmentation

Other Serious/Rare:

• Opportunistic infections
• Lymphoma or other malignancies
• Hypersensitivity reactions
• Alopecia (rare)

Timing:

• Myelosuppression typically appears within 1–2 weeks
• Hepatotoxicity may occur after weeks to months of therapy

• Allopurinol, Febuxostat:
• Inhibit xanthine oxidase → increased mercaptopurine toxicity
• Reduce mercaptopurine dose by 75% if co-administered
• Aminosalicylates (e.g., Mesalamine):
• Inhibit TPMT → increased risk of myelosuppression
• Warfarin:
• Reduced anticoagulant effect reported
• Live Vaccines:
• Avoid during therapy due to immunosuppression

Enzyme Systems Involved:

• TPMT, XO, NUDT15—variations in these affect drug metabolism and toxicity

• Genetic Testing for TPMT/NUDT15: Now strongly recommended before initiating therapy per updated oncology and gastroenterology guidelines
• FDA Label Update: Includes warnings for hepatosplenic T-cell lymphoma in pediatric and young adult patients with IBD
• NICE & ECCO (European Crohn's and Colitis Organization): Recommend thiopurines (mercaptopurine/azathioprine) for steroid-sparing maintenance therapy in IBD

• Temperature: Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C
• Humidity: Protect from moisture; store in a tightly closed container
• Light: Protect from excessive light exposure
• Handling:
• Use gloves when handling tablets
• Wash hands after handling
• Avoid crushing or breaking tablets unless guided by a healthcare professional