}

Mercaptopurine

Chemotherapies

Drug Overview

Mercaptopurine (brand name Purinethol) is a thiopurine antimetabolite used in oncology and immunosuppression. It is structurally similar to purine bases of DNA and RNA.

It is commonly used to treat acute lymphoblastic leukemia, inflammatory bowel disease, and other immune-mediated disorders. As an immunosuppressant, it helps maintain remission in conditions such as Crohn’s disease and ulcerative colitis.

Mercaptopurine is converted inside cells into thioguanine nucleotides (TGN), which incorporate into DNA and RNA, inhibit purine synthesis, and suppress the proliferation of rapidly dividing and immune cells.

Relevant Genes and Their Roles

Two key genes affect mercaptopurine metabolism: TPMT (thiopurine S-methyltransferase) and NUDT15 (nudix hydrolase 15). TPMT methylates thiopurine compounds to less active metabolites, while NUDT15 inactivates thioguanine nucleotides by removing their phosphate groups.

Variants in TPMT and NUDT15 change how quickly mercaptopurine is broken down or activated. Reduced TPMT or NUDT15 activity leads to higher levels of cytotoxic metabolites and greater risk of myelosuppression, while normal activity produces typical metabolite levels and standard toxicity risk.

Impact of Genetics on Drug Response

Genetic variants define metabolizer phenotypes (normal, intermediate, poor) that influence mercaptopurine exposure. Poor metabolizers accumulate high levels of thioguanine nucleotides, increasing risk of severe leukopenia and neutropenia, while intermediate metabolizers have moderate risk. Normal metabolizers have expected drug levels and typical side-effect profiles.

Expected Clinical Effects of Genetic Variation

Normal Function / Normal Metabolizer

  • Effect on drug levels: Typical thioguanine nucleotide concentrations
  • Clinical consequence: Standard efficacy and toxicity profile
  • Side effects: Usual risk of myelosuppression; monitored per standard protocols

Intermediate Function / Intermediate Metabolizer

  • Effect on drug levels: Moderately elevated TGN levels
  • Clinical consequence: Increased risk of leukopenia and neutropenia
  • Side effects: Moderate myelosuppression; may require dose reduction and closer blood count monitoring

Possible Intermediate Metabolizer

  • Effect on drug levels: Moderately elevated TGN levels
  • Clinical consequence: Similar to intermediate metabolizer risk
  • Side effects: Moderate myelosuppression; dose adjustment may be needed

Poor Function / Poor Metabolizer

  • Effect on drug levels: Very high TGN concentrations
  • Clinical consequence: High risk of severe leukopenia, neutropenia, and myelosuppression
  • Side effects: Severe, potentially life-threatening myelosuppression without dose reduction

Indeterminate / Not Available

  • Effect: Unknown metabolizer status
  • Clinical consequence: No specific guidance; follow standard dosing
  • Side effects: Standard monitoring and toxicity management

Dosing Guidelines

The following dosing guidelines are based on CPIC recommendations for mercaptopurine.

TPMT Dosing Guideline

Phenotype Clinical Consequence Guideline Recommendation
Normal Function Lower concentrations of TGN metabolites, normal toxicity risk Start with normal dose (e.g., 75 mg/m²/day or 1.5 mg/kg/day). Adjust per standard protocols; allow 2 weeks to steady state.
Intermediate Function Moderate-to-high TGN; increased risk of myelosuppression Start at 30–80% of normal dose (e.g., 25–60 mg/m²/day or 0.45–1.2 mg/kg/day). Adjust per blood counts; allow 2–4 weeks to steady state.
Possible Intermediate Metabolizer Moderate-to-high TGN; increased risk of myelosuppression Same recommendation as Intermediate Function: 30–80% of normal dose, adjust per response.
Poor Function Extremely high TGN; severe toxicity risk For malignancy, reduce dose 10-fold and give thrice weekly (e.g., 10 mg/m² 3 days/week). For non-malignant, consider alternative non-thiopurine immunosuppressant.
Indeterminate Unknown impact No specific recommendation; initiate standard dose.
Not available Unknown impact No specific recommendation; initiate standard dose.

NUDT15 Dosing Guideline

Phenotype Clinical Consequence Guideline Recommendation
Normal Metabolizer Normal risk of myelosuppression Start with normal dose (75 mg/m²/day or 1.5 mg/kg/day); allow ≥2 weeks to steady state.
Intermediate Metabolizer Increased risk of myelosuppression Start at 30–80% of normal dose (25–60 mg/m²/day or 0.45–1.2 mg/kg/day); adjust per blood counts; allow 2–4 weeks to steady state.
Possible Intermediate Metabolizer Increased risk of myelosuppression Same as Intermediate Metabolizer: reduce to 30–80% of normal dose and monitor.
Poor Metabolizer Greatly increased risk of myelosuppression For malignancy, start at 10 mg/m²/day and adjust per myelosuppression; for non-malignant, consider non-thiopurine alternatives.
Indeterminate Unknown impact Initiate standard dose; monitor clinically.
Not available Unknown impact Initiate standard dose; monitor clinically.

Alternative Treatment Options

For patients with poor TPMT or NUDT15 function, CPIC recommends considering alternative non-thiopurine immunosuppressants. Examples include methotrexate or biologic therapies (e.g., infliximab) in non-malignant conditions. These are guideline examples, not individual medical advice.

Sources and References

Disclaimer: This document is for informational purposes only and is not a substitute for medical advice. Clinical decisions should be made by a qualified healthcare professional.

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