Drug Overview
Azathioprine (brand name Imuran) is an oral immunosuppressant in the thiopurine class. It is a prodrug converted into active thioguanine nucleotides that interfere with DNA and RNA synthesis.
This medication is used to prevent organ transplant rejection and to treat autoimmune disorders such as rheumatoid arthritis and inflammatory bowel disease (Crohn’s disease and ulcerative colitis).
Azathioprine works by inhibiting the proliferation of rapidly dividing immune cells (lymphocytes), thereby reducing inflammation and immune-mediated tissue damage.
Relevant Genes and Their Roles
Two key genes influence azathioprine response: TPMT (thiopurine S-methyltransferase) and NUDT15 (nudix hydrolase 15).
TPMT methylates and inactivates thiopurine metabolites, while NUDT15 degrades active thioguanine nucleotides to less toxic forms. Variations in these enzymes alter drug activation, clearance, and toxicity risk.
Impact of Genetics on Drug Response
Patients are categorized by TPMT and NUDT15 activity—normal, intermediate, or poor metabolizers. Lower enzyme activity leads to accumulation of active metabolites, increasing the risk of bone marrow suppression, while normal activity produces expected drug levels and standard toxicity risk.
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Expected Clinical Effects of Genetic Variation
Normal Function
- Effect on drug levels: Typical levels of active and inactive metabolites.
- Clinical consequence: Standard immunosuppressive effect.
- Side effects: Baseline risk of leukopenia, neutropenia, and myelosuppression.
Intermediate Function
- Effect on drug levels: Elevated active metabolite (TGN) levels; reduced inactive metabolite (meTIMP).
- Clinical consequence: Increased risk of bone marrow suppression.
- Side effects: Moderate severity; more frequent leukopenia and neutropenia than normal metabolizers.
Poor Function
- Effect on drug levels: Markedly elevated active metabolite levels; little to no inactivation.
- Clinical consequence: High risk of life-threatening myelosuppression.
- Side effects: Severe; risk of fatal leukopenia and neutropenia without dose adjustment.
Indeterminate/Not Available
- Effect on drug levels: Unknown impact.
- Clinical consequence: No specific guidance; follow standard dosing with monitoring.
- Side effects: Standard risk profile unless otherwise indicated.
Dosing Guidelines
The following dosing guidelines are based on CPIC recommendations for thiopurine therapy.
TPMT Dosing Guideline
| Phenotype |
Clinical Consequence |
Guideline Recommendation |
| Normal Function |
Normal risk of leukopenia, neutropenia, myelosuppression |
Start with normal dose (2–3 mg/kg/day) and adjust based on disease-specific guidelines; allow 2 weeks to reach steady state. |
| Intermediate Function |
Higher risk of leukopenia, neutropenia, myelosuppression |
Start at 30–80% of normal dose (0.6–2.4 mg/kg/day) and adjust based on myelosuppression; allow 2–4 weeks to steady state. |
| Poor Function |
High risk of severe myelosuppression; potential fatal toxicity |
Non-malignant: consider alternative non-thiopurine therapy.
Malignant: reduce dose 10-fold and dose thrice weekly; adjust based on myelosuppression; allow 4–6 weeks to steady state. |
| Indeterminate |
Unknown impact |
Initiate therapy with recommended starting dose. |
| Not available |
Unknown impact |
Initiate therapy with recommended starting dose. |
NUDT15 Dosing Guideline
| Phenotype |
Clinical Consequence |
Guideline Recommendation |
| Normal Metabolizer |
Normal risk of leukopenia, neutropenia, myelosuppression |
Start with normal dose (2–3 mg/kg/day) and adjust based on disease-specific guidelines; allow 2 weeks to reach steady state. |
| Intermediate Metabolizer |
Increased risk of leukopenia, neutropenia, myelosuppression |
Start at 30–80% of normal dose (0.6–2.4 mg/kg/day) and adjust based on myelosuppression; allow 2–4 weeks to steady state. |
| Poor Metabolizer |
High risk of severe myelosuppression |
Non-malignant: consider alternative non-thiopurine therapy.
Malignant: reduce dose 10-fold and adjust based on myelosuppression; allow 4–6 weeks to steady state. |
| Indeterminate |
Unknown impact |
Initiate therapy with recommended starting dose. |
| Not available |
Unknown impact |
Initiate therapy with recommended starting dose. |
Alternative Treatment Options
For patients with poor TPMT or NUDT15 function, CPIC guidelines suggest considering alternative non-thiopurine immunosuppressants (for example, mycophenolate mofetil or methotrexate) rather than azathioprine.
Genes that affect Azathioprine
See the full list of drugs affected by each gene:
Brand names containing Azathioprine
See how your genetics affect each product Azathioprine shows up in:
Related Guides
Learn more about how genetics may affect your response to Azathioprine and related medications:
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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