Is Imuran affected by genetics?

Yes — the active ingredient is metabolized by a gene known to vary between individuals.

Relevant genes: NUDT15, TPMT

Used for: Organ transplant rejection prevention, Crohn's disease, ulcerative colitis, rheumatoid arthritis, lupus, autoimmune hepatitis

Imuran (azathioprine) has one of the longest-established pharmacogenetic profiles in medicine. Azathioprine is a prodrug that breaks down into 6-mercaptopurine, which is then inactivated by an enzyme called thiopurine S-methyltransferase, encoded by the TPMT gene. Roughly 1 in 300 people of European descent produce essentially no TPMT enzyme, meaning 6-mercaptopurine accumulates to levels that cause life-threatening bone marrow suppression within weeks of starting a standard dose. Another 10 percent or so carry one reduced-activity copy and are intermediate metabolizers who still need dose reduction. TPMT testing has been recommended before starting azathioprine for decades, and most rheumatologists, gastroenterologists, and transplant physicians now order it as a matter of course.

What's in Imuran

azathioprine affected by NUDT15, TPMT

Affected by NUDT15, TPMT · CPIC, FDA · Strong evidence

Azathioprine converts non-enzymatically to 6-mercaptopurine, which then follows several metabolic pathways. TPMT is the key inactivation route. A second gene, NUDT15, has emerged as equally important, particularly in patients of East Asian and Hispanic ancestry, where NUDT15 variants are more common than TPMT variants. CPIC guidelines now recommend testing both TPMT and NUDT15 before starting azathioprine. For patients with low or absent activity in either pathway, dose reductions of 30 to 80 percent are standard, and in some cases the drug is avoided entirely.

Read the full azathioprine genetics guide →

Azathioprine phenotype recommendations

Published guidance from CPIC and FDA on how azathioprine should be dosed or substituted based on your TPMT, NUDT15 phenotype.

Phenotype	What it means	Recommendation	Evidence
Normal Metabolizer TPMT	Your genotype supports standard dosing.	CPIC Initiate therapy with standard starting dose (e.g., 2 mg/kg/day for autoimmune diseases). During therapy, adjust doses of azathioprine based on disease-specific guidelines. It usually takes at least 2 weeks to reach steady state after each dose adjustment.	Strong
Intermediate Metabolizer TPMT	Your genotype reduces your ability to process azathioprine; a lower starting dose is typically recommended.	CPIC Initiate therapy with reduced starting doses (30-80% of standard starting dose) if standard starting dose is ≥2 mg/kg/day. If starting dose is already below standard starting dose, dose reduction might not be necessary. During therapy, adjust the doses of azathioprine based on the degree of myelosuppression and disease-specific guidelines. It usually takes at least 2-4 weeks of stable dosing to reach steady state after each dose adjustment.	Strong
Possible Intermediate Metabolizer TPMT	Your genotype reduces your ability to process azathioprine; a lower starting dose is typically recommended.	CPIC Initiate therapy with reduced starting doses (30-80% of standard starting dose) if standard starting dose is ≥2 mg/kg/day. If starting dose is already below standard starting dose, dose reduction might not be necessary. During therapy, adjust the doses of azathioprine based on the degree of myelosuppression and disease-specific guidelines. It usually takes at least 2-4 weeks of stable dosing to reach steady state after each dose adjustment. FDA Reduce dose per FDA labeling to decrease myelosuppression risk. Monitor blood counts closely.	Strong
Poor Metabolizer TPMT	Your genotype greatly reduces your ability to process azathioprine and substantially increases the risk of severe bone marrow toxicity. An alternative drug is typically recommended.	CPIC Consider alternative nonthiopurine immunosuppressant therapy.	Strong
Indeterminate TPMT	We could not confidently determine your TPMT genotype; standard dosing and close monitoring for toxicity is recommended.	CPIC Based on NUDT15, initiate therapy with standard starting dose (e.g., 2 mg/kg/day for autoimmune diseases). During therapy, adjust doses of azathioprine based on disease-specific guidelines. It usually takes at least 2 weeks to reach steady state after each dose adjustment. FDA Initiate therapy with recommended starting dose.	Strong
Not available TPMT	We do not have a TPMT result for you, so we cannot personalize guidance for azathioprine.	CPIC Use standard azathioprine dosing and monitor closely for bone marrow toxicity. FDA Initiate therapy with recommended starting dose.	—
Normal Metabolizer NUDT15	Your genotype supports standard dosing.	CPIC Initiate therapy with standard starting dose (e.g., 2 mg/kg/day for autoimmune diseases). During therapy, adjust doses of azathioprine based on disease-specific guidelines. It usually takes at least 2 weeks to reach steady state after each dose adjustment. FDA Initiate therapy with recommended starting dose.	Strong
Intermediate Metabolizer NUDT15	Your genotype reduces your ability to process azathioprine; a lower starting dose is typically recommended.	CPIC Initiate therapy with reduced starting doses (30-80% of standard starting dose) if standard starting dose is ≥2 mg/kg/day. If starting dose is already below standard starting dose, dose reduction might not be necessary. During therapy, adjust the doses of azathioprine based on the degree of myelosuppression and disease-specific guidelines. It usually takes at least 2-4 weeks of stable dosing to reach steady state after each dose adjustment. FDA Reduce dose per FDA labeling to decrease myelosuppression risk. Monitor blood counts closely.	Strong
Possible Intermediate Metabolizer NUDT15	Your genotype reduces your ability to process azathioprine; a lower starting dose is typically recommended.	CPIC Initiate therapy with reduced starting doses (30-80% of standard starting dose) if standard starting dose is ≥2 mg/kg/day. If starting dose is already below standard starting dose, dose reduction might not be necessary. During therapy, adjust the doses of azathioprine based on the degree of myelosuppression and disease-specific guidelines. It usually takes at least 2-4 weeks of stable dosing to reach steady state after each dose adjustment. FDA Reduce dose per FDA labeling to decrease myelosuppression risk. Monitor blood counts closely.	Strong
Poor Metabolizer NUDT15	Your genotype greatly reduces your ability to process azathioprine and substantially increases the risk of severe bone marrow toxicity. An alternative drug is typically recommended.	CPIC Consider alternative nonthiopurine immunosuppressant therapy. FDA Consider alternative immunosuppressant therapy due to significantly increased myelosuppression risk.	Strong
Indeterminate NUDT15	We could not confidently determine your NUDT15 genotype; standard dosing and close monitoring for toxicity is recommended.	CPIC Based on TPMT, initiate therapy with standard starting dose (e.g., 2 mg/kg/day for autoimmune diseases). During therapy, adjust doses of azathioprine based on disease-specific guidelines. It usually takes at least 2 weeks to reach steady state after each dose adjustment. FDA Initiate therapy with recommended starting dose.	Strong
Not available NUDT15	We do not have a NUDT15 result for you, so we cannot personalize guidance for azathioprine.	CPIC Use standard azathioprine dosing and monitor closely for bone marrow toxicity. FDA Initiate therapy with recommended starting dose.	—
Normal Function TPMT	Your body processes azathioprine at a normal rate based on this gene, so the standard dose should be appropriate for you.	FDA Initiate therapy with recommended starting dose.	—
Intermediate Function TPMT	Your body breaks down azathioprine more slowly than normal, which increases the risk of a dangerously weakened immune system. A lower dose is recommended, and your doctor will need to monitor your blood counts closely.	FDA Reduce dose per FDA labeling to decrease myelosuppression risk. Monitor blood counts closely.	Strong
Poor Function TPMT	Your body has great difficulty breaking down azathioprine, putting you at serious risk of a severely weakened immune system and dangerously low blood cell counts. A different medication is recommended.	FDA Consider alternative immunosuppressant therapy due to significantly increased myelosuppression risk.	Strong

Sources: CPIC, FDA

The genes behind the guidance

NUDT15 Nudix Hydrolase 15

NUDT15 protects cells from thiopurine chemotherapy by breaking down active thioguanine nucleotides before they cause too much damage. Loss-of-function NUDT15 variants are common in East Asian and Hispanic populations and cause severe bone marrow suppression on standard thiopurine doses. NUDT15 testing is now considered as essential as TPMT testing before starting azathioprine, mercaptopurine, or thioguanine.

The 2025 CPIC update emphasizes interpreting TPMT and NUDT15 together: patients who are intermediate on both genes need a more aggressive dose reduction than either gene alone would suggest.

See all drugs affected by NUDT15 →

TPMT Thiopurine S-Methyltransferase

TPMT inactivates thiopurine drugs like azathioprine, mercaptopurine, and thioguanine. About 1 in 300 people of European descent has essentially no TPMT activity, and standard doses can cause life-threatening bone marrow suppression in those people within weeks. Intermediate activity affects around 10 percent of people and still requires dose reduction.

TPMT testing is one of the oldest and most established pharmacogenetic tests. Most rheumatologists, gastroenterologists, and oncologists order it before starting thiopurine therapy.

See all drugs affected by TPMT →

Browse the full drug-class: Immunosuppressants.

What this means for you

Don't start azathioprine (or its sibling drug mercaptopurine, used in leukemia and other indications) without TPMT and NUDT15 testing. These are two of the highest-value pharmacogenetic tests that exist. The cost is trivial compared to the cost of the weeks of bone marrow suppression that a TPMT-deficient patient would otherwise experience, and most insurance covers them as part of the workup for IBD, autoimmune conditions, and transplant.

FAQ

How often do doctors actually test TPMT before starting azathioprine?

Rates vary but have climbed steadily. In academic and subspecialty settings (rheumatology, gastroenterology, transplant), TPMT testing before azathioprine is now close to universal. In primary care or less specialized settings, it's less consistent. Patients can and should ask whether testing has been done; the answer is almost always that it's a straightforward lab to add.

Is NUDT15 testing necessary if I've already had TPMT tested?

Yes, especially if you're of East Asian, Southeast Asian, or Hispanic ancestry. NUDT15 variants that cause similar toxicity to TPMT deficiency are more common in those populations than TPMT variants, and a patient with normal TPMT but reduced NUDT15 is still at risk. Current CPIC guidelines recommend testing both.

What happens if I'm a TPMT poor metabolizer?

Complete TPMT deficiency (very rare, roughly 1 in 300) is generally considered a contraindication to azathioprine, because safe dosing is so small that effective therapy is difficult. Intermediate TPMT activity (roughly 10 percent of patients) is managed by a 30 to 50 percent dose reduction with close monitoring of blood counts. The condition being treated hasn't changed, so your physician will look for an alternative drug (methotrexate, biologics, etc.) if azathioprine isn't usable.

Find out how your genetics affect Imuran

This page describes the general pharmacogenetics. A Gene2Rx report analyzes your own DNA to tell you which metabolizer group you fall into, across every medication.

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Informational only — not medical advice. Pharmacogenetic guidance describes population-level patterns; your individual response depends on many factors. Never start, stop, or change a medication without talking to your prescribing clinician.