PharmacologyTier 1Medical Sciences concept

Thiopurine methyltransferase (TPMT) pharmacogenomics and azathioprine toxicity

Core concept

Azathioprine is a prodrug: AZA -> 6-mercaptopurine, which then goes down three competing routes

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6-MP

HGPRT -> 6-TIMP -> 6-TGN = therapeutic AND myelotoxic
TPMT -> 6-methylmercaptopurine (6-MMP) = inactive, hepatotoxic at high levels
Xanthine oxidase -> thiouric acid = inactive

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TPMT shunts drug away from 6-TGN
- Low/absent TPMT -> more 6-TGN -> profound, early, life-threatening myelosuppression
- High TPMT -> shunt to 6-MMP -> hepatotoxicity and therapeutic failure ("skewed metaboliser")
NUDT15 dephosphorylates thioguanine nucleotides - the dominant risk allele in East and South Asian populations, where TPMT variants are rare

TPMT status	Frequency (European)	Action
Normal (wild type)	~89%	Standard dose
Intermediate (heterozygous)	~11%	Start at 30-70% of the target dose, titrate slowly
Absent (homozygous deficient)	~0.3% (1 in 300)	Avoid thiopurines, or use ~10% of dose with expert supervision

Test TPMT activity (or genotype) before starting - and NUDT15 in patients of Asian ancestry
- Enzyme activity is falsely normal after recent transfusion (donor red cell TPMT)
A normal TPMT does not remove the need for FBC monitoring - most azathioprine myelosuppression is TPMT-independent, idiosyncratic or late
- FBC weekly for 4-8 weeks, then 3-monthly for life
Allopurinol/febuxostat block xanthine oxidase -> the whole load is shunted to 6-TGN -> catastrophic myelosuppression
- Reduce azathioprine to 25-33% of dose, or avoid the combination
- Paradoxically, deliberate low-dose allopurinol co-therapy is used in IBD to rescue skewed metabolisers with high 6-MMP
Other adverse effects: pancreatitis (idiosyncratic, not TPMT-related), hepatotoxicity, nausea, flu-like hypersensitivity, squamous skin cancer and lymphoma with long-term use
Metabolite monitoring (6-TGN and 6-MMP levels) distinguishes non-adherence, under-dosing, and skewed metabolism in IBD

The exam scenario: a patient on azathioprine started on allopurinol for gout presents pancytopenic two weeks later
Uses: IBD, autoimmune hepatitis, transplant, lupus, vasculitis, myasthenia, atopic dermatitis - and pancytopenia in any of them prompts the same enquiry
Continue azathioprine in pregnancy (safest of the immunosuppressants alongside tacrolimus) - the risk of a flare exceeds the drug risk
Advise sun protection and annual skin surveillance
TPMT is the template for pre-prescription pharmacogenomic testing; the others worth knowing are DPYD (5-FU/capecitabine), UGT1A1 (irinotecan), G6PD (rasburicase, primaquine, dapsone), CYP2C19 (clopidogrel), and the HLA alleles

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