Azathioprine and mercaptopurine, used in inflammatory bowel disease and leukaemia. Two genes decide how much a person can tolerate, and testing before the first dose is standard practice in many hospitals.
Worth knowing before the first dose rather than after a blood count collapses. TPMT breaks thiopurines down, and its activity is inherited codominantly: one low-activity copy means the drug accumulates more than expected, two mean it accumulates a great deal. CPIC recommends a reduced starting dose for intermediate metabolisers and drastically reduced dosing — or a different drug — for those with no working enzyme, because standard doses in that situation cause severe, life-threatening myelosuppression. Testing before starting is routine in many hospitals. The point of it is to choose the right dose, not to withhold a drug that works.
CPIC Guideline for Thiopurine Dosing Based on TPMT and NUDT15 Genotypes: 2018 Update, Clinical Pharmacology & Therapeutics (PMID 30447069)
The second gene, and the reason the guideline was rewritten. NUDT15 does a different job from TPMT — it removes the active thiopurine metabolites once they have acted — and losing it lets them accumulate in dividing cells, causing the same myelosuppression by another route. CPIC states plainly that NUDT15 loss-of-function alleles are common in Asians and Hispanics. That matters here: testing TPMT alone, which was standard practice for years, misses a large share of the risk in east Asian patients, and this site is read in Korean. Dose recommendations follow the same shape as TPMT — reduced start for one no-function copy, drastic reduction or an alternative for two.
CPIC Guideline for Thiopurine Dosing Based on TPMT and NUDT15 Genotypes: 2018 Update, Clinical Pharmacology & Therapeutics (PMID 30447069)
Worth knowing before the first dose rather than after a blood count collapses. TPMT breaks thiopurines down, and its activity is inherited codominantly: one low-activity copy means the drug accumulates more than expected, two mean it accumulates a great deal. CPIC recommends a reduced starting dose for intermediate metabolisers and drastically reduced dosing — or a different drug — for those with no working enzyme, because standard doses in that situation cause severe, life-threatening myelosuppression. Testing before starting is routine in many hospitals. The point of it is to choose the right dose, not to withhold a drug that works.
CPIC Guideline for Thiopurine Dosing Based on TPMT and NUDT15 Genotypes: 2018 Update, Clinical Pharmacology & Therapeutics (PMID 30447069)
The second gene, and the reason the guideline was rewritten. NUDT15 does a different job from TPMT — it removes the active thiopurine metabolites once they have acted — and losing it lets them accumulate in dividing cells, causing the same myelosuppression by another route. CPIC states plainly that NUDT15 loss-of-function alleles are common in Asians and Hispanics. That matters here: testing TPMT alone, which was standard practice for years, misses a large share of the risk in east Asian patients, and this site is read in Korean. Dose recommendations follow the same shape as TPMT — reduced start for one no-function copy, drastic reduction or an alternative for two.
CPIC Guideline for Thiopurine Dosing Based on TPMT and NUDT15 Genotypes: 2018 Update, Clinical Pharmacology & Therapeutics (PMID 30447069)
These are the positions in your own file that carry the genes above. Not every gene in a guideline is one we report — where that is the case the gene appears above without a variant here, and the note says so.
NUDT15 · rs116855232
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