Key points
- DPD deficiency occurs in a few per cent of the population and causes severe, sometimes fatal, toxicity with fluorouracil or capecitabine (diarrhoea, mucositis, neutropenia) [1].
- A DPYD genotype-guided starting dose brought severe toxicity in carriers close to that of non-carriers [2].
- UGT1A1*28 (or *6) homozygotes have more severe neutropenia and diarrhoea with irinotecan; starting dose 70% [3].
- In acute lymphoblastic leukaemia, test TPMT and NUDT15 before mercaptopurine; in complete deficiency the dose is about one tenth [4].
DPYD and fluoropyrimidines
| Activity score | Example genotype | Recommendation |
|---|---|---|
| 2 (normal) | No decreased-function variant | Full dose |
| 1.5 (moderately decreased) | One c.2846A>T or HapB3 (c.1236G>A) allele | Starting dose 50%, then increase based on tolerance |
| 1 (decreased) | One *2A or *13 allele, or two decreased-function alleles | Starting dose 50%, then increase based on tolerance |
| 0.5 or 0 (severe or complete deficiency) | Two no-function alleles | Avoid fluoropyrimidines; if unavoidable, a very low dose with drug level monitoring |
In a prospective Dutch study, carriers given a reduced dose had grade 3 or higher toxicity close to that of non-carriers; carriers of c.1236G>A and c.2846A>T with a 25% reduction still had more toxicity, which is why CPIC recommends a 50% reduction [1, 2]. Genotyping does not find every deficiency; take severe early toxicity in cycle 1 seriously even with a normal genotype.
Severe diarrhoea, mucositis and neutropenia in the first 1 to 2 weeks of a fluoropyrimidine: stop the drug and consider DPD deficiency; the antidote uridine triacetate is effective if given within 96 hours.
UGT1A1 and irinotecan
UGT1A1 inactivates the active metabolite of irinotecan (SN-38). In poor metabolisers (*28/*28, *6/*6 or *28/*6), start at 70% of the dose and increase based on tolerance; intermediate metabolisers need no dose change [3]. Gilbert's syndrome (mildly raised indirect bilirubin) is a possible sign of this genotype.
TPMT, NUDT15 and mercaptopurine
| Phenotype | Starting dose |
|---|---|
| Normal | Full dose |
| Intermediate (one decreased-function allele) | 30 to 80% of the usual dose |
| Poor (two decreased-function alleles) | About 10% of the dose (for example 10 mg/m² daily or 3 times a week) |
NUDT15 variants are more common in East and South Asia; later doses are adjusted by blood counts.
References
4 referencesShow all references, 1 with a study cardClose the reference list
Numbers in the text, such as [1], refer to these sources. Sources with a “Study card” button are summarised in the site’s evidence library.
- 1
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- 4
This page is based on reputable scientific sources and was last updated on 28 October 2026. The content of this website is for educational and informational purposes only and does not replace consultation, diagnosis or treatment by a specialist physician. Consult your treating physician about any treatment decision.
Printed from the website; the full and up-to-date version: https://drdabiri.com/en/learn/dpyd-ugt1a1-pharmacogenomics/