Fluorouracil (brand names Adrucil, Carac) is a fluoropyrimidine antimetabolite chemotherapy agent widely used in oncology.
It is indicated for the treatment of various solid tumors, including colorectal, breast, head and neck, and pancreatic cancers.
Fluorouracil works by inhibiting thymidylate synthase, disrupting DNA and RNA synthesis and inducing cancer cell death.
The primary gene affecting fluorouracil metabolism is DPYD, which encodes dihydropyrimidine dehydrogenase (DPD). DPD is the key enzyme responsible for breaking down fluoropyrimidines in the liver.
Variations in DPYD can alter DPD enzyme activity, leading to faster or slower drug clearance. "Metabolizer" refers to how well an individual processes the drug: poor metabolizers have low DPD activity, while intermediate or normal metabolizers have progressively higher activity.
DPYD genotype–based phenotypes influence fluorouracil exposure. Poor metabolizers exhibit reduced DPD activity and high drug accumulation, increasing toxicity risk. Intermediate metabolizers have moderately reduced clearance and elevated toxicity risk, while normal metabolizers clear the drug normally. Indeterminate or unavailable genotype information yields no specific guidance.
The following dosing guidelines are based on the available guidelines for DPYD from CPIC and the FDA.
| Phenotype | Clinical Consequence | Guideline Recommendation |
|---|---|---|
| Normal Metabolizer | Normal DPD activity and “normal” risk for fluoropyrimidine toxicity | Use label-recommended dosage and administration |
| Intermediate Metabolizer | Decreased DPD activity (30%–70% of normal) and increased risk for severe toxicity | Reduce starting dose by 50% and titrate based on toxicity or therapeutic drug monitoring; some variants may require >50% dose reduction |
| Poor Metabolizer (AS 0.5) | Complete DPD deficiency and high risk for severe or fatal toxicity | Avoid use of fluorouracil or prodrug regimens; if no alternative, administer strongly reduced dose with early therapeutic drug monitoring |
| Poor Metabolizer (AS 0) | Complete DPD deficiency and high risk for severe or fatal toxicity | Avoid use of fluorouracil or prodrug regimens |
| Indeterminate | No CPIC guidance for this phenotype | Initiate therapy with recommended starting dose |
| Not available | No CPIC guidance for this phenotype | Initiate therapy with recommended starting dose |
| Phenotype | Clinical Consequence | Guideline Recommendation |
|---|---|---|
| Normal Metabolizer | No FDA guidance for this phenotype | Use standard dosing |
| Intermediate Metabolizer | Higher risk of severe, life-threatening, or fatal toxicities | Withhold or discontinue on early or unusually severe toxicity |
| Poor Metabolizer | Higher risk of severe, life-threatening, or fatal toxicities; no safe dose established | Consider alternative non-fluoropyrimidine therapy |
| Indeterminate | No FDA guidance for this phenotype | Use standard dosing |
| Not available | No FDA guidance for this phenotype | Use standard dosing |
For patients with DPYD poor metabolizer status (activity score 0), guidelines recommend avoiding fluorouracil and considering non–fluoropyrimidine regimens. Examples include raltitrexed or other non-fluoropyrimidine–based chemotherapy agents. These should be selected in consultation with an oncology specialist and based on individual patient factors.
Interested in learning more about how your genetics may affect your response to medication? Get started with Gene2Rx today.
I'm Interested