Capecitabine

Capecitabine (brand names Xeloda, Xitabin, Kapetral) is an oral chemotherapeutic prodrug of 5-fluorouracil (5-FU) used to treat a variety of solid tumors.

It is commonly indicated for colorectal, breast, and gastric cancers, among others. After absorption, capecitabine undergoes a three‐step enzymatic conversion, with the final activation by thymidine phosphorylase in tumor tissue.

The active metabolite, 5-FU, inhibits thymidylate synthase, blocking DNA synthesis and cell proliferation in rapidly dividing cancer cells.

The key gene involved in capecitabine metabolism is DPYD, which encodes dihydropyrimidine dehydrogenase (DPD). DPD is the rate-limiting enzyme responsible for catabolizing over 80% of administered 5-FU back into inactive metabolites.

Genetic variants in DPYD can lead to reduced or absent DPD activity, altering drug clearance. An “activity score” is assigned based on genotype to predict enzyme function, simplifying how genetic test results translate to expected enzyme activity.

DPYD phenotype groups—from poor to normal metabolizers—influence capecitabine clearance. Poor metabolizers have minimal DPD activity, resulting in high 5-FU exposure and severe toxicity risk, while normal metabolizers clear the drug at expected rates. Intermediate metabolizers fall between these extremes and benefit from dose reduction to avoid adverse events.

Normal Metabolizer

• Effect on drug levels: Standard clearance of 5-FU.
• Clinical consequence: Expected efficacy and toxicity profile as per label.
• Side effects: Diarrhea, hand–foot syndrome, and myelosuppression at labeled frequencies; severity as per standard dosing.

Intermediate Metabolizer

• Effect on drug levels: Reduced DPD activity leads to moderately increased 5-FU exposure.
• Clinical consequence: Elevated risk of grade 3–4 toxicities (e.g., neutropenia, mucositis).
• Side effects: More frequent or severe gastrointestinal and hematologic toxicity; monitor closely.

Poor Metabolizer

• Effect on drug levels: Little to no DPD activity, causing very high 5-FU exposure.
• Clinical consequence: High risk of life-threatening or fatal toxicity.
• Side effects: Severe, potentially fatal neutropenia, mucositis, diarrhea; immediate intervention required.

Indeterminate/Not available

• Effect on drug levels: Unknown impact.
• Clinical consequence: No specific guidance; follow standard dosing.
• Side effects: As per standard labeling; monitor per usual clinical practice.

DPYD Dosing Guideline

For patients with DPYD poor‐metabolizer status or where dose reduction is not feasible, guidelines recommend avoiding fluoropyrimidine therapy and considering alternative non-fluoropyrimidine regimens (e.g., irinotecan- or oxaliplatin-based therapies) as clinically appropriate. These are examples from published guidance and not individual medical advice.

• CPIC – Guideline for Fluoropyrimidines and DPYD
• FDA – Table of Pharmacogenetic Associations