Fluoropyrimidines (Adrucil , Xeloda) – DPYD
Rationale
This drug gene interaction (DGI) pertains to the interaction between the dihydropyrimidine dehydrogenase (DYPD) gene and the fluoropyrimidine drugs fluorouracil and capecitabine (brand names Adrucil and Xeloda). Fluoropyrimidines are chemotherapy drugs that are used to treat various types of cancer, including colon, stomach, pancreatic, and breast cancers. Fluorouracil is also used to treat some skin conditions. In some people, differences in their DPYD gene causes fluoropyrimidines to be broken down more slowly than expected. This causes higher levels of the drug in their body, which can increase side effects such as bone marrow suppression.
Information presented on this page is based on evidence provided by the Clinical Pharmacogenomics Implementation Consortium (CPIC®). CPIC provides peer-reviewed, updated, evidence-based, and freely accessible guidelines for implementing pharmacogenomic results into actionable prescribing decisions for providers. CPIC guidelines include standardized terminology and a systematic grading of evidence and clinical recommendations published in a leading journal (Clinical Pharmacology and Therapeutics).
Genetic Variant Information
The DPYD gene encodes for a rate-limiting enzyme that is involved in the 80% of the metabolism of fluoropyrimidine drugs. There are different (variant) forms of the DPYD gene, or alleles, and differences affect how well fluoropyrimidines are metabolized in the body. Some alleles encode normal functioning enzymes while others encode low or absent functioning enzymes. Each of us carry two alleles of this gene. Assessing both alleles give a better picture of the functional status or phenotype of how fluoropyrimidines are metabolized. See the chart below for a description of each phenotype and any implications for treatment.
DPYD metabolizer status |
Variants (genotype) |
Implication for fluoropyrimidines |
|---|---|---|
| Poor metabolizer | TWO no-function alleles
OR ONE no-function AND ONE decreased function allele |
High risk of serious or fatal toxicities with fluoropyrimidine use. |
| Intermediate metabolizer | ONE normal function allele AND ONE no-function allele
OR ONE normal function allele AND one decreased function allele OR TWO decreased function alleles |
Increased risk of serious or fatal toxicities with fluoropyrimidine use. |
| Normal metabolizer | TWO normal function alleles |
Normal risk of toxicities with fluoropyrimidine use. |
The patient’s reported genotype corresponds to a phenotype (i.e. metabolizer status). To see an interpretation table assigning metabolizer status by genotype, click here to visit CPIC and scroll down to download the “DPYD diplotype-phenotype table”.
Results Interpretation
Fluoropyrimidines (fluorouracil and capecitabine) are medications used to manage several different conditions and genes can affect how well the drugs work. CPIC updates guidelines on how to best use these genetic results to support patient care. To view dosing recommendations for SSRIs based on CYP2C19 phenotypes, click on the most recent guideline publication on CPIC’s website and scroll down to Table 2.
Please review the FDA packet insert for Adrucil and Xeloda for additional clinical considerations such as contradictions as well as dose adjustments based on age, organ function, and drug-drug interactions.
Normal starting doses vary by phenotype and treatment regimens. Frequencies of DPYD variants differ depending on ancestry.
Quality of Results
Genotyping for DPYD was performed within a certified DNA laboratory at Vanderbilt University Medical Center that is in full compliance with all guidelines established by the government as regulated by the Centers for Medicare & Medicaid Services under the Clinical Laboratory Improvement Act of 1988. This validated clinical laboratory developed test is carried out with strict adherence to protocols outlined by the College of American Pathology. The performance of the assay is closely monitored, and the accuracy of the results is determined to be > 99%.
Supporting Evidence
This link will take you to the main page on the CPIC website relating to DPYD and fluoropyrimidines. On the site, you will find links to the main guideline publication and all supplementary information including a table that reports variant frequencies across different ancestries, a table that defines genetic variants, and a table that provides a phenotype interpretation (i.e. metabolizer status).
This link will take you to the main page on the CPIC website relating to DPYD and fluoropyrimidines. On the site, you will find links to the main guideline publication and all supplementary information including a table that reports variant frequencies across different ancestries, a table that defines genetic variants, and a table that provides a phenotype interpretation (i.e. metabolizer status).