The first enzyme in the catabolic pathway which degrades 5-FU.
It is the rate limiting step in the degradation of 5-FU and its oral prodrug capecitabine.
DPD enzyme degrades excess thymine and uracil that has not been incorporated into DNA.
Some DPD function is required for people to survive.
Its function is clinicall relevant when people are receiving high levels of fluoropyrimidine drugs, specifically 5FU and capectiabine.
Fluoropyrimidine drugs interfere with ability of cancer cells to replicate by replacing the body’s normal pyrimine which is a crucial organic compound that serves as a building block for DNA and RNA.
In the presence of a DPD deficiency 5-FU will accumulate, enabling more anabolism of 5-FU to its active metabolite.
When the excess 5-FU is anabolized, results in toxicity to malignant and normal cells.
Associated with the DYPD gene, which has several genetic variations.
4 genetic variants are associated with toxicity of 5-FU.
A partial DPD deficiency (of around 50% reduced activity) compared with normal is present in 6-8 % of North American and European population.
Approximately 4% of the western population has a variant of DYPD to 2A, 9B, 13 or HapB3:there are hundreds of other less well studied variants.
Complete DPD deficiency has an estimated prevalence of 0.01-0.1%.
Patients with DPD deficiency have increased risk of developing severe treatment related toxicity when treated with the standard dose of fluoropyrimidimes.
Patients who have two non-functioning DPYD variants will not be able to tolerate for fluoropyrimidines at all, whereas someone who has one normal allele, and one non-functioning or poorly functioning allele may have half-life of 75% of the normal function of DPD.
The FDA has a boxed warning to 5FU and capecitabine that DPYD variant testing should be conducted before treatment is initiated unless immediate treatment is necessary.
The most dangerous toxicities with DPYD deficiency include mucositis, skin toxicities, hand foot syndrome, and bowel obstruction.
Cardiac toxicity due to 5FU can cause coronary heart disease.
The rate of mortality due to fluoropyrimidines is approximately 3 to 4% and perhaps 2 to 3% in patients with DPD deficiencies.
Dose reductions range from 25 to 75% when using fluoropyrimidines depending upon the activities of alleles.
Commercial anssays are available, and it is a recommended to test for at least 13 alleles.
Capecitabine is considered a more toxic fluoropyrimidine than 5FU.
An antidote for fluoropyrimidine excess, uridine triacetate is available, but it is expensive and not extremely effective.