Dihydropyrimidine Dehydrogenase (DPYD)

DPYD is an enzyme that is responsible for breaking down (metabolizing) fluoropyrimidine drugs. Fluoropyrimidines are anticancer drugs that include fluorouracil and capecitabine. Like many drugs, their effectiveness and side effects can vary from person to person. One of the reasons why this difference occurs is because each person’s ability to metabolize dihydropyrimidines is different based on variations in the DPYD gene. Patients can be divided into 3 genotype categories based on the function of DPYD; this information is used by clinicians to help guide drug therapy decisions.

One feature of DPYD genotyping that is different from some other pharmacogenetic tests is that the current genetic testing is not able to identify all patients who have low DPYD function (the genetic test has a high false negative rate and the result may indicate the patient has normal DPYD function even when it is actually low). So caution is needed when prescribing fluroropyrimidines to patients who have normal DPYD genotype test results.

Intermediate metabolizers – These patients have one normal-function copy of the gene and one no-function copy of the gene. These patients have decreased DPYD enzyme function (30-70% of normal function) and may require modifications in therapy to avoid side effects. About 4 in 100 people have this genotype.

• Drugs that may need to be avoided or have their doses decreased:
  • Capecitabine. Consider reducing the starting dose of capecitabine by at least 50% and titrating the dose according to toxicity and tolerance, or choosing an alternative non-fluoropyrimidine containing regimen.
  • Fluorouracil. Consider reducing the starting dose of fluorouracil by at least 50% and titrating the dose according to toxicity and tolerance, or choosing an alternative non-fluoropyrimidine containing regimen.

Poor metabolizers – These patients have two copies of the no-function gene and there is no normal DPYD enzyme. These patients have complete DPYD enzyme deficiency and therapy modifications are required to avoid side effects. About 2 in 1,000 people have this very high risk priority genotype.

• Capecitabine. Do not use capecitabine. Consider an alternative non-fluoropyrimidine containing regimen.
• Fluorouracil. Do not use fluorouracil. Consider an alternative non-fluoropyrimidine containing regimen.

Routine genotypes

Normal metabolizers – These patients have two copies of the normal-function gene. These patients have normal DPYD enzyme function. About 9 in 10 people have this genotype. No change in fluoropyrimidine dose is recommended based on this genotype.