Clinical implications of dihydropyrimidine dehydrogenase on 5-FU pharmacology

Dihydropyrimidine dehydrogenase (DPD) is the initial rate-limiting enzyme in the catabolism of 5-fluorouracil (5-FU), accounting for catabolism of over 85% of an administered dose of 5-FU. DPD plays an important role in regulating the availability of 5-FU for anabolism. DPD also accounts for much of the variability observed with the therapeutic use of 5-FU. This includes variable 5-FU levels over 24 hours during a continuous infusion; the widely reported variability in the pharmacokinetics of 5-FU; the observed variable bioavailability that led to the recommendation that 5-FU not be administered as an oral agent; and lastly, the observed variability in both toxicity and drug response (resistance) after identical 5-FU doses. Knowledge of the DPD level, as well as the levels of other potentially important molecular markers (e.g., thymidylate synthase), may permit adjustments or modulation of the 5-FU dose that can result in an increase in the therapeutic efficacy of 5-FU.