The role of dihydropyrimidine dehydrogenase (DPD) modulation in 5-FU pharmacology

Over the past several years, the pyrimidine catabolic pathway and, in particular, the first enzymatic step involving dihydropyrimidine dehydrogenase (DPD) have been recognized as being critical in determining the ultimate metabolism and, in turn, the pharmacology of the antimetabolite drug 5-fluorouracil (5-FU). Variability in DPD activity in the normal population accounts for observed differences in the pharmacokinetics and oral bioavailability of 5-FU with an additional smaller percentage (< 5%) of the population having a relatively profound deficiency in DPD activity. Diurnal variation of DPD activity is responsible for the observed variation in 5-FU levels during continuous or protracted 5-FU infusions. Relatively elevated levels of DPD in tumor tissue may also be partially responsible for observed 5-FU tumor resistance. Finally, the pyrimidine catabolic pathway may have a role for at least some of the observed 5-FU clinical toxicities, including cardiotoxicity, hand-foot syndrome, and at least some types of neurotoxicity. In order to reduce DPD variation and potentially some of the 5-FU toxicities, there have been attempts to synthesize new fluoropyrimidine drugs used together with drugs that inhibit DPD activity. In this paper, several new types of DPD inhibitors recently introduced into the clinic will be discussed.