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 dehyd rogenase (DPD) have been recognized as being critical in determining t he ultimate metabolism and, in turn, the pharmacology of the antimetab olite drug 5-fluorouracil (5-FU). Variability in DPD activity in the n ormal population accounts for observed differences in the pharmacokine tics and oral bioavailability of 5-FU with an additional smaller perce ntage (< 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, Fin ally, the pyrimidine catabolic pathway may have a role for at least so me 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.