Oral DPD-inhibitory fluoropyrimidine drugs

Over the past decade, increasing data have emphasized both the importance o f dihydropyrimidine dehydrogenase (DPD) the initial, rate-limiting enzyme i rt the catabolism of fluorouracil (5-FU), and its role as a control step in 5-FU metabolism, regulating the availability of 5-FU for anabolism. It is now clear that DPD also accounts for much of the variability observed with therapeutic use of 5-FU, including variabilities in 5-FU levels over a 24-h our infusion, interindividual pharmacokinetics, bioavailability, toxicity, and drug response (resistance). This variability makes effective dosing of 5-FU and related drugs difficult, lit order to lessen this variability, and potentially improve 5-FU pharmacology, the pharmaceutical industry has mad e an effort to develop DPD inhibitors to modulate 5-FU metabolism, which ha s resulted in the creation of a new subclass of orally administered fluorop yrimidines, known as DPD-inhibiting fluoropyrimidines (DIF), Four drugs-ura cil and tegafur (UFT) or the combination of UFT and leucovorin, ethynylurac il (eniluracil), S-1, and BOF-A2-have recently undergone clinical evaluatio n in the United States, The biochemical basis for using these drugs is revi ewed.