Clinical implications of dihydropyrimidine dehydrogenase inhibition

Dihydropyrimidine dehydrogenase (DPD) is the initial, rate-limiting enzyme in the catabolism of 5-fluorouracil (5-FU). DPD has an important role in re gulating the availability of 5-FU for anabolism. It is now clear that DPD a lso accounts for much of the variability observed with the therapeutic use of 5-FU, including variable drug levels during 24-hour infusion, erratic ph armacokinetics, variable bioavailability, inconsistent toxicity, and variab ility in drug response (resistance). The use of DPD inhibitors has been exp lored as a means to improve 5-FU pharmacology. This article describes how d rugs that modulate DPD activity have been used to develop a new class of or ally administered fluoropyrimidines, now referred to as DPD-inhibiting fluo ropyrimidine (DIF) drugs. The biochemical basis for using four DIF drugs-ur acil and tegafur (UFT), ethynyluracil, S-1, and BOF-A2-currently in clinica l evaluation in the United States, is hereby reviewed. Early clinical data suggest that these drugs may achieve antitumor efficacy equivalent to that of conventional intravenously administered 5-FU therapy, with the additiona l advantages of reduced toxicity, less expense, and improved quality of lif e.