The oral fluorinated pyrimidines

The fluorinated pyrimidines have played a major role in the treatment of ma ny common tumors since 5-fluorouracil (5FU) was first introduced. Studies o f the cellular and clinical pharmacology of 5FU have led to an improved und erstanding of the mechanisms of action of this agent. This knowledge has al lowed the optimal and rational development of fluoropyrimidine therapy, wit h significant therapeutic advances in recent years. Efforts to improve the therapeutic index of 5FU have included alteration of schedule, and the addition of biochemical modulators such as folinic acid. Although protracted continuous infusion of 5FU has led to better response rates and decreased toxicity, the administration of 5FU by protracted infus ion is not only costly, but also inconvenient to the patient. Furthermore i t is often associated with infectious and thrombotic complications related to the required indwelling intravenous catheter. Protracted oral administration is a rational route for administering 5FU, b eing preferred by the patient and the pharmaco-economist. The unpredictable and low oral bioavailability of 5FU initially discouraged this form of tre atment. This problem has now been overcome by the new generation of oral fl uoropyrimidines. Two main strategies have been pursued: 1) The administrati on of an inactive prodrug of 5FU, which is absorbed intact, and subsequentl y converted to 5FU. Capecitabine is converted to 5FU by a 3 step enzymatic process. 2) The administration of 5FU with an inhibitor of dihydropyrimidin e dehydrogenase (DPD) to minimise the erratic absorption and variable clear ance of 5FU: the preparations UFT, S1, and ethinyluracil/5FU contain an ora l fluoropyrimidine co-administered orally with inhibitors of this enzyme. T he development and characteristics of these agents are discussed.