Pharmacology of fluorinated pyrimidines: eniluracil

The pharmacological inactivation of dihydropyrimidine dehydrogenase (DPD) represents one strategy to improve 5-FU therapy, which historically has been associated with unpredictable pharmacological behavior and toxicity. This is principally due to high interpatient differences in the activity of DPD, the enzyme that mediates the initial and rate-limiting step in 5-FU catabolism. By inactivating DPD and suppressing the catabolism of 5-FU, eniluracil has dramatically altered the pharmacological profile of 5-FU. The maximum tolerated dose of oral 5-FU given with oral eniluracil (1.0 to 25 mg/m2) is substantially lower than conventional 5-FU doses. In the presence of eniluracil, bioavailability of 5-FU has increased to approximately 100%, the half-life is prolonged to 4 to 6 hours, and systemic clearance is reduced > 20-fold to values comparable the glomerular filtration rate (46 to 58 mL/min/m2). Renal excretion (approximately 45% to 75%), instead of DPD-related catabolism, is the principal route of elimination of oral 5-FU given with eniluracil. Chronic daily administration of oral 5-FU 1.0 mg/m2 twice daily with eniluracil 20 mg twice daily produces 5-FU steady-state concentrations (8-38 ng/mL) similar to those achieved with protracted intravenous administration on clinically relevant dose-schedules. On a daily x 5 regimen, higher 5-FU AUC values are related to neutropenia, whereas elevated 5-FU AUC and steady-state concentrations are related to diarrhea when oral 5-FU is given daily with eniluracil on a chronic schedule. The pharmacokinetic behavior of oral eniluracil is similar to that for oral 5-FU. Administration of eniluracil 10 to 20 mg twice daily completely inactivates DPD activity both in peripheral blood mononuclear cells and in colorectal tumor tissue, and prolonged inhibition of DPD after discontinuation of eniluracil treatment has been noted. In the presence of eniluracil, oral administration of 5-FU is feasible and variation in 5-FU exposure is reduced, with the anticipation of further reduction in variation as dosing guidelines based on renal function are formulated.