5-ETHYNYLURACIL (776C85) - PROTECTION FROM 5-FLUOROURACIL-INDUCED NEUROTOXICITY IN DOGS

5-Ethynyluracil (776C85) is a potent mechanism-based inactivator of di hydropyrimidine dehydrogenase (DPD), the enzyme that catalyzes the rap id catabolism of 5-fluorouracil (5-FU). Because catabolism is the majo r route for 5-FU clearance, we studied the effect of 5-ethynyluracil o n the pharmacokinetics and toxicity of continuous i.v. 5-FU infusion i n the dog. 5-FU at 40 mg/kg/24 hr resulted in a steady-state plasma 5- FU concentration of 1.3 mu M and was fatal with dogs dying from appare nt neurotoxicity. 5-Ethynyluracil lowered the total clearance of 5-FU from 9.9 to 0.2 L/hr/kg and enabled 1.6 mg/kg/24 hr 5-FU to achieve a steady-state plasma 5-FU concentration of 2.4 mu M with no apparent to xicity. 5-FU at 4 mg/kg/24 hr.achieved a steady-state plasma 5-FU conc entration of 5.3 mu M and produced only mild gastrointestinal disturba nces in 5-ethynyluracil-treated dogs. Thus, a catabolite of 5-FU appea rs to be responsible for the 5-FU-induced neurotoxicity in dogs.