5-Ethynyluracil (776C85): protection from 5-fluorouracil-induced neurotoxicity in dogs.
5-Ethynyluracil (776C85) is a potent mechanism-based inactivator of dihydropyrimidine dehydrogenase (DPD), the enzyme that catalyzes the rapid catabolism of 5-fluorouracil (5-FU). Because catabolism is the major route for 5-FU clearance, we studied the effect of 5-ethynyluracil on the pharmacokinetics and toxicity of continuous i.v. 5-FU infusion in the dog. 5-FU at 40 mg/kg/24 hr resulted in a steady-state plasma 5-FU concentration of 1.3 microM and was fatal with dogs dying from apparent 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 microM with no apparent toxicity. 5-FU at 4 mg/kg/24 hr achieved a steady-state plasma 5-FU concentration of 5.3 microM and produced only mild gastrointestinal disturbances in 5-ethynyluracil-treated dogs. Thus, a catabolite of 5-FU appears to be responsible for the 5-FU-induced neurotoxicity in dogs.
Davis
S T
ST
Division of Molecular Genetics and Microbiology, Wellcome Research Laboratories, Research Triangle Park, NC 27709.
Joyner
S S
SS
Baccanari
D P
DP
Spector
T
T
D000818:Animals; D002493:Central Nervous System Diseases / Q000139:chemically induced / Q000517:prevention & control*; D042943:Dihydrouracil Dehydrogenase (NADP); D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005472:Fluorouracil / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity*; D007262:Infusions, Intravenous; D008297:Male; D010088:Oxidoreductases / Q000037:antagonists & inhibitors; D014498:Uracil / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood; D015091:beta-Alanine / Q000031:analogs & derivatives / Q000032:analysis
D015091:beta-Alanine; C073482:eniluracil; C032348:alpha-fluoro-beta-alanine; D014498:Uracil; D010088:Oxidoreductases; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil