5-Ethynyluracil (776C85): protection from 5-fluorouracil-induced neurotoxicity in dogs

Biochem Pharmacol. 1994 Jul 19;48(2):233-6. doi: 10.1016/0006-2952(94)90092-2.

Abstract

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.

MeSH terms

  • Animals
  • Central Nervous System Diseases / chemically induced
  • Central Nervous System Diseases / prevention & control*
  • Dihydrouracil Dehydrogenase (NADP)
  • Dogs
  • Dose-Response Relationship, Drug
  • Fluorouracil / blood
  • Fluorouracil / pharmacokinetics
  • Fluorouracil / toxicity*
  • Infusions, Intravenous
  • Male
  • Oxidoreductases / antagonists & inhibitors
  • Uracil / administration & dosage
  • Uracil / analogs & derivatives*
  • Uracil / blood
  • beta-Alanine / analogs & derivatives
  • beta-Alanine / analysis

Substances

  • beta-Alanine
  • eniluracil
  • alpha-fluoro-beta-alanine
  • Uracil
  • Oxidoreductases
  • Dihydrouracil Dehydrogenase (NADP)
  • Fluorouracil