Uridine triacetate for lethal 5-FU toxicity due to dihydropyrimidine dehydrogenase (DPD) deficiency.

Abstract

e13505 Background: The enzyme dihydropyrimidine dehydrogenase (DPD) catalyzes the first step in degradation of 5-fluorouracil (5FU). Patients with complete or partial DPD deficiency (about 0.1% and 3% of the population, respectively) can experience severe or lethal toxicities after receiving standard doses of 5FU, and impaired clearance may underlie a large fraction of the ∼1,300 deaths per year due to 5FU toxicity in the US. Orally-administered uridine triacetate (vistonuridine) prevents or diminishes toxicities when administered after 5FU overexposure, and has been used successfully as an antidote in more than 28 patients to date who had received accidental overdoses of 5FU. Because DPD deficiency may alter 5FU clearance kinetics (versus 5FU overdoses in the setting of normal DPD activity), studies were conducted on reversal of 5FU toxicity in mice pretreated with the potent DPD inhibitor ethynyluracil (eniluracil; EU) to model DPD deficiency. Methods: Balb/C mice received 2 mg/kg EU i.p., followed by 1...