Uridine Triacetate For Lethal 5-Fu Toxicity Due To Dihydropyrimidine Dehydrogenase (Dpd) Deficiency.

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 100 mg/kg 5FU (weekly bolus MTD in mice). Groups of 10 mice each then received either vehicle or oral uridine triacetate (2,000 mg/kg t.id. × 5) beginning at a range of times after 5FU. Survival was monitored. Results: 100 mg/kg 5FU was lethal in mice pretreated with EU. Uridine triacetate administration beginning within 24 hours after EU + 5FU resulted in survival of all the mice in the treatment groups. Fewer mice survived if treated with uridine triacetate at later time points after EU plus 5FU. Conclusions: Timely treatment with uridine triacetate reduced 5FU toxicity and mortality in DPD-inhibited mice. Its benefit has previously been demonstrated in patients (and mice) overdosed with 5FU. Therefore, DPD-deficient patients who have received 5FU should also benefit from treatment with uridine triacetate if the deficiency is identified soon enough after 5FU dosing. Therapeutic monitoring of 5FU during or after infusions could permit rapid detection of 5FU overexposure due to DPD-deficiency, enabling the use of uridine triacetate as an antidote in DPD-deficient patients. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Wellstat Therapeutics Corporation