Clinical and pharmacokinetic studies of prolonged administration of high-dose uridine intended for rescue from 5-FU toxicity.
A clinical and pharmacokinetic investigation of prolonged administration of high-dose uridine was performed in seven patients with advanced-stage cancer. Uridine administration was examined as a continuous infusion at 1 and 2.5 g/m2/hr (two patients) and as a series of intermittent infusions during 72 hrs at doses of 1-3 g/m2/hr, whereby 3-hr uridine administration was alternated with a 3-hr treatment-free interval (six patients). Continuous infusions of uridine resulted in plasma uridine concentrations of 0.5-1 mM, but was discontinued due to rapid increase in body temperature. Further studies focused on the intermittent schedule in an attempt to avoid the development of fever. Intermittent uridine infusion resulted in markedly elevated plasma uridine levels in the millimolar range. However, during the treatment-free period, rapid elimination of uridine was observed, resulting in plasma levels of 138-335 microM for 3 g/m2/hr. Plasma uracil concentrations also increased markedly, but smaller fluctuations compared to uridine were seen. Total urinary excretion of uridine was 15%-40% of the dose, while uracil excretion in urine was 2%-17%. Intermittent uridine infusion resulted in little or no rise in body temperature (less than or equal to 1.0 degrees C) in ten of 12 courses, and fever of greater than 39 degrees C in two courses. Both intermittent and continuous infusion of uridine gave rise to phlebitis, which necessitated central venous administration. These data show that using an intermittent infusion schedule, long-term administration of uridine is tolerable, with fever being dose-limiting. Intermittent infusion provides for the maintenance of markedly elevated plasma uridine levels and long-term uridine exposure to the tissues, and may be useful in further studies aimed at testing the potential of uridine to rescue patients from 5-FU toxicity.
D000368:Aged; D001831:Body Temperature / Q000187:drug effects; D004334:Drug Administration Schedule; D005260:Female; D005472:Fluorouracil / Q000009:adverse effects / Q000378:metabolism*; D006801:Humans; D007263:Infusions, Parenteral; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D014498:Uracil / Q000097:blood; D014529:Uridine / Q000008:administration & dosage* / Q000378:metabolism / Q000494:pharmacology
D014498:Uracil; D005472:Fluorouracil; D014529:Uridine