Pharmacokinetic and pharmacodynamic effects of oral eniluracil, fluorouracil and leucovorin given on a weekly schedule

Xiao Du Guo, Nancy Harold, M. Wasif Saif, Barbara Schuler, Eva Szabo, J. Michael Hamilton, Brian P. Monahan, Mary G. Quinn, Janet Cliatt, Diana Nguyen, Frank Grollman, Rebecca R. Thomas, Elizabeth A. McQuigan, Richard Wilson, Chis H. Takimoto, Jean L. Grem

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Abstract

Purpose: To determine the toxicities and pharmacokinetic effects of eniluracil (EU) given on two weekly dosing schedules with 5-fluorouracil (5-FU) and leucovorin (LV). Methods: A group of 26 patients received a single 24-h i.v. infusion of 5-FU 2300 mg/m2 to provide a pharmacokinetic reference. After 2 weeks, patients received oral EU 20 mg plus LV 30 mg on days 1-3 with a single dose of 5-FU 15-29 mg/m2 on day 2, or LV 30 mg on days 1-2 with a single dose of EU at least 1 h prior to 5-FU 29 mg/m2 on day 2 weekly for 3 of 4 weeks. Results: Diarrhea was the most common dose-limiting toxicity. The recommended dose of 5-FU is 29 mg/m2 per day. EU on either schedule decreased 5-FU plasma clearance by 48 to 52-fold, prolonged the half-life to > 5 h, and increased the percentage of 5-FU excreted in the urine from 2% to 64-66%. With EU, plasma fluoro-β-alanine was not detected while urinary excretion was reduced to < 1% of that seen with i.v. 5-FU alone. Marked increases in both plasma and urinary uracil were seen. Thymidylate synthase ternary complex formation was demonstrated in bone marrow mononuclear cells isolated 24 h after the first oral 5-FU dose; the average was 66.5% bound. Conclusions: Either a single 20-mg dose of EU given prior to or for 3 days around the oral 5-FU dose led to comparable effects on 5-FU pharmacokinetic parameters, and inhibition of dihydropyrimidine dehydrogenase and thymidylate synthase.

Original languageEnglish (US)
Pages (from-to)79-85
Number of pages7
JournalCancer Chemotherapy and Pharmacology
Volume52
Issue number1
DOIs
StatePublished - Jul 1 2003

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Keywords

  • Dihydropyrimidine dehydrogenase
  • Eniluracil
  • Fluorouracil
  • Pharmacokinetics
  • Thymidylate synthase

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

Cite this

Guo, X. D., Harold, N., Wasif Saif, M., Schuler, B., Szabo, E., Hamilton, J. M., Monahan, B. P., Quinn, M. G., Cliatt, J., Nguyen, D., Grollman, F., Thomas, R. R., McQuigan, E. A., Wilson, R., Takimoto, C. H., & Grem, J. L. (2003). Pharmacokinetic and pharmacodynamic effects of oral eniluracil, fluorouracil and leucovorin given on a weekly schedule. Cancer Chemotherapy and Pharmacology, 52(1), 79-85. https://doi.org/10.1007/s00280-003-0613-0