Estimation of the effect of food on the disposition of oral 5-fluorouracil in combination with eniluracil

Dale R. Shepard, Sridhar Mani, Helen Kastrissios, Susan Learned-Coughlin, Deborah Smith, Phillip Ertel, Steve Magnum, Linda Janisch, Gini F. Fleming, Richard L. Schilsky, Mark J. Ratain

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

Aims: To determine the effect of food on the pharmacokinetics of 5-fluoruracil (5-FU) taken orally with eniluracil and to compare the performance of different pharmacokinetic analysis methods in the detection a potential food-drug interaction. Methods: In a randomized, open-label, two-way crossover study, 12 patients received eniluracil (50 mg, orally) on days 1 and 2 and 5-FU (20 mg/m2, orally) on day 2 following either a 2-h fast or 20 min after a standard meal. Treatments were separated by 7 days. Timed blood samples were collected during the first two treatment periods and 5-FU concentrations determined by GC/MS. Data were analyzed and pharmacokinetic parameter estimates were obtained using a noncompartmental, two-stage and population analysis methods. Results: In fasted individuals, the clearance/bioavailability of 5-FU was estimated to be 5.6 l/h. The mean absorption lag-time was 0.24 h and was followed by rapid absorption of 5-FU. Administration of 5-FU and eniluracil with food resulted in a decrease in the 5-FU absorption rate constant by 90%. As a result, the peak plasma concentration (Cmax) of 5-FU was decreased by 21% and the time to Cmax was increased 2.9-fold. Clearance of 5-FU, relative bioavailability, and area under the plasma concentration vs time curve (AUC) remained unchanged with coad-ministration of food. Similar results were obtained using all three data analysis methods. Conclusions: Administration of food with oral 5-FU and eniluracil slowed absorption of 5-FU and decreased 5-FU Cmax, but did not e+ect AUC. Further investigation of the incorporation of population pharmacokinetic approaches in food e+ect studies is warranted.

Original languageEnglish (US)
Pages (from-to)398-402
Number of pages5
JournalCancer Chemotherapy and Pharmacology
Volume49
Issue number5
DOIs
StatePublished - May 6 2002
Externally publishedYes

Keywords

  • 5-Fluorouracil
  • Eniluracil
  • Food-drug interaction
  • Pharmacokinetic analysis

ASJC Scopus subject areas

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

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    Shepard, D. R., Mani, S., Kastrissios, H., Learned-Coughlin, S., Smith, D., Ertel, P., Magnum, S., Janisch, L., Fleming, G. F., Schilsky, R. L., & Ratain, M. J. (2002). Estimation of the effect of food on the disposition of oral 5-fluorouracil in combination with eniluracil. Cancer Chemotherapy and Pharmacology, 49(5), 398-402. https://doi.org/10.1007/s00280-002-0431-9