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 Citations (Scopus)

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 - 2002
Externally publishedYes

Fingerprint

Fluorouracil
Food
Pharmacokinetics
Biological Availability
Area Under Curve
eniluracil
Drug interactions
Food-Drug Interactions
Plasmas
Cross-Over Studies
Population
Meals
Labels
Rate constants
Blood

Keywords

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

ASJC Scopus subject areas

  • Cancer Research
  • Pharmacology
  • Oncology

Cite this

Estimation of the effect of food on the disposition of oral 5-fluorouracil in combination with eniluracil. / Shepard, Dale R.; Mani, Sridhar; Kastrissios, Helen; Learned-Coughlin, Susan; Smith, Deborah; Ertel, Phillip; Magnum, Steve; Janisch, Linda; Fleming, Gini F.; Schilsky, Richard L.; Ratain, Mark J.

In: Cancer Chemotherapy and Pharmacology, Vol. 49, No. 5, 2002, p. 398-402.

Research output: Contribution to journalArticle

Shepard, DR, Mani, S, Kastrissios, H, Learned-Coughlin, S, Smith, D, Ertel, P, Magnum, S, Janisch, L, Fleming, GF, Schilsky, RL & Ratain, MJ 2002, 'Estimation of the effect of food on the disposition of oral 5-fluorouracil in combination with eniluracil', Cancer Chemotherapy and Pharmacology, vol. 49, no. 5, pp. 398-402. https://doi.org/10.1007/s00280-002-0431-9
Shepard, Dale R. ; Mani, Sridhar ; Kastrissios, Helen ; Learned-Coughlin, Susan ; Smith, Deborah ; Ertel, Phillip ; Magnum, Steve ; Janisch, Linda ; Fleming, Gini F. ; Schilsky, Richard L. ; Ratain, Mark J. / Estimation of the effect of food on the disposition of oral 5-fluorouracil in combination with eniluracil. In: Cancer Chemotherapy and Pharmacology. 2002 ; Vol. 49, No. 5. pp. 398-402.
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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.",
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T1 - Estimation of the effect of food on the disposition of oral 5-fluorouracil in combination with eniluracil

AU - Shepard, Dale R.

AU - Mani, Sridhar

AU - Kastrissios, Helen

AU - Learned-Coughlin, Susan

AU - Smith, Deborah

AU - Ertel, Phillip

AU - Magnum, Steve

AU - Janisch, Linda

AU - Fleming, Gini F.

AU - Schilsky, Richard L.

AU - Ratain, Mark J.

PY - 2002

Y1 - 2002

N2 - 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.

AB - 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.

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KW - Pharmacokinetic analysis

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