Impact of two weekly schedules of oral eniluracil given with fluorouracil and leucovorin on the duration of dihydropyrimidine dehydrogenase inhibition

Bruce Keith, Xiao Du Guo, Suzanne Zentko, Nancy Harold, Barbara Schuler, Mary Quinn, Jeremy Shapiro, Jean L. Grem

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Purpose: This study determined the effect of different weekly dosing schedules of 5-fluorouracil (5-FU)/leucovorin (LV)/eniluracil on dihydropyrimidine dehydrogenase (DPD) activity and plasma uracil levels. Methods: Plasma and mononuclear cells were isolated from peripheral blood samples obtained before, during, and at various times after 5-FU/LV/eniluracil therapy. Two schedules were studied: 20 mg of eniluracil p.o. plus 30 mg of LV p.o. on days 1-3 with a single dose of 5-FU given day 2, or 30 mg of LV p.o. on days 1-2 with a single dose of eniluracil and 5-FU on day 2. DPD activity was determined with a radioisotopic enzyme assay; the reaction products were separated by high-performance liquid chromatography. Plasma uracil levels were determined by gas chromatography-mass spectroscopy. Results: During oral therapy, DPD activity was profoundly depressed, and uracil levels were strikingly elevated with both schedules. With the daily-for-3-days schedule, DPD activity was similar to baseline values by 3 weeks after the earlier eniluracil dose, whereas it appeared to recover earlier in patients receiving the single-dose schedule, reaching baseline values by 2 weeks. Although baseline uracil values did not predict DPD activity accurately, plasma uracil levels >0.95 μM were associated with significantly lower DPD activity (median, 18.4 versus 287.6 pmol/min/mg). Conclusions: When eniluracil is given with 5-FU/LV, DPD inhibition appears to be influenced by schedule, and the time to recovery is much longer than has been observed with eniluracil given alone.

Original languageEnglish (US)
Pages (from-to)1045-1050
Number of pages6
JournalClinical Cancer Research
Volume8
Issue number5
StatePublished - May 2002

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Dihydrouracil Dehydrogenase (NADP)
Leucovorin
Fluorouracil
Uracil
Appointments and Schedules
Enzyme Assays
Plasma Cells
eniluracil
Gas Chromatography
Mass Spectrometry
High Pressure Liquid Chromatography
Therapeutics

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Impact of two weekly schedules of oral eniluracil given with fluorouracil and leucovorin on the duration of dihydropyrimidine dehydrogenase inhibition. / Keith, Bruce; Guo, Xiao Du; Zentko, Suzanne; Harold, Nancy; Schuler, Barbara; Quinn, Mary; Shapiro, Jeremy; Grem, Jean L.

In: Clinical Cancer Research, Vol. 8, No. 5, 05.2002, p. 1045-1050.

Research output: Contribution to journalArticle

Keith, Bruce ; Guo, Xiao Du ; Zentko, Suzanne ; Harold, Nancy ; Schuler, Barbara ; Quinn, Mary ; Shapiro, Jeremy ; Grem, Jean L. / Impact of two weekly schedules of oral eniluracil given with fluorouracil and leucovorin on the duration of dihydropyrimidine dehydrogenase inhibition. In: Clinical Cancer Research. 2002 ; Vol. 8, No. 5. pp. 1045-1050.
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T1 - Impact of two weekly schedules of oral eniluracil given with fluorouracil and leucovorin on the duration of dihydropyrimidine dehydrogenase inhibition

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AU - Guo, Xiao Du

AU - Zentko, Suzanne

AU - Harold, Nancy

AU - Schuler, Barbara

AU - Quinn, Mary

AU - Shapiro, Jeremy

AU - Grem, Jean L.

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N2 - Purpose: This study determined the effect of different weekly dosing schedules of 5-fluorouracil (5-FU)/leucovorin (LV)/eniluracil on dihydropyrimidine dehydrogenase (DPD) activity and plasma uracil levels. Methods: Plasma and mononuclear cells were isolated from peripheral blood samples obtained before, during, and at various times after 5-FU/LV/eniluracil therapy. Two schedules were studied: 20 mg of eniluracil p.o. plus 30 mg of LV p.o. on days 1-3 with a single dose of 5-FU given day 2, or 30 mg of LV p.o. on days 1-2 with a single dose of eniluracil and 5-FU on day 2. DPD activity was determined with a radioisotopic enzyme assay; the reaction products were separated by high-performance liquid chromatography. Plasma uracil levels were determined by gas chromatography-mass spectroscopy. Results: During oral therapy, DPD activity was profoundly depressed, and uracil levels were strikingly elevated with both schedules. With the daily-for-3-days schedule, DPD activity was similar to baseline values by 3 weeks after the earlier eniluracil dose, whereas it appeared to recover earlier in patients receiving the single-dose schedule, reaching baseline values by 2 weeks. Although baseline uracil values did not predict DPD activity accurately, plasma uracil levels >0.95 μM were associated with significantly lower DPD activity (median, 18.4 versus 287.6 pmol/min/mg). Conclusions: When eniluracil is given with 5-FU/LV, DPD inhibition appears to be influenced by schedule, and the time to recovery is much longer than has been observed with eniluracil given alone.

AB - Purpose: This study determined the effect of different weekly dosing schedules of 5-fluorouracil (5-FU)/leucovorin (LV)/eniluracil on dihydropyrimidine dehydrogenase (DPD) activity and plasma uracil levels. Methods: Plasma and mononuclear cells were isolated from peripheral blood samples obtained before, during, and at various times after 5-FU/LV/eniluracil therapy. Two schedules were studied: 20 mg of eniluracil p.o. plus 30 mg of LV p.o. on days 1-3 with a single dose of 5-FU given day 2, or 30 mg of LV p.o. on days 1-2 with a single dose of eniluracil and 5-FU on day 2. DPD activity was determined with a radioisotopic enzyme assay; the reaction products were separated by high-performance liquid chromatography. Plasma uracil levels were determined by gas chromatography-mass spectroscopy. Results: During oral therapy, DPD activity was profoundly depressed, and uracil levels were strikingly elevated with both schedules. With the daily-for-3-days schedule, DPD activity was similar to baseline values by 3 weeks after the earlier eniluracil dose, whereas it appeared to recover earlier in patients receiving the single-dose schedule, reaching baseline values by 2 weeks. Although baseline uracil values did not predict DPD activity accurately, plasma uracil levels >0.95 μM were associated with significantly lower DPD activity (median, 18.4 versus 287.6 pmol/min/mg). Conclusions: When eniluracil is given with 5-FU/LV, DPD inhibition appears to be influenced by schedule, and the time to recovery is much longer than has been observed with eniluracil given alone.

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