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Impact of Two Weekly Schedules of Oral Eniluracil Given with Fluorouracil and Leucovorin on the Duration of Dihydropyrimidine Dehydrogenase Inhibition

National Cancer Institute-Navy Medical Oncology, Cancer Therapeutics Branch, Center for Cancer Research, National Naval Medical Center, Bethesda, Maryland 20889-5105

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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