title: Impact of two weekly schedules of oral eniluracil given with fluorouracil and leucovorin on the duration of dihydropyrimidine dehydrogenase inhibition.
abstract: OBJECTIVE
  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 microM 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.
authors: National Cancer Institute-Navy Medical Oncology, Cancer Therapeutics Branch, Center for Cancer Research, National Naval Medical Center, Bethesda, Maryland 20889-5105, USA.
authors: Bruce
authors: B
authors: Keith
authors: Xiao-Du
authors: XD
authors: Guo
authors: Suzanne
authors: S
authors: Zentko
authors: Nancy
authors: N
authors: Harold
authors: Barbara
authors: B
authors: Schuler
authors: Mary
authors: M
authors: Quinn
authors: Jeremy
authors: J
authors: Shapiro
authors: Jean L
authors: JL
authors: Grem
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D042943:Dihydrouracil Dehydrogenase (NADP); D004334:Drug Administration Schedule; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D010088:Oxidoreductases / Q000037:antagonists & inhibitors* / Q000097:blood; D013997:Time Factors; D014498:Uracil / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood
chemical_list: C073482:eniluracil; D014498:Uracil; D010088:Oxidoreductases; D042943:Dihydrouracil Dehydrogenase (NADP); D002955:Leucovorin; D005472:Fluorouracil