Leukopenia-inducing effect of a combination of a new 5-fluorouracil (5-FU)-derived drug, BOF-A2 (emitefur), with other 5-FU-derived drugs or BV-araU (sorivudine) in rats

Jpn J Pharmacol. 1996 Feb;70(2):139-48. doi: 10.1254/jjp.70.139.

Abstract

BOF-A2 (emitefur: 3-(3-[6-benzoyloxy-3-cyano-2-pyridyloxycarbonyl]benzoyl)-1-ethoxy- methyl-5- fluorouracil), a novel 5-FU (5-fluorouracil)-derived drug, was co-administered with other conventional 5-FU-derived drugs or BV-araU [sorivudine: 1-beta-D-arabinofuranosyl-(E)-5-(2-bromovinyluracil)] for 8 consecutive days to rats. BOF-A2 (6 or 8 mg/kg, p.o.) co-administered with other 5-FU-derived drugs elevated the plasma 5-FU concentration 3- to 23.3-fold and decreased the peripheral white blood cell (WBC). The percentage decreases of WBC by 5-FU (4 mg/kg, i.p.), UFT (16 mg/kg, p.o.), tegafur (FT; 16 mg/kg, p.o.), carmofur (HCFU; 15 mg/kg, p.o.), doxifluridine (5'-DFUR; 16 mg/kg, p.o.) and flucytosine (200 mg/kg, p.o.) were 25.7%, 31.9%, 70.3%, 32.0%, 58.6% and 30.0%, respectively, compared with each drug alone. On the other hand, these phenomena did not occur with BV-araU. These findings can be attributed to the fact that the inhibitory activity of CNDP (3-cyano-2,6-dihydroxypyridine) for 5-FU degradation (IC50: 6.3 x 10(-9) M) is potent and 6000 times greater than that of BVU [(E)-5-(2-bromovinyl) uracil], another inhibitor of 5-FU degradation.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Antiviral Agents / pharmacology*
  • Arabinofuranosyluracil / analogs & derivatives*
  • Arabinofuranosyluracil / pharmacology
  • Dose-Response Relationship, Drug
  • Drug Combinations
  • Fluorouracil / analogs & derivatives*
  • Fluorouracil / metabolism
  • Fluorouracil / pharmacology
  • Leukopenia / metabolism*
  • Male
  • Rats
  • Rats, Sprague-Dawley

Substances

  • Antineoplastic Agents
  • Antiviral Agents
  • Drug Combinations
  • Arabinofuranosyluracil
  • Emitefur
  • sorivudine
  • Fluorouracil