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

BOF-A2 (emitefur: xy-3-cyano-2-pyridyloxycarbonyl]benzoyl}-1-ethoxy- m ethyl-5-fluorouracil), a novel 5-FU (5-fluorouracil)-derived drug, was co-administered with other conventional 5-FU-derived drugs or BV-araU [sorivudine: eta-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). T he 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, c ompared with each drug alone. On the other hand, these phenomena did n ot occur with BV-araU. These findings can be attributed to the fact th at 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 grea ter than that of BVU [(E)-5-(2-bromovinyl) uracil], another inhibitor of 5-FU degradation.