Jpn. J. Pharmacol. 70 (2), 139-148 (1996)

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

Shun Miyauchi (1), Takeshi Imaoka (1), Tadashi Okada (1), Masaaki Motoyama (1), Teruhisa Kawaguchi (2), Hitoshi Akiyama (2) and Masaaki Odomi (2)

(1) Fujii Memorial Research Institute, Otsuka Pharmaceutical Co., Ltd., 11-1, 1-chome, Karasaki, Ohtsu, Shiga 520-01, Japan (2) Tokushima Research Institute, Otsuka Pharmaceutical Co., Ltd., 463-10, Kawauchi, Tokushima 771-01, Japan

Abstract: BOF-A2 (emitefur: 3-{3-[6-benzoyloxy-3-cyano-2-pyridyloxycarbonyl] benzoyl}-1-ethoxymethyl-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.

Keywords: Emitefur (BOF-A2), 5-Fluorouracil-derived drug, Sorivudine (BV-araU), Leukopenia

Copyright© The Japanese Pharmacological Society 1996

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