Pharmacokinetic Studies of New 5-FU Derivative, BOF A2 (2): Absorption and Excretion after Single and Repeated Oral Administration to Dogs, Monkeys and Guinea Pigs
1994 Volume 9 Issue 5 Pages 651-660
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1994 Volume 9 Issue 5 Pages 651-660
The absorption and excretion of the main metabolites, 1-ethoxymethyl-5fluorouracil (EM-FU, a masked form of 5-fluorouracil), 3-cyano-2, 6-dihydroxypyridine (CNDP, a potent inhibitor of dihydrouracil dehydrogenase) and 5-fluorouracil (5-FU), after a single and repeated oral administration of BOF-A2 (3-[3 (6-benzoyloxy-3-cyano-2-pyridyloxycarbonyl) benzoyl]-1-ethoxymethyl-5-fluorouracil) were investigated in dogs, monkeys and guinea pigs. The plasma profiles of benzoic acid and isophthalic acid were also studied.
1. After a single administration to fasting and non-fasting dogs, EM-FU reached Cmax at 8 hr and declined with the biological half life (T1/2) of 19.4 and 48.2 hr, respectively. There were no differences in the plasma concentrations of EM-FU and CNDP between fasting and non-fasting dogs. 5-FU was not detected in the plasma at any time studied.
2. After a single administration to dogs, isophthalic acid was detected in the plasma but showed a lower concentration than EM-FU and CNDP.
3. After a repeated administration to monkeys at 6 or 20 mg/kg/day, EMFU, CNDP and 5-FU showed dose-dependent plasma concentrations on Day 1. Each metabolite was gradually eliminated from the plasma. At 20 mg/kg, EMFU and CNDP declined with a T1/2 of 22 and 10 hr, respectively, and the concentration of 5-FU continued to increase until 24 hr after administration.
4. After a repeated administration to monkeys, the Cmax and AUC0-24 hr, of 5-FU tended to decrease as the dosing periods were prolonged, and T1/2 was shortened.
5. After a single administration to monkeys, no benzoic acid was detected in the plasma at any time studied. Isophthalic acid showed Cmax at 1 hr, but was eliminated slowly after 6 hr.
6. After a single administration to guinea pigs, neither 5-FU nor benzoic acid were detected in the plasma at any time studied.
7. Within 72 hr after a single administration to dogs, urinary excretion of the metabolites was 10.1% for EM-FU and 30.1% for CNDP, with almost no 5-FU being excreted in the urine. Within 96 hr after single administration to monkeys, urinary excretion of the metabolites was 12.7% for EM-FU, 7.1% for 5-FU and 50.9% for CNDP. The excretion of each metabolite in dogs and monkeys tended to be delayed as compared to that in rats.
