Pharmacokinetic Studies of New 5-FU Derivative, BOF-A2 (1) : Absorption, Distribution, Metabolism and Excretion after Single and Repeated Oral Administration to Rats

Abstract

The absorption, distribution, metabolism and excretion of the main metabolites, 1-ethoxymethyl-5-fluorouracil (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 rats.
1. There was no difference in the plasma concentration profile of each metabolite between SD and Donryu rats.
2. Cmax and AUC_0-24hr of each metabolite increased in dose-dependent manner, but showed non-linearity at the dose of 1000 mg/kg.
3. The plasma concentration of 5-FU was observed for a longer period after administration of BOF-A₂ than after co-administration of 5-FU and CNDP or of EM-FU and CNDP.
4. After a single administration to fasting and non-fasting male rats, the plasma concentration of EM-FU was higher in non-fasting rats and those of CNDP and 5-FU were higher in fasting rats.
5. After a single administration to male and female rats, the plasma concentration of EM-FU was higher in females, while that of 5-FU was higher in male rats.
6. The serum concentration of 5-FU in tumor-bearing male rats was lower than the plasma concentration in normal male rats. It was considered that these differences in the plasma concentrations of EM-FU and 5-FU are mainly dependent on the activities of EM-FU metabolyzing enzyme and that the difference in CNDP concentration was due to a different absorption.
7. After a repeated administration to male rats, the plasma concentration of EM-FU was higher and that of 5-FU was lower on Day 7 than on Day 1.
8. At 2-8 hr after a single administration to male and female rats, the concentrations of EM-FU, CNDP and 5-FU were higher in the digestive organs and kidney than in the plasma, but declined rapidly until 24 hr after the administration. In male rats, none of the metabolites showed any accumulation in tissues after a repeated administration.
9. After a single concurrent administration of cimetidine or cisplatin with BOF-A2 to male rats, the plasma concentration and urinary excretion of EM-FU increased and those of 5-FU decreased compared to the BOF-A2 administration alone. This result suggested that cimetidine and cisplatin inhibited the activity of EM-FU metabolizing enzyme.
10. Within 48 hr after a single administration to male rats, the urinary excretion of the metabolites was 6.8% for EM-FU, 17.9% for 5-FU and 58.4% for CNDP. 6.6% of BOF-A2 was detected in feces. Bilary excretion of each metabolite was very low.
11. After a repeated administration to male rats, the urinary excretion of EM-FU increased and that of 5-FU decreased.
12. After a repeated administration at 3, 10, or 30 mg/kg/day for 14 days to male rats, NADPH Cytochrome C reductase activity decreased in dose-dependent fashon, with DHUDase activity increasing at 30 mg/kg/day.