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 radioactivity and 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 14C-BOF-A2 (3-[3-(6-benzoyloxy-3-cyano-2-pyridyloxycarbonyl) benzoyl]-1-ethoxymethyl-5-fluorouracil) were investigated in rats. 1. After a single administration to fasting and non-fasting male rats, blood levels of the radioactivity were higher in fasting than in non-fasting rats. 2. After a single administration to male and female rats, there was no marked difference in blood levels of the radioactivity between male and female rats. 3. After a repeated administration to male rats, the Cmax of blood radioactivity on Day 7 and 14 increased 1.8 and 2.2 times respectively, as compared to values on Day 1. The AUCO-24 hr increased in a manner similar to the Cmax. 4. After a single administration to male and female rats, the ratio of the AUC0-24 hr of 5-FU to total radioactivity was 7% in male and 5% in female, and that of EM-FU to total radioactivity was 63% in male and 78% in female. 5. After a single administration to male and female rats, the level of the radioactivity was higher in the liver, kidney, adrenal and bone marrow than in the plasma between 2-8 hr except for the stomach and small intestine. After 12 hr, elimination of the radioactivity from many tissues was slow compared to that from the plasma, and the radioactivity tended to remain. 6. After a repeated administration to male rats for 14 days, elimination of the radioactivity 24 hr after the final dosing was slow and the radioactivity tended to remain in many tissues. 7. Within 7 days after a single administration to non-fasting male rats, the excretion of the radioactivity accounted for 47.1% in the urine, 41.1% in the feces and 8.6% in the expired air. 1.2% remained in the body. The excretion was almost completed within 48 hr. Within 48 hr after a single administration to fasting male rats, the excretion of the radioactivity accounted for 64.9, 13.1 and 11.8% in urine, feces and expired air, respectively. 8. After a repeated administration to male rats for 14 days, the excretion of the radioactivity within 24 hr after each dose accounted for 40% in the urine, 35-55% in the feces and 10% in the expired air, showing no notable changes due to repeated administration. 9. Within 24 hr after a single administration to fasting and non-fasting male rats, the ratio of EM-FU to total radioactivity excreted in the urine amounted to 13% in fasting rats and 56% in non-fasting rats, and that of 5-FU amounted to 24% in fasting rats and 9% in non-fasting rats. 10. Within 48 hr after a single administration to non-fasting male rats, the biliary excretion of the radioactivity amounted to 4.5% About 50% of the radioactivity excreted in the bile was attributable to EM-FU. 11. Plasma protein binding in vitro of EM-FU was 34-46% for rats, 47-51% for dogs, and 27-38% for humans; that of 5-FU was 14-21% for rats, 16-17% for dogs, and 14-17% for humans; and that of CNDP was 53-58% for rats, 63-71% for dogs, and 67-69% for humans. Plasma protein binding of total radioactivity in vivo, 4 and 24 hr after a single administration to rats, were 39 and 93%, respectively.