Disposition of KW-4679 (2) : Absorption, Distribution, Excretion of 14C-KW-4679 after Multiple Oral Administrations in Rats and Effect of KW-4679 on Drug Metabolizing Enzyme in Rats

The disposition of 14C-KW-4679 after a single and repeated oral administration for 21 days to male rats at a dose of 1 mg/kg and the effect of repeated oral administration of KW-4679 to female rats for 7 days on drug metabolizing enzyme system, were studied. 1) Plasma levels of radioactivity collected at 24 hr after 1st, 7th, 14th and 21st dose was 7.8, 10.8, 13.3 and 12.1 ng eq./ml, respectively and nearly reached the steady state during 7th to 14th dose. The level of radioactivity at 24 hr after the last administration was 1.2 times higher than that after the initial administration. But the Cmax and AUC0-24 of plasma level of radio activity after the last administration were similar to those after the initial administration. The tissue level of radioactivity, which was measured at 24 hr after the 1st, 7th, 14th and 21st dose, reached the steady state during 7th to 14th dose as observed with blood and plasma levels of radioactivity. After the last administration, the level of radioactivity in fat decreased more slowly compared to that after a single dose. 2) The radioactivity excreted into urine and feces was measured every 24 hr after daily administration. The excretion was kept constant after the 8th dose. The cumulative excretion until 168 hr after 21th dose were 36.5% in urine and 57.2% in feces, respectively. This ratio was kept virtually constant from the initial to the final administration. 3) Repeated oral administrations of 0.1 to 25 mg/kg of KW-4679 to female rats for 7 days did not affect drug metabolizing enzyme system of the liver microsomes.