Absorption, Distribution, Excretion and Effects on Drug Metabolizing Enzyme Activities of a New Antiplatelet Drug, Ethyl 2-(4,5-bis(4-methoxyphenyl)thiazol-2-yl)pyrrol-1-ylacetate(KBT-3022), after Multiple Oral Administration in Mice.

Abstract

Absorption, distribution, excretion, enzyme induction and effect to platelet were investigated in male mice after oral administration of an antiplatelet drug, KBT-3022. 1. Radioactivity levels in the plasma 24 hr after daily oral administration of 14C-KBT-3022 reached a steady state by the 4th dosing. The radioactivity levels after the 21st dosing showed a broad peak with about half of the Cmax after single dosing but had a similar AUC0-24 h.2. Radioactivity levels in tissues 24 hr after daily oral administration of 14CKBT-3022 increased with the number of doses and reached a steady state by the 21st dosing except the spleen. The radioactivity levels in the lung, heart and testis after the 21st dosing were 5-6 times higher than those after single dosing, but those in the other tissues were lower than 4 times. Elimination of radioactivity from tissues after the 21st dosing was slower than that after single dosing. At 72 hr after the 21st dosing, the radioactivity level in the aorta was 50% of the maximum and those in the skin, testis, lung, fat and spleen were 24-35% of the maximum. High level of radioactivity was noted in the deferent duct as revealed by whole body autoradiography. 3. No marked difference was observed in plasma concentration of 6-keto-PGF1α and serum concentration of TXB2 between the single and repeated dosing groups, although the accumulation of radioactivity was noted in the aorta after multiple doses of 14C-KBT-3022. From these results, metabolites in the aorta would not inhibit the production of PGI2. 4. Excretion of radioactivity in the urine and feces did not change with the number of doses and was 1.3 and 92.7% of the cumulative dose, respectively, within 120 hr after the 21st dosing. 5. No significant effect on hepatic drug-metabolizing enzyme system was observed after repeated dosing of KBT-3022.