Disposition of KW-4679 (5): Transfer of 14C-KW-4679 to Fetus and Milk after Oral Administration to Rats

The transfer of 14C-KW-4679 to fetus and milk after oral administration at a dose of 1 mg/kg to rats was investigated. 1) The plasma level of radioactivity rapidly increased after oral administration of 14C-KW-4679 to 12th and 19th-day pregnant rats. Radioactivity was then eliminated from plasma almost biexponentially. 2) The level of radioactivity in fetus after oral administration to 12th-day pregnant rats was lower than that in maternal plasma, the ratio was as low as 0.18. In dams, level of radioactivity higher than that in the plasma was observed in the kidney and liver. 3) The level of radioactivity in fetal plasma and tissues was 0.07 to 0.38 times that in maternal plasma after oral administration to 19th-day pregnant rats. The fetal tissue level of radioactivity decreased virtually in parallel with the level in maternal plasma. 4) When 14C-KW-4679 was administered to lactating rats, the level of radioactivity in the milk showed the delayed peak as compared to that in the plasma. The level of radioactivity in the milk was always higher than that in the plasma from 4 hr after administration, and the radioactivity was eliminated from the milk more slowly than from the plasma. The AUC of radioactivity in the milk was about 1.5 times larger than that in the plasma. The radioactivity in the suckling rats reached the peak level at 24 hr after administration, decreasing nearly in parallel with radioactivity in the milk afterward. When 14C-KW-4679 was orally administered to 3-weeks rats, a higher Cmax but almost similar elimination of radioactivity was observed as compared with matured rats. 5) When 1 mg/kg of the unlabeled KW-4679 was orally administered to lactating rats, the milk to plasma concentration ratio of unchanged KW-4679 rose from 0.36 to 1.97 during 0.25 to 24 hr after administration. The AUC0-24 of unchanged KW-4679 in the milk and plasma were 66.3% and 74.5% of AUC0-24 of radioactivity in the milk and plasma, respectively.