Disposition of Posatirelin. (2). The Transfer into the Fetus and Milk after Single Intravenous Dosing, and the Plasma Level, Distribution and Excretion of Radioactivity after Repeated Intravenous Administration of Posatirelin in Rats.

Abstract

The transfer of radioactivity into the fetus and milk was studied in pregnant and lactating rats, respectively, after a single intravenous administration of [14C]posatirelin. The plasma level, tissue distribution and excretion of radioactivity were investigated in male rats after 21 consecutive daily intravenous administration of [14C]posatirelin at a dose of 20 mg/kg/day. 1. The fetal concentrations of radioactivity reached the maximum level at 1 hr after dosing, which was about 15% of the maternal plasma concentrations. The fetal concentrations of radioactivity at 48 hr after dosing were about 6 % of the levels in fetus at 1 hr after administration. 2. The levels of radioactivity in the milk reached ap proximately 4.6 μg eq./ml at 1 hr after administration, decreased thereafter with the half life of 5.8 hr. After 6 hr, the milk levels were 3-6 times higher than the corresponding plasma levels. 3. The plasma levels of the radioactivity at 5 min after every dosing were at virtually plateau level of 53-78 μg eq./ml. Those at 24 hr after every dosing increased gradually until 6 days, and reached the plateau level of 0.20-0.34 μg eq./ml thereafter. The plasma levels after the final dosing decreased biphasically with the half lives of about 17 min (α-phase) and about 46 hr (β-phase). The AUC(0-∞) after the final dosing was about 54 μg eq.·hr/ml, which was not of statistically significant different from that after single administration. 4. Among the tissues and organs studied, the kidney showed the highest level of radioactivity at 5 min after repeated administration. In most tissues, the radioactivities were eliminated rapidly until 24 hr after administration but thereafter, the radioactivities decreased slowly. 5. During the period of repeated administration, the ex cretion of the radioactivity in the urine, feces and expired air were of almost constant values of 72-80%, 10-11% and 9-12%, respectively.