Disposition of Taltirelin. (2): The Transfers into the Fetus and Milk, Sex-Related Difference after Single Oral Administration and Blood Concentration after Repeated Oral Dosing in Rats.

Abstract

The transfers of 14C-taltirelin into the fetus and milk and sex-related difference were investigated after a single oral administration of 14C-taltirelin at a dose of 3 mg/kg to rats. The blood level after repeat ed oral dosing was also studied. 1. In pregnant rats on the 13th and 19th day of pregnancy, the levels of radioactivity in whole fetus reached the maximum levels at 3 hr after oral administration, which accounted for 1/7 and 1/3 of the maternal blood concentration, respectively. At 3 hr, the transfered radioactivity in fetus of 19th day pregnant rats was less than 0.002% of dose per one fetus. 2. In lactating rats on the 14th day af ter delivery, levels of radioactivity in the blood and milk at 1 hr after dosing were 11.0 and 8.9 ng eq./g, respectively. The radioactivity in the milk decreased more slowly than that in blood and the radioactivity level in the milk was about 2 times higher than the corresponding blood level from 6hr after dosing. 3. There were no significant sex-related differences in the pharmacokinetic parameters of blood radioactivity and urinary excretion. MDOA, found in the urine of male and female rats, accounted for approximately 18 and 30% of urinary radioactivity, respectively, but any sex difference in kind of urinary metabolite was not observed. 4. After 15 times repeated oral administrations to male rats, the Cmax, t1/2 and AUCinf values of blood radioactivity increased by 1.3, 2.2 and 3.1 times compared with those after the first dosing, respectively. The blood level of radioactivity at 1 hr after each dosing reached steady-state within 7 times dosing.