PHARMACOKINETICS OF THE NEW THYROTROPIN-RELEASING-HORMONE ANALOG MONTIRELIN HYDRATE - 2ND COMMUNICATION - DISTRIBUTION AND TRANSFER INTO THE FETUS AND MILK AFTER A SINGLE INTRAVENOUS ADMINISTRATION, AND PHARMACOKINETICS AND ENZYME-INDUCTION AFTER REPEATED INTRAVENOUS ADMINISTRATION TO RATS

Pharmacokinetics of C-14-labeled montirelin hydrate (CAS 90243-66-6, N S-3) in rats was studied after single or repeated intravenous administ ration. 1. Radioactivity concentrations in tissues after single admini stration to male and female rats were highest in the kidney followed ( in this order) by plasma, liver, blood, pancreas, uterus (female rats) , lung and skin and low in various brain sites 5 min after administrat ion. The concentrations in most tissues were practically parallel to t hose in plasma over the 24-h period after administration. After decrea sing rapidly the concentrations rose slightly for 10 h and then decrea sed gradually. 2. Five min after single administration to male rats, t he concentration of the main metabolite CNK-6004 (deamidated product) was lower in the plasma, but higher in the liver and kidney than the N S-3 concentration. From 0.5 to 2 h after administration, the concentra tion of CNK-6004 was higher than that of NS-3 in the plasma, liver and kidney, accounting for 33-64 % of the radioactivity concentration. 3. After administration to rats on the 18th day of pregnancy, the radioa ctivity concentrations in the fetal whole body and fetal tissues peake d later than those in the maternal plasma, tissues and placenta. The m aximum concentration in the fetal tissues was 2 % or less of that in t he maternal plasma. 4. After administration to lactating rats, the rad ioactivity concentration in milk reached the maximum 10 h after admini stration, and decreased gradually in parallel with the concentration i n the plasma 24 to 168 h after administration. 5. During repeated once daily administration for 10 days, the radioactivity concentration in the plasma 24 h after each administration reached practically steady s tate level after the 7th administration and decreased with a half-life of 38.1 h after the last administration. 6. The radioactivity concent rations in most tissues after the last administration were not signifi cantly different from those after a single administration. Decreased e limination of the radioactivity was observed in the white fat and skin , in which radioactivity levels were higher than those in the other ti ssues a long time after the last dose. 7. Excretion of the radioactivi ty in the urine and feces during repeated administration was constant after the 2nd administration. The excretion by 168 h after the last ad ministration was 66.9 and 14.3 % of the cumulative dose in the urine a nd feces, respectively (total: 81.2 %). 8. The composition of metaboli tes in the plasma, liver, kidney and urine after the last administrati on did not differ markedly from that after a single administration. On ce daily repeated administration for 7 days had no effect on the liver drug metabolizing enzyme activities.