PHARMACOKINETICS OF THE NEW THYROTROPIN-RELEASING-HORMONE ANALOG MONTIRELIN HYDRATE - 1ST COMMUNICATION - PLASMA-CONCENTRATIONS METABOLISM AND EXCRETION AFTER A SINGLE INTRAVENOUS ADMINISTRATION TO RATS, DOGS AND MONKEYS

The plasma concentrations, metabolism and excretion were studied in ra ts, dogs and monkeys after a single intravenous administration of C-14 -montirelin hydrate (CAS 90243-66-6, C-14-NS-3), 1. The plasma concent ration of radioactivity and the area under curve (AUC(0-infinity)) inc reased with the dose after intravenous administration of 0.25, 1 and 4 mg/kg to male rats. 2. Until 4 h after intravenous administration of 0.25 mg/kg, the plasma concentration of radioactivity decreased with h alf-lives of 0.512, 0.771 and 0.786 h in male rats, dogs and monkeys, respectively. The plasma concentration of radioactivity in rats increa sed 6-10 h after administration, suggesting enterohepatic circulation. 3. The plasma concentration of NS-3 in various animal species decreas ed biphasically after intravenous administration. The elimination half -lives, t(1/2)beta, in rats, dogs and monkeys were 0.324, 0.679 and 0. 682 h, respectively, and the steady state volumes of distribution, V-d ss were 0.248, 0.319 and 0.306 1/kg, respectively. 4. The binding of N S-3 to serum protein was less than 3% in rats, dogs, monkeys and human s. 5. Within 48 h after intravenous administration of 1 mg/kg to male rats, the excretion of radioactivity in urine, feces and expired air w as 67.3, 15.0 and 14.8 % of the dose, respectively (total 97.1 %). The biliary excretion of radioactivity was 26.6 % within 24 h after dosin g. 6. No sex-related difference was found in plasma concentration of r adioactivity or the excretion of radioactivity in urine, feces and exp ired air after intravenous administration of 1 mg/kg to male and femal e rats. 7. In male dogs, the excretion of radioactivity in urine and f eces was 92.3 and 5.6 % of the dose, respectively, during 72 h after i ntravenous administration of 0.25 mg/kg (total 97.9 %). 8. In male mon keys, the excretion of radioactivity in urine and feces was 91.7 and 2 .9 % of the dose, respectively, during 72 h after intravenous administ ration of 0.25 mg/kg (total 94.6 %). 9. The urinary excretion of NS-3 and its main metabolite CNK-6004 (deamidation product) during 24 h aft er intravenous administration was 31.4 and 25.3 % of the dose in male rats, 45.4 and 30.1 % in male dogs, and 20.2 and 48.0 % in male monkey s, respectively. The biliary excretion of NS-3 and CNK-6004 in male ra ts was 1.1 and 17.4 %, respectively, during 24 h after administration. 10. The radioactivity in the bile collected from donor rats that had received C-14-NS-3 was easily absorbed from the intestinal tract of re cipient rats after intraduodenal administration of the donor's bile.