title: Pharmacokinetics of the new thyrotropin releasing hormone analogue montirelin hydrate. 1st communication: plasma concentrations, metabolism and excretion after a single intravenous administration to rats, dogs and monkeys.
abstract: The plasma concentrations, metabolism and excretion were studied in rats, dogs and monkeys after a single intravenous administration of 14C-montirelin hydrate (CAS 90243-66-6, 14C-NS-3). 1. The plasma concentration of radioactivity and the area under curve (AUC0-infinity) increased 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 half-lives of 0.512, 0.771 and 0.786 h in male rats, dogs and monkeys, respectively. The plasma concentration of radioactivity in rats increased 6-10 h after administration, suggesting enterohepatic circulation. 3. The plasma concentration of NS-3 in various animal species decreased biphasically after intravenous administration. The elimination half-lives, t1/2 beta, in rats, dogs and monkeys were 0.324, 0.679 and 0.682 h, respectively, and the steady state volumes of distribution, Vdss, were 0.248, 0.319 and 0.306 l/kg, respectively. 4. The binding of NS-3 to serum protein was less than 3% in rats, dogs, monkeys and humans. 5. Within 48 h after intravenous administration of 1 mg/kg to male rats, the excretion of radioactivity in urine, feces and expired air was 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 dosing. 6. No sex-related difference was found in plasma concentration of radioactivity or the excretion of radioactivity in urine, feces and expired air after intravenous administration of 1 mg/kg to male and female rats. 7. In male dogs, the excretion of radioactivity in urine and feces was 92.3 and 5.6% of the dose, respectively, during 72 h after intravenous administration of 0.25 mg/kg (total 97.9%). 8. In male monkeys, the excretion of radioactivity in urine and feces was 91.7 and 2.9% of the dose, respectively, during 72 h after intravenous administration 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 after 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 monkeys, respectively. The biliary excretion of NS-3 and CNK-6004 in male rats 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 14C-NS-3 was easily absorbed from the intestinal tract of recipient rats after intraduodenal administration of the donor's bile.
authors.affiliation: Research Laboratories, Nippon Shinyaku Co., Ltd., Kyoto, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Sugimoto
authors.forename: T
authors.initials: T
authors.lastname: Hayashi
authors.forename: A
authors.initials: A
authors.lastname: Okita
authors.forename: A
authors.initials: A
authors.lastname: Morino
mesh_terms: D000818:Animals; D001646:Bile / Q000378:metabolism; D002855:Chromatography, Thin Layer; D004285:Dogs; D004764:Enterohepatic Circulation / Q000502:physiology; D005243:Feces / Q000737:chemistry; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D008252:Macaca fascicularis; D008297:Male; D008954:Models, Biological; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D012727:Sex Characteristics; D013045:Species Specificity; D013973:Thyrotropin-Releasing Hormone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics
chemical_list: C031926:montirelin; D013973:Thyrotropin-Releasing Hormone