title: Pharmacokinetics of NS-105, a novel cognition enhancer. 1st communication: absorption, metabolism and excretion in rats, dogs and monkeys after single administration of 14C-NS-105.
abstract: The absorption, metabolism and excretion of NS-105 ((+)-5-oxo-D-prolinepiperidinamide monohydrate, CAS 110958-19-5), a novel cognition enhancer, were studied in rats, dogs and monkeys after intravenous or oral administration of 14C-NS-105. The protein binding of this drug was also investigated in vivo and in vitro. After the intravenous and oral administrations of 14C-NS-105, the unchanged drug accounted for most of the plasma radioactivity in all the species tested. After the intravenous injection, the plasma concentration of NS-105 decreased monoexponentially with respective elimination half-lives of 0.67, 2.1 and 1.3 h for the rats, dogs and monkeys. After the oral administration, the plasma concentration of NS-105 reached a maximum within 1 h, then decreased as in intravenous administration in all the species tested. NS-105 was almost completely absorbed from the small intestine, and first-pass metabolism was very limited. As a result, its systemic availability was high; 97% in the rats, 90% in the dogs and 79% in the monkeys. No significant sex-related differences in the plasma concentration profiles of radioactivity were observed in the rats after the oral administration of 14C-NS-105 (p > 0.05). Food affected the absorption of NS-105. The Cmax and AUC0-infinity of radioactivity concentration were proportional to the dose for 1-100 mg/kg of 14C-NS-105. There were no marked differences between the intravenous and oral routes in the compositions of urinary radioactivity for any of the species tested. In the urine of dogs, LAM-162 (oxidative metabolite with C-N cleavage of the piperidine ring), LAM-79 (metabolite with 4-hydroxylated piperidine ring), LAM-163 (metabolite with 3-hydroxylated piperidine ring) and M1 (not identified) accounted for 20%, 3%, 6% and 1% of the urinary radioactivity, respectively. In the urine of rats and monkeys, LAM-162 and LAM-79 accounted for 1-6% of the urinary radioactivity, but LAM-163 and M1 were not detected. After the intravenous and oral administrations, NS-105 was primarily eliminated by renal excretion in all the species tested, approximately 90% of the dose being excreted unchanged in the urine for rats and monkeys and 60% of it for dogs. Excretions of radioactivity in the bile and exhaled air in rats were less than 1.4% of the dose, and lymphatic absorption of radioactivity was only 0.3% of the dose. The percentage of 14C-NS-105 bound to serum proteins was less than 3.3% in all the animal species tested, including humans.
authors.affiliation: Research Laboratories, Nippon Shinyaku Co., Ltd., Kyoto, Japan. h.mukai@po.nippon-shinyaku.co.jp
authors.forename: H
authors.initials: H
authors.lastname: Mukai
authors.forename: T
authors.initials: T
authors.lastname: Sugimoto
authors.forename: M
authors.initials: M
authors.lastname: Ago
authors.forename: A
authors.initials: A
authors.lastname: Morino
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001646:Bile / Q000378:metabolism; D001711:Biotransformation; D001798:Blood Proteins / Q000378:metabolism; D004285:Dogs; D005243:Feces / Q000737:chemistry; D005260:Female; D018565:Food-Drug Interactions; D007275:Injections, Intravenous; D007408:Intestinal Absorption; D008196:Lymph / Q000378:metabolism; D008252:Macaca fascicularis; D008297:Male; D018697:Nootropic Agents / Q000493:pharmacokinetics*; D010880:Piperidines / Q000493:pharmacokinetics*; D011392:Proline / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D012727:Sex Characteristics
chemical_list: C106626:5-oxo-D-prolinepiperidinamide monohydrate; D001798:Blood Proteins; D018697:Nootropic Agents; D010880:Piperidines; D011392:Proline