The safety and pharmacokinetics of NM441, a prodrug of a new thiazeto-quinoline carboxylic acid derivative, NM394, were evaluated in healthy male volunteers given the drug orally in single doses of 20, 50, 100, 200, and 400 mg, and multiple doses of 300 mg twice daily for 6.5 days. No remarkable abnormalities were observed in symptoms, physical tests, laboratory tests, electrocardiogram (ECG), electroencephalogram (EEG), or equilibrium test. The mean plasma concentrations of active metabolite NM394 peaked between 0.5 and 1.0 hours, and the maximum concentrations were 0.68, 1.09, and 1.88 micrograms/mL at doses of 100, 200, and 400 mg, respectively. The mean half-lives were 7.7 to 8.9 hours and were not affected by dose. The mean urinary excretion rates of NM394 were 46.0, 38.3, and 30.6% of the doses within 48 hours, respectively, and other metabolites were excreted in urine by 7% of the doses. The mean salivary concentrations of NM394 were approximately 20% of the plasma concentrations. The mean fecal excretion rates of NM394 and NM441 were 52.9 and 4.2%, respectively within 72 hours after dosing of 400 mg. The Cmax, AUC, and urinary excretion rates were not altered by food intake, whereas the Tmax was prolonged slightly. In the multiple-dose study, the steady state of plasma concentration of NM394 was achieved on day 3 or 4, and further accumulation did not occur thereafter. The mean urinary excretion rate of NM394 was 49.0% during and 48 hours after the multiple administration. The acceptable safety and tolerance and defined pharmacokinetic characteristics of NM441 support further testing.
The absorption and excretion of NS-49 ((R)-(-)-3'-(2-amino-1-hydroxyethyl)-4'-fluoromethanesulfonanilide hydrochloride, CAS 137431-04-0), a phenethylamine class alpha 1A-adrenoceptor agonist, were studied in rats after a single administration of 14C-NS-49. In addition, the protein binding of this drug was investigated in vivo and in vitro. After oral administration of 14C-NS-49 (1 mg/kg) to male rats, the radioactivity concentrations in the blood and plasma reached maximums within 1 h, then decreased biexponentially with respective elimination half-lives of 25.4 and 11.9 h. Most of the plasma radioactivity was due to unchanged NS-49, indicating of the poor metabolism of this drug in rats. The results of the in situ absorption study using the intestinal loop method showed that 14C-NS-49 was well absorbed from the small intestine. Systemic availability was high (86%), as determined by a comparison of the areas under the plasma concentration-time curves of unchanged NS-49 for oral and intravenous administrations. Food affected the absorption of NS-49. There were no significant sex-related differences in the plasma concentration profiles after the intravenous administration of 14C-NS-49 (p > 0.05). NS-49 was primarily eliminated by renal excretion, 76% and 62% of the dose being excreted unchanged in the urine after intravenous and oral administrations, respectively. The absorption rate, determined on the basis of the urinary excretion of radioactivity, was 83%, being almost the same as the systemic availability. First-pass metabolism of NS-49, therefore, is considered to be very limited in rats. The excretion of radioactivity in the bile within 48 h after the oral administration of 14C-NS-49 (1 mg/kg) was 5.9% of the dose, and the excretion of radioactivity in the exhaled air after the intravenous administration (0.2 mg/kg) was negligible. The percentage of 14C-NS-49 bound to serum proteins in vitro was less than 15% in all the animal species tested. The percentage of radioactivity bound to rat serum proteins after the oral administration of 14C-NS-49 (1 mg/kg) was 16-21%.
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.
1. The metabolism of irsogladine (ISG) was studied in hepatic microsomes from the rat, dog, monkey and man, and marked species differences were observed in N-oxidation of ISG. The rank order of the activity of the N-oxidation was shown to be man < monkey < dog < rat. 2. Anti-NADPH-P450 reductase antibody inhibited the formation of the N-oxidized metabolite of ISG (ISG-N-oxide) in hepatic microsomes from rats by 74%. Anti-CYP2C11 antibody also inhibited the formation of ISG-N-oxide in hepatic microsomes from rat by 73%, whereas anti-CYP2E1, 3A2 and 4A1 antibody did not inhibit N-oxidation. Thus, CYP2C11 in the rat is at least partially responsible for the N-oxidation of ISG in the rat. 3. Anti-CYP2C11 antibody also inhibited the formation of ISG-N-oxide in hepatic microsomes from the dog and monkey by 61 and 46% respectively. Therefore, a isoform(s) similar to CYP2C11 partially contributed to the N-oxidation of ISG in the dog and monkey. In contrast, human CYP2C9, a member of the human CYP2C subfamily, did not catalyse the N-oxidation of ISG. 4. These findings show that the marked species difference in the N-oxidation of ISG is caused by the difference in the catalytic properties of CYP2C among the species examined.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
customersupport@researchsolutions.com
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.