Pharmacokinetics of NS-49, a phenethylamine class alpha 1A-adrenoceptor agonist. 3rd communication: metabolism in rats, rabbits, dogs and monkeys, and effects on hepatic drug-metabolizing enzyme activities in rats after repeated administration.
The metabolism of NS-49 ((R)-(-)-3'-(2-amino-1-hydroxyethyl)-4'-fluoro-methanesulfonanilide++ + hydrochloride, CAS 137431-04-0), a phenethylamine class alpha 1A-adrenoceptor agonist, was investigated in rats, rabbits, dogs, and monkeys after single intravenous or oral administration of 14C-NS-49 or unlabeled NS-49. The N-acetylated form, the only metabolite was identified in the urine of all the species tested by thin layer chromatography and mass spectrometry. The unchanged drug and N-acetylated form accounted for almost all the radioactivity in the urine. The order of the percentage of the N-acetylated form in the urinary radioactivity after oral administration was monkeys (66%) > rabbits (22%) > rats (14%) > dogs (1.3%). There were no marked differences between the intravenous and oral routes in the percentages of NS-49 and its N-acetylated form for the rats, rabbits, and dogs, indicative of negligible first-pass metabolism. In the monkeys, however, the percentage of NS-49 in the urinary radioactivity after oral administration was about half that after intravenous injection due to first-pass metabolism, and the N-acetylated form showed an inverse relation. The N-acetylated form also was the only metabolite in the plasma and tissues (liver, kidney, heart, and lung) 1 and 4 h after the oral administration of 14C-NS-49 to rats. NS-49 and its N-acetylated form accounted for more than 80% of the radioactivity in the plasma and the four tissues. The percentages of NS-49 and its N-acetylated form in the total radioactivity did not differ markedly among the plasma and tissues. Repeated oral administrations of 1, 10, and 100 mg/kg of NS-49 to male rats once a day for 7 days had no effects on their hepatic drug-metabolizing enzyme activities.
Mukai
H
H
Research Laboratories, Nippon Shinyaku Co., Ltd., Kyoto, Japan.
Watanabe
S
S
Morino
A
A
D000284:Administration, Oral; D000316:Adrenergic alpha-Agonists / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000813:Anilides / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000818:Animals; D001711:Biotransformation; D004285:Dogs; D007275:Injections, Intravenous; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008252:Macaca fascicularis; D008297:Male; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects*; D014018:Tissue Distribution
C092989:3'-(2-amino-1-hydroxyethyl)-4'-fluoromethanesulfonanilide; D000316:Adrenergic alpha-Agonists; D000813:Anilides; D018341:Receptors, Adrenergic, alpha-2