Renal excretion mechanism of NS-49, a phenethylamine class alpha 1A-adrenoceptor agonist.
Renal handling of NS-49, which is an organic cation and a chiral compound, was investigated in rats, rabbits and dogs. Renal clearance (Cl(re)) of NS-49 was 3.4-fold the glomerular filtration rate (GFR) in the rat in vivo study. The clearance ratio (Cl(re)/GFR) approached unity during cimetidine infusion. Change in the urine flow rate or urinary pH did not affect the Cl(re) of NS-49. The stop-flow patterns of NS-49 in the rabbits and dogs showed a secretion peak in the proximal tubules. On concomitant administration of cimetidine, the secretion peak disappeared, the stop-flow pattern showing neither a secretion nor reabsorption peak. These findings indicate that in these species NS-49 undergoes glomerular filtration and extensive proximal tubular secretion, but little reabsorption. A transport mechanism study of NS-49 in brush-border membrane vesicles (BBMVs) isolated from rat kidney cortex showed that it is transported via the carrier-mediated H(+)/organic cation antiport system. In the rat renal clearance studies (in vivo) tubular secretion of NS-49 was significantly inhibited by quinine (p<0.01) but not by quinidine. Transport studies done with rat BBMVs (in vitro) also showed quinine to be more potent than quinidine in inhibiting NS-49 uptake. These results indicate that stereoselective interaction occurs in active renal tubular secretion.
Mukai
H
H
Research Laboratories, Nippon Shinyaku Co. Ltd., 14, Nishinosho-Monguchi-cho, Kisshoin, Minami-ku, Kyoto 601-8550, Japan.
Morino
A
A
D058646:Adrenergic alpha-1 Receptor Agonists; D000316:Adrenergic alpha-Agonists / Q000097:blood / Q000493:pharmacokinetics*; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000813:Anilides / Q000097:blood / Q000493:pharmacokinetics*; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002250:Carbon Radioisotopes; D004285:Dogs; D005919:Glomerular Filtration Rate; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D007672:Kidney Cortex / Q000187:drug effects / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008871:Microvilli / Q000378:metabolism; D011802:Quinidine / Q000494:pharmacology; D011803:Quinine / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D018340:Receptors, Adrenergic, alpha-1 / Q000502:physiology; D012636:Secretory Rate / Q000187:drug effects; D013237:Stereoisomerism
C092989:3'-(2-amino-1-hydroxyethyl)-4'-fluoromethanesulfonanilide; C547715:Adra1a protein, rat; D058646:Adrenergic alpha-1 Receptor Agonists; D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D000813:Anilides; D002250:Carbon Radioisotopes; D018340:Receptors, Adrenergic, alpha-1; D011803:Quinine; D011802:Quinidine