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-4 9 was 3.4-fold the glomerular filtration rate (GFR) in the rat in vivo stud y. The clearance ratio (Cl-re/GFR) approached unity during cimetidine infus ion. Change in the urine flow rate or urinary pH did not affect the Cl-re o f NS-49. The stop-flow patterns of NS-49 in the rabbits and dogs showed a s ecretion peak in the proximal tubules. On concomitant administration of cim etidine, the secretion peak disappeared, the stop-flow pattern showing neit her a secretion nor reabsorption peak. These findings indicate that in thes e species NS-49 undergoes glomerular filtration and extensive proximal tubu lar secretion, but Little reabsorption. A transport mechanism study of NS-4 9 in brush-border membrane Vesicles (BBMVs) isolated from rat kidney cortex showed that it is transported via the carrier-mediated H+/organic cation a ntiport system. In the rat renal clearance studies (in vivo) tubular secret ion of NS-49 was significantly inhibited by quinine (p < 0.01) but not by q uinidine. Transport studies done with rat BBMVs (in vitro) also showed quin ine to be more potent than quinidine in inhibiting NS-49 uptake. These resu lts indicate that stereoselective interaction occurs in active renal tubula r secretion. (C) 1999 John Wiley & Sons, Ltd.