Effects of renal insufficiency and aging on the pharmacokinetics of a phenethylamine class alpha(1A)-adrenoceptor agonist NS-49

Effects of renal insufficiency and of aging on the pharmacokinetics of NS-4 9, a newly developed phenethylamine class alpha(1A)-adrenoceptor agonist el iminated mainly by renal excretion, were investigated in rats after a singl e administration of C-14-NS-49. The glomerular filtration rate (GFR) in the partially nephrectomized rats was about half that in the sham-operated rat s, and the plasma creatinine concentration in the former was well above the normal limit. Plasma concentrations of radioactivity after intravenous or oral administration of C-14-NS-49 were much higher in the nephrectomized ra ts than in the intact and sham-operated rats. As a result, the areas under the plasma concentration-time curve (AUC(0-infinity)) after intravenous and oral administrations respectively increased 5-fold and 7-fold after partia l nephrectomy. The elimination half-life (t(1/2,beta)) was increased about 2-fold by partial nephrectomy. The systemic availability for the partially nephrectomized rats remained unchanged, indicative that partial nephrectomy does not affect the absorption of NS-49. Plasma concentrations of radioact ivity after intravenous or oral administration of C-14-NS-49 to 88-week-old rats were higher than in 7-week-old rats, the AUC(0-infinity) value for th e aged rats being about two times higher. The aged rats, unlike the nephrec tomized rats, showed no marked difference in the t(1/2,beta), value, wherea s their V-ss value was about half that for the young rats. These findings a re considered to be caused by physiologic age-related changes; decrease in renal function and loss of body water. Systemic availability in the aged ra ts did not differ from that in the young, indicative that aging has no effe ct on the extent of absorption of this drug. (C) 1999 Elsevier Science B.V. All rights reserved.