Pharmacokinetics of NS-49, a phenethylamine class alpha(1A)-adrenoceptor agonist, at therapeutic doses in several animal species and interspecies scaling of its pharmacokinetic parameters

The pharmacokinetics of NS-49, a newly developed phenethylamine class alpha (1A)-adrenoceptor agonist, was investigated in rats, rabbits, and dogs give n intravenous and oral doses that have little effect on the renal blood flo w rate (approximating the range of clinical doses). A three-compartment ope n model adequately described the plasma NS-49 profiles with respective elim ination half-lives of 18, 19, and 13 h after intravenous administration of NS-49 to rats, rabbits and dogs. After oral administration, the NS-49 plasm a concentrations reached their maximums within 1.5 h in all the species tes ted, then decreased as in intravenous administration. The systemic availabi lity was 80% for the rats, 70% for the rabbits, and 101% for the dogs. From the pharmacokinetic parameter values for these three species, we predicted human pharmacokinetics of NS-49 after oral administration with an animal s cale-up approach. The area under the plasma concentration-time curve (AUC) after oral administration, as well as the total body clearance showed an ex cellent allometric relationship to body weight across the three species. Th e oral AUC value for humans therefore could be predicted from this correlat ion. The predicted value agreed well with the observed value in the clinica l phase I study. It was difficult to predict the plasma concentration profi le of NS-49 for humans after oral administration because the absorption rat e constant (k(a)) that is essential for estimation of the maximum concentra tion exhibited no correlation across the species tested. But we approximate ly could simulate the plasma concentration profile of NS-49 for humans by u sing the k(a) value for the rats or rabbits. (C) 1999 Elsevier Science B.V. All rights reserved.