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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.

Abstract：

:The pharmacokinetics of NS-49, a newly developed phenethylamine class alpha(1A)-adrenoceptor agonist, was investigated in rats, rabbits, and dogs given intravenous and oral doses that have little effect on the renal blood flow rate (approximating the range of clinical doses). A three-compartment open model adequately described the plasma NS-49 profiles with respective elimination 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 plasma concentrations reached their maximums within 1.5 h in all the species tested, then decreased as in intravenous administration. The systemic availability 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 scale-up approach. The area under the plasma concentration-time curve (AUC) after oral administration, as well as the total body clearance showed an excellent allometric relationship to body weight across the three species. The oral AUC value for humans therefore could be predicted from this correlation. The predicted value agreed well with the observed value in the clinical phase I study. It was difficult to predict the plasma concentration profile of NS-49 for humans after oral administration because the absorption rate constant (k(a)) that is essential for estimation of the maximum concentration exhibited no correlation across the species tested. But we approximately could simulate the plasma concentration profile of NS-49 for humans by using the k(a) value for the rats or rabbits.

journal_name

Int J Pharm

journal_title

International journal of pharmaceutics

authors

Mukai H,Watanabe S,Tsuchida K,Morino A

doi

10.1016/s0378-5173(99)00184-2

keywords:

subject

Has Abstract

pub_date

1999-09-20 00:00:00

pages

215-22

issue

eissn

0378-5173

issn

1873-3476

pii

S0378517399001842

journal_volume

186

pub_type

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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.