Akira Morino

Permeability of NS‐3, a Thyrotropin‐releasing Hormone Analogue, into the Brain After Its Systemic Administration in Rats: A Microdialysis Study

The concentration of NS‐3 (montirelin hydrate, CG 3703), a thyrotropin‐releasing hormone (TRH) analogue, in the cerebral cortex of urethane‐anaesthetized rats was measured after its systemic administration (1 mgkg−1, i.v.), using in‐vivo microdialysis coupled with a radioimmunoassay.

Pharmacokinetics of NS-49, a phenethylamine class α1A-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 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.

Receptor-mediated model relating anticonvulsant effect to brain levels of camazepam in the presence of its active metabolites

In a displacement test using3H-diazepam as a radioligand, the in vitro affinities of metabolites of camazepam (CZ) for the benzodiazepine receptors were 1–50 times more potent than that of CZ. In contrast, only three metabolites (temazepam, oxazepam, and hydroxy CZ), as well as CZ itself, exhibited an in vivo affinity parallel to their ability to protect against pentylenetetrazole-induced clonic convulsion in rats. In addition, CZ and these active metabolites displaced the radioligand from their receptor sites in a concentration-dependent saturable manner, indicating the competitive bimolecular interaction of these molecules with their receptors. The percent anticonvulsant effect was a nonlinear, single-valued function of the in vivo percent displacement of specific3H-diazepam binding, independent of these displacers after i.v. dosing; this relationship could be approximated by the Hill equation. On the basis of these findings, a receptor-mediated model, including the Langmuir equation to describe the receptor binding-brain concentration relationship and the Hill equation to accommodate the anticonvulsant effect-receptor binding relationship, was constructed. This model was found to adequately relate the time course values of anticonvulsant effect and of brain levels of CZ and its active metabolites after oral administration. These results demonstrate that CZ and its active metabolites exert anticonvulsant effect by competitive binding to the benzodiazepine receptors.

Effects of renal insufficiency and aging on the pharmacokinetics of a phenethylamine class α1A-adrenoceptor agonist NS-49

Effects of renal insufficiency and of aging on the pharmacokinetics of NS-49, a newly developed phenethylamine class alpha(1A)-adrenoceptor agonist eliminated mainly by renal excretion, were investigated in rats after a single administration of (14)C-NS-49. The gromerular filtration rate (GFR) in the partially nephrectomized rats was about half that in the sham-operated rats, and the plasma creatinine concentration in the former was well above the normal limit. Plasma concentrations of radioactivity after intravenous or oral administration of (14)C-NS-49 were much higher in the nephrectomized rats 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 partial 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 radioactivity after intravenous or oral administration of (14)C-NS-49 to 88-week-old rats were higher than in 7-week-old rats, the AUC(0-infinity) value for the aged rats being about two times higher. The aged rats, unlike the nephrectomized rats, showed no marked difference in the t(1/2,beta), value, whereas their V(ss) value was about half that for the young rats. These findings are considered to be caused by physiologic age-related changes; decrease in renal function and loss of body water. Systemic availability in the aged rats did not differ from that in the young, indicative that aging has no effect on the extent of absorption of this drug.

Pharmacokinetics of NS-49, a Phenethylamine Class α1A-Adrenoceptor Agonist

The tissue distribution, placental transfer and milk secretion of 14 C-NS-49 ((R)-(-) -3’-(2-amino-1-hydroxyethyl)-4’-fluoro-methanesulfonanilide hydrochloride, CAS 137431-04-0), a phenethylamine class α 1A -adrenoceptor agonist, have been studied after a single oral administration (1 mg/kg) of a suspension formulation to rats. Radioactivity concentrations in tissues were generally highest 1 or 4 h, and for most tissues, exceeded those in the corresponding plasma. Concentrations were generally similar in male and female rats and persisted for at least 24 h. Radioactivity concentrations in most tissues declined in parallel with those in plasma. Placental transfer of radioactivity was low accounting for 14 C-NS-49 readily diffused from the plasma into the milk. The absorption, distribution and excretion of 14 C-NS-49 have been studied after the repeated administration (1 mg/ kg) of a suspension formulation to rats for up to 21 days. At 21 days, radioactivity concentrations in plasma reached a peak 1 h and declined with a terminal half-life of 67 h. Steady state concentrations were reached during 14 days. Peak concentrations in tissues occurred 1 h and, in most tissues exceeded the plasma value. Radioactivity concentrations in tissues appeared to reach steady state during the 21-day dosing period. Tissue and blood cell concentrations declined more slowly than those in the plasma. Radioactivity excretion was relatively constant during the repeated administration and similar in urine (mean 45.8 % total dose) and feces (mean 48.2 % total dose). At 7 days after the last of 21 daily oral doses, only 0.2 % of the total dose remained in the body, indicating that there is no marked accumulation of radioactivity in the tissues. The results obtained in these studies indicated that rats receiving NS-49 at 24 h intervals during chronic and reproductive toxicity studies would be continually exposed to the parent compound and/or its metabolites.

Renal excretion mechanism of NS-49, a phenethylamine class α1A-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 (Clre) of NS‐49 was 3.4‐fold the glomerular filtration rate (GFR) in the rat in vivo study. The clearance ratio (Clre/GFR) approached unity during cimetidine infusion. Change in the urine flow rate or urinary pH did not affect the Clre 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. Copyright