Pharmacokinetics and brain uptake of AM-36, a novel neuroprotective agent, following intravenous administration to rats.
J Pharm Pharmacol
; 60(2): 171-8, 2008 Feb.
Article
em En
| MEDLINE
| ID: mdl-18237464
ABSTRACT
The plasma pharmacokinetics and brain uptake of the novel neuroprotective agent AM-36 (1-(2-(4-chlorophenyl)-2-hydroxy)ethyl-4-(3,5-bis-(1,1dimethylethyl)-4-hydroxyphenyl) methylpiperazine) were assessed over 72 h following i.v. administration to male Sprague-Dawley rats. At nominal i.v. doses of 0.2, 1 and 3mg kg(-1), AM-36 exhibited an extremely large volume of distribution (18.2-24.6 L kg(-1)) and a long terminal elimination half-life, ranging from 25.2 to 37.7 h. Over this dose range, AM-36 exhibited linear pharmacokinetics, with no apparent change in clearance, volume of distribution or dose-normalised area under the plasma concentration - time curve. AM-36 was very highly bound to plasma proteins (> 99.6%); however, this did not appear to affect the ability of AM-36 to permeate the blood-brain barrier. Following a single i.v. dose of AM-36 at 3mg kg(-1) to rats, brain concentrations were detected for up to 72 h, and the brain-to-plasma ratios were high at all time points (ranging from 8.2 at 5 min post-dose to 0.9 at 72 h post-dose). The very high brain uptake of AM-36 supports previous in-vivo efficacy studies demonstrating the neuroprotective effects of this compound when administered to rats with middle cerebral artery occlusion.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Piperazinas
/
Encéfalo
/
Barreira Hematoencefálica
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Fármacos Neuroprotetores
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Ano de publicação:
2008
Tipo de documento:
Article