Preclinical pharmacokinetics of SB-203580, a potent inhibitor of p38 mitogen-activated protein kinase.
Xenobiotica
; 31(11): 783-97, 2001 Nov.
Article
em En
| MEDLINE
| ID: mdl-11765141
ABSTRACT
1. SB-203580 (4-(4-fluorophenyl)-2-(4-methylsulphinylphenyl)-5-(4-pyridyl)imidazole) is a potent, selective inhibitor of p38 MAP kinase used extensively as a tool inhibitor in various pharmacological and toxicological models. This study was designed to evaluate the pharmacokinetics of SB-203580 in several preclinical species, both to assist with the interpretation of existing studies and to aid in the design of future studies with this inhibitor. 2. In vitro, SB-203580 was stable in mouse, rat, dog, monkey and human plasma over 24 h. However, species differences in plasma protein binding were observed; SB-203580 was 96-97% bound in human plasma and 78-92% bound in other species. These data suggest that protein binding may influence the results of in vitro studies using SB-203580, particularly when comparing results from different in vitro systems that incorporate plasma components. In vivo, SB-203580) demonstrated moderate to high clearance in all species tested, with non-linear elimination observed in the rat at plasma concentrations > 1,000 ngml(-1). Although good solution bioavailability was observed in non-rodents (78% in dog, 32% in monkey), lower and more variable bioavailability was observed in the rat and mouse (3 -48%). 3. These interspecies differences in bioavailability, and the non-linear pharmacokinetics observed in rat, highlight the importance of monitoring SB-203580 systemic exposure in parallel witb the pharmacological endpoint during in vivo pharmacology
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Piridinas
/
Proteínas Quinases Ativadas por Mitógeno
/
Inibidores Enzimáticos
/
Imidazóis
Tipo de estudo:
Evaluation_studies
/
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Xenobiotica
Ano de publicação:
2001
Tipo de documento:
Article
País de afiliação:
Estados Unidos