| Autor: |
Ward, K. W., Proksch, J. W., Azzarano, L. M., Mumaw, J. A., Roethke, T. J., Stelman, G. J., Walsh, M. J., Zeigler, K. S., McSurdy-Freed, J. E., Kehler, J. R, Chokshi, J., Levy, M. A., Smith, B. R. |
| Předmět: |
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| Zdroj: |
Xenobiotica; Nov2001, Vol. 31 Issue 11, p783-797, 15p |
| Abstrakt: |
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 > 1000ng ml[sup -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 with the pharmacological endpoint during in vivo pharmacology studies. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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