Preclinical pharmacokinetics of SB-203580, a potent inhibitor of p38 mitogen-activated protein kinase

Xenobiotica. 2001 Nov;31(11):783-97. doi: 10.1080/00498250110065621.


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

Publication types

  • Evaluation Study

MeSH terms

  • Administration, Oral
  • Animals
  • Biological Availability
  • Blood Proteins / metabolism
  • Dogs
  • Drug Stability
  • Enzyme Inhibitors / metabolism
  • Enzyme Inhibitors / pharmacokinetics*
  • Imidazoles / metabolism
  • Imidazoles / pharmacokinetics*
  • Macaca fascicularis
  • Male
  • Metabolic Clearance Rate
  • Mice
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors*
  • Pyridines / metabolism
  • Pyridines / pharmacokinetics*
  • Rats
  • p38 Mitogen-Activated Protein Kinases


  • Blood Proteins
  • Enzyme Inhibitors
  • Imidazoles
  • Pyridines
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • SB 203580