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

1. SB-203580 (4-(4-fluorophenyl)-2-(4-methylsulphinylphenyl)-5-(4-pyridyl) imidazole) is a potent, selective inhibitor of p38 MAP kinase used extensiv ely 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 exis ting 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 plas ma over 24 h. However, species differences in plasma protein binding were o bserved; SB-203580 was 96-97% bound in human plasma and 78-92% bound in oth er species. These data suggest that protein binding may influence the resul ts of in vitro studies using SB-203580, particularly when comparing results from different in vitro systems that incorporate plasma components. In viv o, SB-203580 demonstrated moderate to high clearance in all species tested, with non-linear elimination observed in the rat at plasma concentrations > 1000 ng ml(1). Although good solution bioavailability was observed in non- rodents (78% in dog, 32% in monkey), lower and more variable bioavailabilit y was observed in the rat and mouse (3-48%). 3. These interspecies differences in bioavailability, and the non-linear ph armacokinetics observed in rat, highlight the importance of monitoring SB-2 03580 systemic exposure in parallel with the pharmacological endpoint durin g in vivo pharmacology studies.