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 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
Ward
K W
KW
Preclinical Drug Discovery, Cardiovascular, Urogenitary, and Oncology Centre for Excellence in Drugs Discovery, GlaxoSmithKline R&D, King of Prussia, PA 19406, USA. KEITH_W_WARD@GSK.COM
Prokscht
J W
JW
Azzaranot
L M
LM
Mumawa
J A
JA
Roethke
T J
TJ
Stelman
G J
GJ
Walsh
M J
MJ
Zeigler
K S
KS
McSurdy-Freed
J E
JE
Kehlert
J R
JR
Chokshi
J
J
Levy
M A
MA
Smith
B R
BR
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D001798:Blood Proteins / Q000378:metabolism; D004285:Dogs; D004355:Drug Stability; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000493:pharmacokinetics*; D007093:Imidazoles / Q000378:metabolism / Q000493:pharmacokinetics*; D008252:Macaca fascicularis; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000378:metabolism / Q000493:pharmacokinetics*; D051381:Rats; D048051:p38 Mitogen-Activated Protein Kinases
D001798:Blood Proteins; D004791:Enzyme Inhibitors; D007093:Imidazoles; D011725:Pyridines; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580