SB-239063, a potent and selective inhibitor of p38 map kinase: preclinical pharmacokinetics and species-specific reversible isomerization.
OBJECTIVE
A series of studies was conducted to evaluate the preclinical pharmacokinetics of SB-239063 (trans-1-(4-hydroxycyclohexyl)-4-(4-fluorophenyl)-5-[(2-methoxy)pyrimidin-4-yl] imidazole), a potent and selective p38 MAP kinase inhibitor.


METHODS
SB-239063 was administered both i.v. and p.o. in the rat, dog, cynomolgus monkey, and rhesus monkey, with standard pharmacokinetic parameters generated from the concentration vs. time data.


RESULTS
Initial rat studies suggested possible nonlinear disposition, however, assay refinement revealed an in vivo trans-cis isomerization of SB-239063 to a metabolite with nearly identical chromatographic and mass spectral properties. SB-239063 exhibited low to moderate clearance and good bioavailability in the rat and dog, but poor bioavailability in the cynomolgus monkey. Substantial in vivo trans-cis isomerization occurred in the rat and cynomolgus monkey, but occurred to a far lesser extent in the dog. The isomerization reaction was reversible, with a recycled fraction of 0.20 and 0.0003 in the rat and cynomolgus monkey, respectively. In the rhesus monkey, bioavailability was also poor. but no in vivo isomerization was observed. Conclusions. These studies demonstrate the necessity of exercising vigilance in conducting high-throughput analytical method development, and the importance of using a variety of preclinical species when evaluating the disposition of new drug candidates.
Ward
K W
KW
Preclinical Drug Discovery, Cardiovascular, Urogenitary and Oncology Center for Excellence in Drug Discovery, GlaxoSmithKline, King of Prussia, PA 19406, USA. keith_w_ward@gsk.com
Proksch
J W
JW
Azzarano
L M
LM
Salyers
K L
KL
McSurdy-Freed
J E
JE
Molnar
T M
TM
Levy
M A
MA
Smith
B R
BR
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D004285:Dogs; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D007093:Imidazoles / Q000008:administration & dosage / Q000493:pharmacokinetics*; D007275:Injections, Intravenous; D007536:Isomerism; D008252:Macaca fascicularis; D008253:Macaca mulatta; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051381:Rats; D013045:Species Specificity; D013379:Substrate Specificity; D048051:p38 Mitogen-Activated Protein Kinases
D004791:Enzyme Inhibitors; D007093:Imidazoles; D011743:Pyrimidines; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C406525:SB 239063