SB-239063, a Potent and Selective Inhibitor of P38 Map Kinase: Preclinical Pharmacokinetics and Species-Specific Reversible Isomerization

Purpose . 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.