SB-239063, a potent and selective inhibitor of p38 map kinase: Preclinicalpharmacokinetics and species-specific reversible isomerization

Purpose. A series of studies was conducted to evaluate the preclinical phar macokinetics 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, cyn omolgus monkey, and rhesus monkey, with standard pharmacokinetic parameters generated from the concentration vs. time data. Results. Initial rat studies suggested possible nonlinear disposition: howe ver, assay refinement revealed an in vivo trans-cis isomerization of SB-239 063 to a metabolite with nearly identical chromatographic and mass spectral properties. SB-239063 exhibited low to moderate clearance and good bioavai lability in the rat and dog, but poor bioavailability in the cynomolgus mon key. Substantial in vivo trans-cis isomerization occurred in the rat and cy nomolgus monkey, but occurred to a far lesser extent in the dog. The isomer ization reaction was reversible, with a recycled fraction of 0.20 and 0.000 3 in the rat and cynomolgus monkey, respectively. In the rhesus monkey, bio availability was also poor, but no in vivo isomerization was observed. Conclusions. These studies demonstrate the necessity of exercising vigilanc e in conducting high-throughput analytical method development, and the impo rtance of using a variety of preclinical species when evaluating the dispos ition of new drug candidates.