SB-242235 demonstrates generally favourable pharmacokinetic properties in all species examined(including rat, dog and monkey). Systemic plasma clearance was high in rat, but in the non-rodent species SB-242235 demonstrated low to moderate clearance with plasma half-lives > 4h. Oral bioavailability in each preclinical species was high. In rat and monkey, SB-242235 demonstrated non-linear elimination kinetics that manifested as a decrease in clearance with increasing dose and apparent oral bioavailability > 100% at high oral doses [2].In the skin of SKH-1 hairless mice, SB242235, prior to UVB irradiation, blocked activation of the p38 MAPK cascade, and abolished MAPKAPK-2 kinase activity and phosphorylation of HSP27. Moreover, SB242235 inhibited expression of the pro-inflammatory cytokines interleukin (IL)-6 and KC (murine IL-8) and COX-2 [3]. The preclinical pharmacokinetics of SB-242235 have been described previously. The present studies were conducted to describe the in vitro metabolic rates and routes of SB-242235 metabolism, to characterize its in vivo preclinical metabolism, and to use these data to aid in the prediction of the pharmacokinetic behaviour of SB-242235 in man [4].
In Vitro
SB 242235 inhibited intracellular p38 activity, human chondrocytes were treated with different doses of SB 242235 prior to stimulation with IL-1_ for 15 min. MAPKAP K2 was then isolated from these cells and assayed using HSP27 as a substrate. SB 242235 dose-dependently inhibited the activation of MAPKAP K2 with an IC50 of 1.0 uM [1].
Kinase Assay
Cell Assay
Animal Administration
References
[1]. Badger, A.M., et al., Differential effects of SB 242235, a selective p38 mitogen-activated protein kinase inhibitor, on IL-1 treated bovine and human cartilage/chondrocyte cultures. Osteoarthritis Cartilage, 2000. 8(6): p. 434-43.
[2]. Ward, K.W., et al., SB-242235, a selective inhibitor of p38 mitogen-activated protein kinase. I: preclinical pharmacokinetics. Xenobiotica, 2002. 32(3): p. 221-33.
[3]. Kim, A.L., et al., Role of p38 MAPK in UVB-induced inflammatory responses in the skin of SKH-1 hairless mice. J Invest Dermatol, 2005. 124(6): p. 1318-25.
[4]. Ward, K.W., et al., SB-242235, a selective inhibitor of p38 mitogen-activated protein kinase. II: in vitro and in vivo metabolism studies and pharmacokinetic extrapolation to man. Xenobiotica, 2002. 32(3): p. 235-50.
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