TY - JOUR T1 - Brain distribution of a novel MEK inhibitor E6201: implications in the treatment of melanoma brain metastases JF - Drug Metabolism and Disposition JO - Drug Metab Dispos DO - 10.1124/dmd.117.079194 SP - dmd.117.079194 AU - Gautham Gampa AU - Minjee Kim AU - Nicholas Cook-Rostie AU - Janice Laramy AU - Jann N. Sarkaria AU - Linda Paradiso AU - Louis DePalatis AU - William F. Elmquist Y1 - 2018/01/01 UR - http://dmd.aspetjournals.org/content/early/2018/02/02/dmd.117.079194.abstract N2 - Clinically meaningful efficacy in the treatment of brain tumors, including melanoma brain metastases (MBM), requires selection of a potent inhibitor against a suitable target, and adequate drug distribution to target sites in the brain. Deregulated constitutive signaling of mitogen-activated protein kinase (MAPK) pathway has been frequently observed in melanoma, and MEK has been identified to be an important target. E6201 is a potent synthetic small molecule MEK inhibitor. The purpose of this study was to evaluate brain distribution of E6201, and examine the impact of active efflux transport at the BBB on the CNS exposure of E6201. In vitro studies utilizing transfected MDCKII cells indicate that E6201 is not a substrate of P-gp and Bcrp. In vivo studies also suggest a minimal involvement of P-gp and Bcrp in E6201's brain distribution. The total concentrations in brain were higher than in plasma, resulting in a brain-to-plasma AUC ratio (Kp) of 2.66 in wild-type mice. The brain distribution was modestly enhanced in Mdr1a/b-/-, Bcrp1-/-, and Mdr1a/b-/-Bcrp1-/- knockout mice. E6201 non-specific binding was higher in brain compared to plasma. However, free drug concentrations in brain following 40 mg/kg intravenous dose reach levels that exceed reported in vitro IC50 values, suggesting that E6201 may be efficacious in inhibiting MEK-driven brain tumors. The superior brain distribution characteristics compared to other currently available MEK inhibitors (e.g., trametinib and cobimetinib) makes E6201 attractive for clinical testing in MBM, glioblastoma (GBM) and other CNS tumors that may be effectively targeted with inhibition of MEK signaling. ER -