Brain Barriers Research Center, Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota (G.G., M.K., N.C.-R., J.K.L., W.F.E.); Radiation Oncology, Mayo Clinic, Rochester, Minnesota (J.N.S.); and Strategia Therapeutics Inc., Spring, Texas (L.P., L.D.).
Brain Barriers Research Center, Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota (G.G., M.K., N.C.-R., J.K.L., W.F.E.); Radiation Oncology, Mayo Clinic, Rochester, Minnesota (J.N.S.); and Strategia Therapeutics Inc., Spring, Texas (L.P., L.D.)
Drug Metab Dispos. 2018 May;46(5):658-666. doi: 10.1124/dmd.117.079194. Epub 2018 Feb 2.
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 mitogen-activated protein/extracellular signal-regulated kinase (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 blood-brain barrier on the central nervous system (CNS) exposure of E6201. In vitro studies utilizing transfected Madin-Darby canine kidney II (MDCKII) cells indicate that E6201 is not a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (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 and knockout mice. The nonspecific binding of E6201 was higher in brain compared with plasma. However, free-drug concentrations in brain following 40 mg/kg intravenous dose reach levels that exceed reported in vitro half-maximal inhibitory concentration (IC) values, suggesting that E6201 may be efficacious in inhibiting MEK-driven brain tumors. The brain distribution characteristics of E6201 make it an attractive targeted agent for clinical testing in MBM, glioblastoma, and other CNS tumors that may be effectively targeted with inhibition of MEK signaling.
在治疗脑肿瘤（包括黑色素瘤脑转移瘤 [MBM]）方面具有临床意义的疗效需要选择针对合适靶点的有效抑制剂，并使药物充分分布到脑部靶位。在黑色素瘤中，有丝分裂原激活的蛋白激酶（MAPK）途径的组成性信号失调经常发生，而丝裂原激活蛋白/细胞外信号调节激酶（MEK）已被确定为重要靶点。E6201 是一种有效的合成小分子 MEK 抑制剂。本研究旨在评估 E6201 的脑内分布，并研究血脑屏障（BBB）中的主动外排转运对 E6201 中枢神经系统（CNS）暴露的影响。体外研究利用转染的 Madin-Darby 犬肾 II（MDCKII）细胞表明，E6201 不是 P 糖蛋白（P-gp）和乳腺癌耐药蛋白（Bcrp）的底物。体内研究也表明 P-gp 和 Bcrp 对 E6201 的脑内分布的参与程度很小。脑内总浓度高于血浆，导致野生型小鼠的脑/血浆 AUC 比值（Kp）为 2.66。在 和 基因敲除小鼠中，脑内分布略有增加。E6201 在脑中的非特异性结合高于在血浆中。然而，静脉给予 40mg/kg 后，E6201 的脑中游离药物浓度达到超过报道的体外半数最大抑制浓度（IC）值，表明 E6201 可能有效抑制 MEK 驱动的脑肿瘤。E6201 的脑内分布特征使其成为 MBM、胶质母细胞瘤和其他可能通过 MEK 信号抑制有效靶向的 CNS 肿瘤临床测试的有吸引力的靶向药物。
