Role of P-Glycoprotein on the Brain Penetration and Brain Pharmacodynamic Activity of the MEK Inhibitor Cobimetinib
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- 作者：Edna F. Choo ; Justin Ly ; Jocelyn Chan ; Sheerin K. Shahidi-Latham ; Kirsten Messick ; Emile Plise ; Cristine M. Quiason ; Lulu Yang
- 刊名：Molecular Pharmaceutics
- 出版年：2014
- 出版时间：November 3, 2014
- 年：2014
- 卷：11
- 期：11
- 页码：4199-4207
- 全文大小：469K
- ISSN：1543-8392
文摘
Cobimetinib is a MEK inhibitor currently in clinical trials as an anticancer agent. The objectives of this study were to determine in vitro and in vivo if cobimetinib is a substrate of P-glycoprotein (P-gp) and/or breast cancer resistance protein (Bcrp1) and to assess the implications of efflux on cobimetinib pharmacokinetics (PK), brain penetration, and target modulation. Cell lines transfected with P-gp or Bcrp1 established that cobimetinib was a substrate of P-gp but not a substrate of Bcrp1. In vivo, after intravenous and oral administration of cobimetinib to FVB (wild-type; WT), Mdr1a/b(鈭?鈭?, Bcrp1 (鈭?鈭?, and Mdr1a/b(鈭?鈭?/Bcrp(鈭?鈭? knockout (KO) mice, clearance was similar in WT (35.5 卤 16.7 mL/min/kg) and KO animals (22.0 卤 3.6 to 27.6 卤 5.2 mL/min/kg); oral exposure was also similar between WT and KO animals. After an oral 10 mg/kg dose of cobimetinib, the mean total brain to plasma ratio (Kp) at 6 h postdose was 0.3 and 0.2 in WT and Bcrp1(鈭?鈭? mice, respectively. In Mdr1a/b(鈭?鈭? and Mdr1a/1b/Bcrp1(鈭?鈭? KO mice and WT mice treated with elacridar (a P-gp and BCRP inhibitor), Kp increased to 11, 6, and 7, respectively. Increased brain exposure in Mdr1a/b(鈭?鈭? and Mdr1a/1b/Bcrp1(鈭?鈭? KO and elacridar treated mice was accompanied by up to 鈭?5% suppression of the target (pErk) in brain tissue, compared to WT mice. By MALDI imaging, the cobimetinib signal intensity was relatively high and was dispersed throughout the brain of Mdr1a/1b/Bcrp1(鈭?鈭? KO mice compared to low/undetectable signal intensity in WT mice. The efflux of cobimetinib by P-gp may have implications for the treatment of patients with brain tumors/metastases.