Poly (ADP–ribose) polymerase (PARP) inhibitors are a relatively new class of anticancer agents that have attracted attention for treatment of glioblastoma because of their ability to potentiate temozolomide chemotherapy. Previous studies have demonstrated that sufficient brain penetration is a prerequisite for efficacy of PARP inhibitors in glioma mouse models. Unfortunately, however, most of the PARP inhibitors developed to date have a limited brain penetration due to the presence of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) at the blood–brain barrier. AZD2461 is a novel PARP inhibitor that is unaffected by P-gp mediated resistance in breast cancer models and thus appears to have promising characteristics for brain penetration. We here use a comprehensive set of in vitro and in vivo models to study the brain penetration and oral bioavailability of AZD2461. We report that AZD2461 has a good membrane permeability. However, it is a substrate of P-gp and BCRP, and P-gp in particular limits its brain penetration in vivo. We show that AZD2461 has a low oral bioavailability, although it is not affected by P-gp and BCRP. Together, these findings are not in favor of further development of AZD2461 for treatment of glioblastoma.

中文翻译：

---

ABCB1减弱PARP抑制剂AZD2461的脑渗透。

聚（ADP-核糖）聚合酶（PARP）抑制剂是一类相对较新的抗癌药物，由于它们具有增强替莫唑胺化学疗法的能力，因此已引起人们对胶质母细胞瘤治疗的关注。先前的研究表明，足够的大脑渗透能力是胶质瘤小鼠模型中PARP抑制剂功效的前提。然而，不幸的是，由于在血脑屏障中存在P-糖蛋白（P-gp）和乳腺癌抗性蛋白（BCRP），迄今为止开发的大多数PARP抑制剂的大脑渗透能力均受到限制。AZD2461是一种新型PARP抑制剂，在乳腺癌模型中不受P-gp介导的抗性影响，因此似乎具有令人鼓舞的脑渗透特性。我们在这里使用一套完整的体外和体内模型来研究AZD2461的大脑渗透性和口服生物利用度。我们报告说AZD2461具有良好的膜渗透性。但是，它是P-gp和BCRP的底物，特别是P-gp限制了其在体内的大脑渗透。我们显示AZD2461具有较低的口服生物利用度，尽管它不受P-gp和BCRP的影响。总之，这些发现不利于进一步开发用于治疗胶质母细胞瘤的AZD2461。