Drug distribution in the brain is generally associated with an affinity for fatty brain tissues and therefore known to be species- and concentration-independent. We report here the effect of target affinity on brain tissue binding for 10 small molecules designed to inhibit brain heat shock protein 90 (HSP90), a widespread protein whose expression is 1–2% of total cytosolic proteins in eucaryotes. Our results show that increasing the test item concentrations from 0.3 to 100 µM increased the unbound fraction 32-fold for the most potent molecules, with no change for the inactive one (1.1 fold change). Saturation of HSP90 led to normal concentration-independent brain tissue binding. In vivo pharmacokinetics performed in rats showed that the overall volume of distribution of compounds is correlated with their affinity for HSP90. The in vitro binding and in vivo pharmacokinetics (PK) performed in rats showed that small molecule HSP90 inhibitors followed the principle of target-mediated drug disposition. We demonstrate that assessing unbound fractions in brain homogenate was subject to HSP90 target interference; this may challenge the process of linking systemic-free drug concentrations to central nervous system unbound concentrations necessary to establish the proper pharmacokinetics/pharmacodynamics (PK/PD) relation needed for human dose prediction.

中文翻译：

---

目标介导的脑组织结合的热休克蛋白90的小分子抑制剂。

大脑中的药物分布通常与对脂肪脑组织的亲和力有关，因此已知与物种和浓度无关。我们在这里报告了目标亲和力对旨在抑制脑热激蛋白90（HSP90）的10个小分子的脑组织结合的影响，该蛋白是一种广泛表达的蛋白，其表达占真核生物总胞质蛋白的1-2％。我们的结果表明，将测试项目的浓度从0.3 µM增加到100 µM，对于最有效的分子，未结合的部分增加了32倍，无活性的分子则没有变化（变化了1.1倍）。HSP90饱和导致正常的非浓度依赖性脑组织结合。在大鼠中进行的体内药代动力学显示，化合物的总体分布量与其对HSP90的亲和力相关。在大鼠中进行的体外结合和体内药代动力学（PK）表明，小分子HSP90抑制剂遵循靶标介导的药物处置原理。我们证明评估脑匀浆中的未结合部分受到HSP90目标干扰；这可能会挑战将无系统药物浓度与建立人类剂量预测所需的正确药代动力学/药效学（PK / PD）关系所必需的中枢神经系统未结合浓度联系起来的过程。