Badolo Lassina, Thirstrup Kenneth, Nielsen Søren Møller, Püschl Ask, Jensen Thomas, Watson Steve, Bundgaard Christoffer
Translational DMPK, H. Lundbeck A/S, 2500 Copenhagen-Valby, Denmark.
Neurodegeneration, H. Lundbeck A/S, 2500 Copenhagen-Valby, Denmark.
Pharmaceutics. 2020 Oct 22;12(11):1009. doi: 10.3390/pharmaceutics12111009.
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.
药物在大脑中的分布通常与对富含脂肪的脑组织的亲和力相关，因此已知其与物种和浓度无关。我们在此报告了针对10种旨在抑制脑热休克蛋白90（HSP90）的小分子的靶标亲和力对脑组织结合的影响，HSP90是一种广泛存在的蛋白质，其表达量在真核生物中占总胞质蛋白的1-2%。我们的结果表明，将测试化合物浓度从0.3 μM提高到100 μM，对于最有效的分子，未结合分数增加了32倍，而无活性的分子则无变化（变化1.1倍）。HSP90的饱和导致了正常的与浓度无关的脑组织结合。在大鼠体内进行的药代动力学研究表明，化合物的总体分布体积与其对HSP90的亲和力相关。在大鼠体内进行的体外结合和药代动力学（PK）研究表明，小分子HSP90抑制剂遵循靶标介导的药物处置原则。我们证明，评估脑匀浆中的未结合分数会受到HSP90靶标的干扰；这可能会挑战将全身游离药物浓度与中枢神经系统未结合浓度联系起来的过程，而这是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。
