Zhang Wenqiu, Oh Ju-Hee, Zhang Wenjuan, Aldrich Courtney C, Sirianni Rachael W, Elmquist William F
Department of Pharmaceutics, Brain Barriers Research Center, University of Minnesota, Minneapolis, Minnesota.
Department of Pharmaceutics, Brain Barriers Research Center, University of Minnesota, Minneapolis, Minnesota.
J Pharmacol Exp Ther. 2025 Jan;392(1):100014. doi: 10.1124/jpet.124.002170. Epub 2024 Nov 22.
Histone deacetylase expression and activity are often dysregulated in central nervous system (CNS) tumors, providing a rationale for investigating histone deacetylase inhibitors (HDACIs) in selected brain tumor patients. Although many HDACIs have shown potential in in vitro studies, they have had modest efficacy in vivo. This lack of activity could be due to insufficient CNS exposure to the unbound drug. In this study, we investigated the systemic pharmacokinetics and subsequent CNS distribution of 2 potent HDACIs, vorinostat and quisinostat, in the murine model. Both compounds undergo in vitro degradation in mouse plasma, requiring precautions during sample processing. They also have short half-lives in vivo, in both plasma and the CNS, which may lead to diminished efficacy. Transgenic transporter-deficient mouse models show that the CNS delivery of vorinostat was not limited by the 2 major blood-brain barrier efflux transporters, p-glycoprotein and breast cancer resistance protein. Vorinostat had an unbound CNS tissue-to-plasma partition coefficient of 0.06 ± 0.02. Conversely, the exposure of unbound quisinostat in the brain was only 0.02 ± 0.001 of that in the plasma, and the CNS distribution of quisinostat was limited by the activity of p-glycoprotein. To gain further context for these findings, the CNS distributional kinetics for vorinostat and quisinostat were compared with another hydroxamic acid HDACI, panobinostat. A comprehensive understanding of the CNS target exposure to unbound HDACI, along with known potencies from in vitro testing, can inform the prediction of a therapeutic window for HDACIs that have limited CNS exposure to unbound drug and guide targeted dosing strategies. SIGNIFICANCE STATEMENT: This study indicates that quisinostat and vorinostat are susceptible to enzymatic degradation in the plasma, and to a lesser degree, in the target central nervous system (CNS) tissues. Employing techniques that minimize the postsampling degradation in plasma, brain, and spinal cord, accurate CNS distributional kinetic parameters for these potentially useful compounds were determined. A knowledge of CNS exposure, time to peak, and duration can inform dosing strategies in preclinical and clinical trials in selected CNS tumors.
组蛋白脱乙酰酶的表达和活性在中枢神经系统（CNS）肿瘤中常常失调，这为在特定脑肿瘤患者中研究组蛋白脱乙酰酶抑制剂（HDACIs）提供了理论依据。尽管许多HDACIs在体外研究中已显示出潜力，但它们在体内的疗效并不显著。活性不足可能是由于未结合药物在中枢神经系统中的暴露不足。在本研究中，我们在小鼠模型中研究了两种强效HDACIs（伏立诺他和喹西诺他）的全身药代动力学及随后的中枢神经系统分布。两种化合物在小鼠血浆中都会发生体外降解，因此在样品处理过程中需要采取预防措施。它们在体内血浆和中枢神经系统中的半衰期也很短，这可能会导致疗效降低。转基因转运体缺陷小鼠模型表明，伏立诺他向中枢神经系统的递送不受血脑屏障的两种主要外排转运体（P-糖蛋白和乳腺癌耐药蛋白）的限制。伏立诺他的未结合中枢神经系统组织与血浆的分配系数为0.06±0.02。相反，喹西诺他在脑中未结合部分的暴露量仅为血浆中的0.02±0.001，且喹西诺他在中枢神经系统的分布受P-糖蛋白活性的限制。为了进一步理解这些发现，将伏立诺他和喹西诺他的中枢神经系统分布动力学与另一种异羟肟酸HDACI帕比司他进行了比较。全面了解中枢神经系统对未结合HDACI的靶点暴露情况，以及体外测试中已知的效力，可以为预测未结合药物在中枢神经系统中暴露有限的HDACIs的治疗窗提供信息，并指导靶向给药策略。意义声明：本研究表明，喹西诺他和伏立诺他在血浆中易受酶降解，在靶中枢神经系统（CNS）组织中酶降解程度较小。采用能将血浆、脑和脊髓采样后降解降至最低的技术，确定了这些潜在有用化合物准确的中枢神经系统分布动力学参数。了解中枢神经系统暴露情况、达峰时间和持续时间可为特定中枢神经系统肿瘤的临床前和临床试验中的给药策略提供信息。
