Zhang Wenqiu, Oh Ju-Hee, Zhang Wenjuan, Aldrich Courtney C, Sirianni Rachael W, Elmquist William F
Departments of Pharmaceutics, Brain Barriers Research Center (Wenq. Zhang, J.-H.O., Wenj. Zhang, W.F.E.) and Medicinal Chemistry (C.C.A.), University of Minnesota, Minneapolis, Minnesota; and Department of Neurologic Surgery, UMass Chan Medical School, Worcester, Massachusetts (R.W.S.)
Departments of Pharmaceutics, Brain Barriers Research Center (Wenq. Zhang, J.-H.O., Wenj. Zhang, W.F.E.) and Medicinal Chemistry (C.C.A.), University of Minnesota, Minneapolis, Minnesota; and Department of Neurologic Surgery, UMass Chan Medical School, Worcester, Massachusetts (R.W.S.).
J Pharmacol Exp Ther. 2024 Mar 15;389(1):96-105. doi: 10.1124/jpet.123.002051.
The deregulation of histone deacetylase (HDAC) expression is often seen in many cancers, and HDAC inhibitors have shown potency against a variety of cancer types. Panobinostat is a potent pan-HDAC inhibitor that has been tested in multiple studies for the treatment of brain tumors. There have been contrasting views surrounding its efficacy for the treatment of tumors in the central nervous system (CNS) following systemic administration when examined in different models or species. We conducted experiments using three different mouse strains or genotypes to have a more comprehensive understanding of the systemic as well as the CNS distributional kinetics of panobinostat. Our study found that panobinostat experienced rapid degradation in vitro in Friend leukemia virus strain B mouse matrices and a faster degradation rate was observed at 37°C compared with room temperature and 4°C, suggesting that the in vitro instability of panobinostat was due to enzymatic metabolism. Panobinostat also showed interstrain and interspecies differences in the in vitro plasma stability and was stable in human plasma. The objective of this study was to examine the in vitro metabolic stability of panobinostat in different matrices and assess the influence of that metabolic stability on the in vivo pharmacokinetics and CNS delivery of panobinostat. Importantly, the plasma stability in various mouse strains was not reflected in the in vivo systemic pharmacokinetic behavior of panobinostat. Several hypotheses arise from this finding, including: the binding of panobinostat to red blood cells, the existence of competing endogenous compounds to enzyme(s), the distribution into tissues with a lower level of enzymatic activity or the metabolism occurring in the plasma is a small fraction of the total metabolism in vivo. SIGNIFICANCE STATEMENT: Panobinostat showed different in vitro degradation in plasma from different mouse strains and genotypes. However, despite the differences surrounding in vitro plasma stability, panobinostat showed similar in vivo pharmacokinetic behavior in different mouse models. This suggests that the interstrain difference in enzymatic activity did not affect the in vivo pharmacokinetic behavior of panobinostat and its central nervous system distribution in mice. This lack of translation between in vitro metabolism assays and in vivo disposition can confound drug development.
组蛋白去乙酰化酶（HDAC）表达失调在许多癌症中屡见不鲜，HDAC抑制剂已显示出对多种癌症类型的效力。帕比司他是一种强效的泛HDAC抑制剂，已在多项治疗脑肿瘤的研究中进行了测试。在不同模型或物种中进行研究时，对于其全身给药后治疗中枢神经系统（CNS）肿瘤的疗效存在不同观点。我们使用三种不同的小鼠品系或基因型进行实验，以更全面地了解帕比司他的全身以及CNS分布动力学。我们的研究发现，帕比司他在体外于B型Friend白血病病毒小鼠基质中迅速降解，与室温及4°C相比，在37°C时观察到更快的降解速率，这表明帕比司他的体外不稳定性是由于酶促代谢所致。帕比司他在体外血浆稳定性方面也表现出品系间和种间差异，并且在人血浆中稳定。本研究的目的是检测帕比司他在不同基质中的体外代谢稳定性，并评估该代谢稳定性对帕比司他体内药代动力学和CNS递送的影响。重要的是，帕比司他在各种小鼠品系中的血浆稳定性并未反映在其体内全身药代动力学行为中。这一发现引发了几种假设，包括：帕比司他与红细胞的结合、存在与酶竞争的内源性化合物、分布到酶活性较低的组织中或血浆中发生的代谢在体内总代谢中占比很小。意义声明：帕比司他在来自不同小鼠品系和基因型的血浆中表现出不同的体外降解。然而，尽管体外血浆稳定性存在差异，但帕比司他在不同小鼠模型中表现出相似的体内药代动力学行为。这表明酶活性的品系间差异并未影响帕比司他在小鼠体内的药代动力学行为及其在中枢神经系统的分布。体外代谢试验与体内处置之间缺乏转化可能会混淆药物开发。
