Burhenne Jürgen, Liu Lu, Heilig Christoph E, Meid Andreas D, Leisen Margarete, Schmitt Thomas, Kasper Bernd, Haefeli Walter E, Mikus Gerd, Egerer Gerlinde
Department of Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.
Department of Hematology, Oncology and Rheumatology, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.
Cancer Chemother Pharmacol. 2017 Aug;80(2):433-439. doi: 10.1007/s00280-017-3357-y. Epub 2017 Jun 13.
In the regulation of chromatin-structure and histone function, histone deacetylases (HDACs) are key enzymes and thus modulators of epigenetic regulation and gene expression. Accesses of the HDAC inhibitor vorinostat to intracellular compartments are essential to exert epigenetic effects.
In ten sarcoma patients receiving oral Zolinza (400 mg qd) vorinostat concentrations in plasma and peripheral blood mononuclear cells (PBMCs) were quantified using validated LC/MS/MS assays to determine intracellular and extracellular pharmacokinetic data. Cellular HDAC activity was evaluated using a fluorogenic assay. Concentration-response relationships were established between intracellular and extracellular vorinostat concentrations and HDAC inhibition in PBMCs.
Pharmacokinetics of vorinostat and its two main inactive metabolites were determined over 8 h in plasma and PBMCs. Steady state AUCs (±SD) and T (±SD) were calculated to 4.61 ± 0.87 h µM and 1.73 ± 0.69 h (plasma) and 15.2 ± 9.03 h µM and 5.30 ± 4.27 h (PBMCs). Intracellular accumulation of vorinostat was determined together with prolonged vorinostat elimination in PBMCs. Cellular HDAC inhibition increased parallel with vorinostat concentrations in plasma and PBMCs. For effective inhibition of cellular HDACs (IC) vorinostat concentrations of 0.05 µM in plasma and 0.17 µM in PBMCs were necessary.
HDAC inhibition closely followed intracellular vorinostat concentrations and was short-lasting, which may contribute to the limited efficacy seen with vorinostat in solid tumors so far.
在染色质结构和组蛋白功能的调控中，组蛋白脱乙酰酶（HDACs）是关键酶，因此也是表观遗传调控和基因表达的调节因子。HDAC抑制剂伏立诺他进入细胞内区室对于发挥表观遗传效应至关重要。
在10例接受口服Zolinza（400mg每日一次）的肉瘤患者中，使用经过验证的液相色谱-串联质谱（LC/MS/MS）测定法对血浆和外周血单核细胞（PBMCs）中的伏立诺他浓度进行定量，以确定细胞内和细胞外的药代动力学数据。使用荧光测定法评估细胞HDAC活性。建立了细胞内和细胞外伏立诺他浓度与PBMCs中HDAC抑制之间的浓度-反应关系。
在血浆和PBMCs中对伏立诺他及其两种主要无活性代谢物的药代动力学进行了8小时的测定。计算出稳态曲线下面积（AUCs，±标准差）和达峰时间（T，±标准差），血浆中分别为4.61±0.87小时·微摩尔和1.73±0.69小时，PBMCs中分别为15.2±9.03小时·微摩尔和5.30±4.27小时。确定了伏立诺他在细胞内的蓄积以及在PBMCs中伏立诺他消除时间的延长。细胞HDAC抑制与血浆和PBMCs中伏立诺他浓度平行增加。为有效抑制细胞HDACs（IC），血浆中伏立诺他浓度需达到0.05微摩尔，PBMCs中需达到0.17微摩尔。
HDAC抑制与细胞内伏立诺他浓度密切相关且持续时间较短，这可能是迄今为止伏立诺他在实体瘤中疗效有限的原因之一。
