Center for Phytochemical Epigenome Studies, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey , Piscataway, New Jersey 08854, United States.
Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey , Piscataway, New Jersey 08854, United States.
Mol Pharm. 2017 Nov 6;14(11):3709-3717. doi: 10.1021/acs.molpharmaceut.7b00469. Epub 2017 Oct 25.
The triterpenoid ursolic acid (UA) has been proposed as a potential cancer chemopreventive agent in many preclinical and clinical studies. In the present work, we aimed to characterize the pharmacokinetics (PK) of UA and to quantitatively assess the antioxidative and anti-inflammatory effects of UA, which are potentially linked to its chemopreventive efficacy. UA was administered intravenously (i.v., 20 mg/kg) or by oral gavage (100 mg/kg) to male Sprague-Dawley rats, and blood samples were collected at a series of designated time points. The plasma concentration of UA was determined using a validated liquid chromatography-mass spectrometry (LC-MS) approach. A biexponential decline in the UA plasma concentration was observed after i.v. dosing and was fitted to a two-compartmental model. The expression levels of phase II drug metabolism (DM)/antioxidant genes and the inflammatory iNos gene in corresponding treatment arms were measured using qPCR as a pharmacodynamic (PD) marker. The expression of phase II DM/antioxidant genes increased and peaked approximately 3 h after 20 mg/kg UA treatment. In a lipopolysaccharide (LPS)-induced acute inflammation model, UA inhibited LPS-stimulated iNos expression and that of the epigenetic markers the DNA methyltransferases (DNMTs) and histone deacetylases (HDACs) in leukocytes. A PK-PD model using Jusko's indirect response model (IDR) with transition compartments (TC) was established to describe the time delay and magnitude of the gene expression elicited by UA. The PK-PD model provided reasonable fitting linking the plasma concentration of UA simultaneously with the PD response based on leukocyte mRNA expression. Overall, our results indicate that UA is effective at inducing various phase II DM/antioxidant genes and inhibiting pro-inflammatory genes in vivo. This PK-PD modeling approach may provide a conceptual framework for the future clinical evaluation of dietary chemopreventive agents in humans.
熊果酸（UA）是一种三萜类化合物，在许多临床前和临床研究中被提出是一种有潜力的癌症化学预防剂。在本工作中，我们旨在描述 UA 的药代动力学（PK），并定量评估 UA 的抗氧化和抗炎作用，这些作用可能与其化学预防功效有关。将 UA 静脉内（i.v.，20mg/kg）或口服灌胃（100mg/kg）给予雄性 Sprague-Dawley 大鼠，并在一系列指定时间点采集血样。使用经过验证的液相色谱-质谱（LC-MS）方法测定 UA 的血浆浓度。静脉内给药后，UA 血浆浓度呈双指数下降，拟合为二室模型。使用 qPCR 作为药效学（PD）标志物，测量相应处理臂中 II 相药物代谢（DM）/抗氧化基因和炎症 iNos 基因的表达水平。在 20mg/kg UA 处理后约 3 小时，II 相 DM/抗氧化基因的表达增加并达到峰值。在脂多糖（LPS）诱导的急性炎症模型中，UA 抑制 LPS 刺激的 iNos 表达以及白细胞中的表观遗传标记物 DNA 甲基转移酶（DNMTs）和组蛋白去乙酰化酶（HDACs）的表达。使用 Jusko 的间接反应模型（IDR）与过渡隔室（TC）建立 PK-PD 模型，以描述 UA 引发的基因表达的时间延迟和幅度。PK-PD 模型基于白细胞 mRNA 表达，合理地将 UA 的血浆浓度与 PD 反应联系起来。总之，我们的结果表明，UA 有效地诱导体内各种 II 相 DM/抗氧化基因，并抑制促炎基因。这种 PK-PD 建模方法可为未来人类膳食化学预防剂的临床评估提供概念框架。
