A simple blood microdialysis in freely-moving rats for pharmacokinetic-pharmacodynamic modeling study of Shengmai injection with simultaneous determination of drug concentrations and efficacy levels in dialysate
A simple blood microdialysis in freely-moving rats for pharmacokinetic-pharmacodynamic modeling study of Shengmai injection with simultaneous determination of drug concentrations and efficacy levels in dialysate
复制标题
自由活动大鼠的简单血液微透析，用于生脉注射液的药代动力学-药效学建模研究，同时测定透析液中的药物浓度和疗效水平
DOI：
10.1016/j.jpba.2018.02.061
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发表时间：
2018-05-30
影响因子：
3.4
通讯作者：
Shao, Qing
中科院分区：
文献类型：
--
作者：
Zhan, Shuyu;Ding, Baoyue;Shao, Qing
微透析是一种强大的体内采样技术，可用于临床前和临床研究中药物的药代动力学-药效学（PK-PD）建模。然而，以往微透析研究的局限性在于整个实验过程中动物均处于麻醉状态，以及微透析与采血相结合进行药物和（或）效应检测，会明显影响药物的PK和PD行为。本研究建立了一种简单的自由活动大鼠血液微透析采样系统，用于同步研究生脉注射液（SMI）对异丙肾上腺素（ISO）诱导的大鼠心肌缺血模型一氧化氮（NO）释放的实时PK和PD效应。建立了LC-MS/MS和HPLC-FLD法分别测定SMI中主要有效成分人参皂苷Rg 1、Rg 2、Re、Rf、Rb 1、Rd和Rc以及透析液中NO的主要氧化产物NOx-的含量。通过同时测定透析液中的药物浓度和NO有效水平，成功地应用所开发的方法建立了浓度-时间和效应-时间曲线，随后建立了丹参诱导心肌缺血大鼠静脉注射10.8 mL/kg（-1）丹参后NO释放的PK-PD模型。PK-PD模型能较好地描述参麦注射液的量效关系，具有较好的预测能力。建立自由活动大鼠血液微透析模型，选择合适的血液内源性小分子作为效应标志物，是合理研究PK-PD的一种有吸引力的技术。(C)2018 Elsevier B. V.版权所有。
Microdialysis is a powerful in vivo sampling technique for pharmacokinetic-pharmacodynamic (PK-PD) modeling of drugs in pre-clinical and clinical studies. However, the noticeable limitations of previous studies using microdialysis were that animals anesthesia in the whole experiment and the combination of microdialysis and blood sampling for drug and (or) effect detection, which can obviously influence PK and PD behavior of drugs. In this study, a simple blood microdialysis sampling system in freely moving rats was established for simultaneous study of PK and PD of Shengmai injection (SMI) effect on inducing real-time nitric oxide (NO) release on isoproterenol (ISO) induced myocardial ischemia rats. The LC-MS/MS and HPLC with fluorescence detection (HPLC-FLD) methods were developed to determine ginsenside Rg1, Rg2, Re, Rf, Rb1, Rd and Rc, the main effective components of SMI, and NOx-, the main oxidation products of NO, in dialysates respectively. Through simultaneous determination of drug concentrations and NO efficacy levels in dialysate, the developed methods were successfully applied to set up concentration-time and effect-time profiles followed by PK-PD modeling of SMI effect on inducing NO release after intravenous administration of 10.8 mL kg(-1) SMI in myocardial ischemia rats. The PK-PD modeling characterized the dose-effect relationships of SMI and behaved good prediction ability. The established blood microdialysis in freely-moving rats is an appealing technology for rational PK-PD studies when selecting suitable blood endogenous micromolecule as effect marker. (C) 2018 Elsevier B.V. All rights reserved.