Department of Pharmaceutics, Medical College of Jiaxing University, Jiaxing 314001, China.
Department of Pharmaceutics, Medical College of Jiaxing University, Jiaxing 314001, China.
J Pharm Biomed Anal. 2018 May 30;154:23-30. doi: 10.1016/j.jpba.2018.02.061. Epub 2018 Mar 9.
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 NO, 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 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.
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，先前使用微透析的研究存在明显的局限性，即在整个实验中对动物进行麻醉，以及将微透析与血液采样相结合以检测药物和（或）效应，这显然会影响药物的 PK 和 PD 行为。在这项研究中，建立了一种简单的自由移动大鼠血液微透析采样系统，用于同时研究参麦注射液（SMI）对诱导实时一氧化氮（NO）释放对异丙肾上腺素（ISO）诱导的心肌缺血大鼠的 PK 和 PD 作用。建立了 LC-MS/MS 和 HPLC 荧光检测（HPLC-FLD）方法，分别用于测定参麦注射液中主要有效成分 Ginsenoside Rg1、Rg2、Re、Rf、Rb1、Rd 和 Rc 以及透析液中的 NO，NO 的主要氧化产物。通过同时测定药物浓度和透析液中 NO 疗效水平，该方法成功地应用于建立参麦注射液静脉注射 10.8 mL/kg 后诱导 NO 释放的浓度-时间和效应-时间曲线，并进行 PK-PD 建模。PK-PD 建模描述了参麦注射液的剂量-效应关系，表现出良好的预测能力。当选择合适的血液内源性小分子作为效应标志物时，建立的自由移动大鼠血液微透析是一种有吸引力的 PK-PD 研究技术。
