Department of Neuroscience, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
Department of Anesthesiology and Critical Care, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
PLoS One. 2018 Apr 23;13(4):e0194949. doi: 10.1371/journal.pone.0194949. eCollection 2018.
Mechanisms through which anesthetics disrupt neuronal activity are incompletely understood. In order to study anesthetic mechanisms in the intact brain, tight control over anesthetic pharmacology in a genetically and neurophysiologically accessible animal model is essential. Here, we developed a pharmacokinetic model that quantitatively describes propofol distribution into and elimination out of the brain. To develop the model, we used jugular venous catheters to infuse propofol in mice and measured propofol concentration in serial timed brain and blood samples using high performance liquid chromatography (HPLC). We then used adaptive fitting procedures to find parameters of a three compartment pharmacokinetic model such that all measurements collected in the blood and in the brain across different infusion schemes are fit by a single model. The purpose of the model was to develop target controlled infusion (TCI) capable of maintaining constant brain propofol concentration at the desired level. We validated the model for two different targeted concentrations in independent cohorts of experiments not used for model fitting. The predictions made by the model were unbiased, and the measured brain concentration was indistinguishable from the targeted concentration. We also verified that at the targeted concentration, state of anesthesia evidenced by slowing of the electroencephalogram and behavioral unresponsiveness was attained. Thus, we developed a useful tool for performing experiments necessitating use of anesthetics and for the investigation of mechanisms of action of propofol in mice.
麻醉剂破坏神经元活动的机制尚不完全清楚。为了在完整的大脑中研究麻醉机制，在遗传和神经生理学上可及的动物模型中对麻醉药理学进行严格控制至关重要。在这里，我们开发了一个可以定量描述丙泊酚在大脑内分布和消除的药代动力学模型。为了开发该模型，我们使用颈静脉导管在小鼠中输注丙泊酚，并使用高效液相色谱法（HPLC）在不同时间间隔的脑和血样中测量丙泊酚浓度。然后，我们使用自适应拟合程序来找到三腔药代动力学模型的参数，以使通过单个模型拟合不同输注方案在血液和大脑中收集的所有测量值。该模型的目的是开发能够将大脑中丙泊酚浓度维持在所需水平的靶控输注（TCI）。我们在未用于模型拟合的独立实验队列中验证了针对两种不同靶向浓度的模型。模型的预测是无偏的，并且测量的脑浓度与靶向浓度无法区分。我们还验证了在靶向浓度下，脑电图减慢和行为无反应表明达到了麻醉状态。因此，我们开发了一种有用的工具，用于进行需要使用麻醉剂的实验，并研究丙泊酚在小鼠中的作用机制。
