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首页> 外文期刊>Canadian Journal of Physiology and Pharmacology >Simulation of differential drug pharmacokinetics under heat and exercise stress using a physiologically based pharmacokinetic modeling approach.
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Simulation of differential drug pharmacokinetics under heat and exercise stress using a physiologically based pharmacokinetic modeling approach.

机译：使用基于生理的药代动力学建模方法，模拟在热和运动压力下的差异药物药代动力学。

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摘要

Under extreme conditions of heat exposure and exercise stress, the human body undergoes major physiological changes. Perturbations in organ blood flows, gastrointestinal properties, and vascular physiology may impact the body's ability to absorb, distribute, and eliminate drugs. Clinical studies on the effect of these stressors on drug pharmacokinetics demonstrate that the likelihood of pharmacokinetic alteration is dependent on drug properties and the intensity of the stressor. The objectives of this study were to use literature data to quantify the correlation between exercise and heat exposure intensity to changing physiological parameters and further, to use this information for the parameterization of a whole-body, physiologically based pharmacokinetic model for the purposes of determining those drug properties most likely to demonstrate altered drug pharmacokinetics under stress. Cardiac output and most organ blood flows were correlated with heart rate using regression analysis. Other altered parameters included hematocrit and intravascular albumin concentration. Pharmacokinetic simulations of intravenous and oral administration of hypothetical drugs with either a low or high value of lipophilicity, unbound fraction in plasma, and unbound intrinsic hepatic clearance demonstrated that the area under the curve of those drugs with a high unbound intrinsic clearance was most affected (up to a 130% increase) following intravenous administration, whereas following oral administration, pharmacokinetic changes were smaller (<40% increase in area under the curve) for all hypothetical compounds. A midazolam physiologically based pharmacokinetic model was also used to demonstrate that simulated changes in pharmacokinetic parameters under exercise and heat stress were generally consistent with those reported in the literature.
机译：在暴露于热和运动压力的极端条件下，人体发生重大的生理变化。器官血流，胃肠道特性和血管生理的扰动可能会影响人体吸收，分配和消除药物的能力。这些应激源对药物药代动力学的影响的临床研究表明，药代动力学改变的可能性取决于药物的性质和应激源的强度。这项研究的目的是利用文献数据量化运动和热暴露强度与变化的生理学参数之间的相关性，并且进一步将该信息用于全身，基于生理学的药代动力学模型的参数化，以确定那些在压力下最有可能证明药物药代动力学发生变化的药物特性。使用回归分析，心输出量和大多数器官血流量与心率相关。其他改变的参数包括血细胞比容和血管内白蛋白浓度。对具有低或高亲脂性，血浆未结合分数和未结合固有肝清除率的假设药物进行静脉和口服给药的药代动力学模拟表明，那些未结合固有清除率高的药物曲线下面积受到最大影响（静脉给药后最多可增加130％），而口服后，所有假设化合物的药代动力学变化均较小（曲线下面积增加<40％）。咪达唑仑基于生理学的药代动力学模型也被用来证明运动和热应激下药代动力学参数的模拟变化通常与文献报道的一致。

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