Three methods for estimation of the equilibrium tissue-to-plasma partition ratios (Kp values) in the presence of tissue concentration time data have been investigated. These are the area method, the open loop (tissue specific) method and the whole body model(closed loop) method, each with different model assumptions. Additionally, multiple imputations, a technique for dealing with deficiencies in data sets (i.e., missing tissues) is used. The estimated Kp values by the three methods have been compared and the limitations and advantages of each approach drawn. The area method, which is essentially model free, gives only a crude estimate of Kp without making any statement of its uncertainty; whereas both the open and closed loop methods provide an estimate of this. The closed loop method, where the most assumptions are made, is the approach that gives the best overall estimates of Kp, which was confirmed by comparing the predicted concentration-time profiles with experimental data. Although the estimates from the closed loop method, as well as the other two methods, are conditioned on the data, they are the most reliable for both propagating parameter variability and uncertainty through a whole body physiologically based model, as well as for extrapolation to human. A series of benzodiazepines, namely alprazolam, chlordiazepoxide, clobazam, diazepam, flunitrazepam, midazolam and triazolam in rat is used as a case study in the current investigation.

中文翻译：

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全身生理学模型的发展，以表征苯二氮卓类药物的药代动力学。1：估计大鼠组织-血浆分配比。

研究了在存在组织浓度时间数据的情况下估算平衡的组织与血浆分配比（Kp值）的三种方法。这些是面积方法，开环（组织专用）方法和全身模型（闭环）方法，每种方法都有不同的模型假设。另外，使用多重插补，一种用于处理数据集中的缺陷（即，缺失的组织）的技术。比较了三种方法的估计Kp值，并得出了每种方法的局限性和优点。面积法基本上是无模型的，它仅给出Kp的粗略估计，而没有对其不确定性作任何陈述。而开环法和闭环法都可以对此进行估算。进行最多假设的闭环方法，这种方法可提供最佳的Kp总体估算值，这是通过将预测的浓度-时间曲线与实验数据进行比较来证实的。尽管闭环方法以及其他两种方法的估计值均以数据为条件，但它们对于通过全身生理模型传播参数可变性和不确定性以及对人类的推断都是最可靠的。在本研究中，使用了一系列苯二氮卓类药物，即大鼠中的阿普唑仑，氯二氮卓，克霉唑，地西epa，氟硝西epa，咪达唑仑和三唑仑。以数据为条件，它们对于通过全身生理模型传播参数可变性和不确定性，以及对人的推断都是最可靠的。在本研究中，使用了一系列苯二氮卓类药物，即大鼠中的阿普唑仑，氯二氮卓，克霉唑，地西epa，氟硝西epa，咪达唑仑和三唑仑。以数据为条件，它们对于通过全身生理模型传播参数可变性和不确定性，以及对人类进行外推都是最可靠的。在本研究中，使用了一系列苯二氮卓类药物，即大鼠中的阿普唑仑，氯二氮卓，克霉唑，地西epa，氟硝西epa，咪达唑仑和三唑仑。