Compartmental models for apical efflux by P-glycoprotein--part 1: evaluation of model complexity.
Compartmental models for apical efflux by P-glycoprotein--part 1: evaluation of model complexity.
复制标题
p-糖蛋白的顶端外排的隔室模型 - 部分：模型复杂性的评估。
DOI：
10.1007/s11095-013-1164-7
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发表时间：
2014-02
影响因子：
3.7
通讯作者：
Korzekwa, Ken
中科院分区：
文献类型：
--
作者：
Nagar, Swati;Tucker, Jalia;Weiskircher, Erica A.;Bhoopathy, Siddhartha;Hidalgo, Ismael J.;Korzekwa, Ken
为了量化P-gp转运动力学，这些手稿的第1部分评估了不同的室室模型，第2部分将这些模型应用于动力学数据。建立了模型来模拟顶端外排转运体对六种药物细胞内浓度的影响。评估了实验变率对模型预测的影响。对几种模型进行了评估，其特征包括膜结构、脂质含量和根尖表面积（asa）各不相同。与MDCK对照细胞相比，MDCK- mdr1细胞在环孢素作用下的被动通透性模型误差更低。与第2部分的结果一致，模型配置对计算模型误差的影响很小。5室模型是再现实验滞后时间最简单的模型。脂质含量和asa对模型误差、预测滞后时间和细胞内浓度的影响最小。包括内源性基底外侧摄取活性可以减少模型误差。有和没有明确膜屏障的模型在预测基底外侧药物暴露的细胞内浓度方面存在显著差异。单点数据产生的间隙与时间航线数据相似。室室模型有助于评估外排转运体对细胞内浓度的影响。虽然3室模型可能足以预测转运体从细胞外排药物的影响，但可能需要具有外显膜的5室模型来预测从膜外排发生时的细胞内浓度。更复杂的模型包括额外的隔室可能是不必要的。
With the goal of quantifying P-gp transport kinetics, Part 1 of these manuscripts evaluates different compartmental models and Part 2 applies these models to kinetic data. Models were developed to simulate the effect of apical efflux transporters on intracellular concentrations of six drugs. The effect of experimental variability on model predictions was evaluated. Several models were evaluated, and characteristics including membrane configuration, lipid content, and apical surface area (asa) were varied. Passive permeabilities from MDCK-MDR1 cells in the presence of cyclosporine gave lower model errors than from MDCK control cells. Consistent with the results in Part 2, model configuration had little impact on calculated model errors. The 5-compartment model was the simplest model that reproduced experimental lag times. Lipid content and asa had minimal effect on model errors, predicted lag times, and intracellular concentrations. Including endogenous basolateral uptake activity can decrease model errors. Models with and without explicit membrane barriers differed markedly in their predicted intracellular concentrations for basolateral drug exposure. Single point data resulted in clearances similar to time course data. Compartmental models are useful to evaluate the impact of efflux transporters on intracellular concentrations. Whereas a 3-compartment model may be sufficient to predict the impact of transporters that efflux drugs from the cell, a 5-compartment model with explicit membranes may be required to predict intracellular concentrations when efflux occurs from the membrane. More complex models including additional compartments may be unnecessary.
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DOI：
10.1111/j.1365-2885.2008.01007.x
发表时间：
2009-02-01
影响因子：
1.3
作者：
Geyer, J.;Gavrilova, O.;Petzinger, E.
通讯作者：
Petzinger, E.
影响因子：
3.7
作者：
Kalvass, JC;Graff, CL;Pollack, GM
通讯作者：
Pollack, GM
影响因子：
7.3
作者：
Hendrikse, NH;Schinkel, AH;Franssen, EJF
通讯作者：
Franssen, EJF
影响因子：
2.1
作者：
Fujino, Hideki;Yamada, Iwao;Kojima, Junji
通讯作者：
Kojima, Junji
影响因子：
3.8
作者：
Salama, NN;Kelly, EJ;Ho, RJY
通讯作者：
Ho, RJY