Purpose

The purpose of this research is to analyze non-linear pharmacokinetics of P-glycoprotein (P-gp) substrates in a cell based assay of a microfluidic device, which might be affected by hydrodynamic barrier (unstirred water layer, UWL).

Results

Apparent permeability (P_app) were obtained using non-P-gp substrates (propranolol, metoprolol, and atenolol) and P-gp substrates (quinidine and talinolol) in a commercially available microfluidic device, organoplate ® of Caco-2 cell based assay. The previous UWL resistance model was well fitted to P_app of static and flow condition by assuming UWL including and negligible condition, while P-gp substrates of higher passive permeability (quinidine) was apart from the fitting curve. The concentration dependent non-linear kinetics of P-gp substrates, quinidine and talinolol, was more analyzed in detail, and apparent V_max discrepancy between static and flow assay condition in the quinidine assay was observed, while that was not observed in talinolol, the lower permeable substrate. Based on the experimental results, a mathematical model for P-gp substrates including UWL compartment on the previous 3-compartment model was developed, and it indicated that the apparent V_max was variable along with the ratio between passive permeability and UWL permeability.

Conclusions

The mathematical model adding UWL compartment well explained non-linear pharmacokinetics of apparent permeability of P-gp substrate in the microfluidic device. The model also has a potential to be applied to P-gp substrate permeability analysis in vivo.

中文翻译：

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使用包含未搅拌水层 (UWL) 隔室的数学模型分析微流体装置中 P-糖蛋白底物的非线性药代动力学

目的

本研究的目的是在微流体装置的基于细胞的测定中分析 P-糖蛋白 (P-gp) 底物的非线性药代动力学，这可能会受到流体动力学屏障（未搅拌水层，UWL）的影响。

结果

使用非 P-gp 底物（普萘洛尔、美托洛尔和阿替洛尔）和 P-gp 底物（奎尼丁和他林洛尔）在市售微流体装置、基于 Caco-2 细胞的测定中获得表观渗透性 (P _app )。通过假设 UWL 包括和可忽略的条件，先前的 UWL 阻力模型与静态和流动条件的P _app很好地拟合，而具有更高被动渗透性的 P-gp 底物（奎尼丁）与拟合曲线分开。对 P-gp 底物奎尼丁和他林洛尔的浓度依赖性非线性动力学进行了更详细的分析，表观_Vmax在奎尼丁试验中观察到静态和流动试验条件之间的差异，而在低渗透性底物塔里洛尔中未观察到这种差异。基于实验结果，对P-gp的底物，包括对以前的3室模型UWL隔室的数学模型被开发，并且它表明该表观V_最大是与被动渗透性和渗透性UWL之间的比率沿变量。

结论

添加 UWL 隔室的数学模型很好地解释了微流体装置中 P-gp 底物表观渗透性的非线性药代动力学。该模型还具有应用于体内P-gp 底物渗透性分析的潜力。