Predicting Transport of 3,5,6-Trichloro-2-Pyridinol Into Saliva Using a Combination Experimental and Computational Approach.
Predicting Transport of 3,5,6-Trichloro-2-Pyridinol Into Saliva Using a Combination Experimental and Computational Approach.
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使用实验和计算相结合的方法预测 3,5,6-三氯-2-吡啶醇向唾液中的转运。
DOI：
10.1093/toxsci/kfx055
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发表时间：
2017
期刊：
影响因子：
--
通讯作者：
Timchalk,Charles
中科院分区：
文献类型：
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作者：
Smith,JordanNed;Carver,ZanaA;Weber,ThomasJ;Timchalk,Charles
结合实验和计算的方法来预测化学运输到唾液中。建立了一种血清-腺泡化学转运试验，用于测量农药毒死蜱代谢产物3，5，6-三氯-2-吡啶酚（TCPy）在非生理（标准细胞培养基）和生理（使用替代血浆和唾液培养基）条件下的化学转运。在细胞培养基和大鼠血浆中观察到高水平的TCPy蛋白结合，导致在2种实验条件下TCPy转运行为不同。在非生理转运实验中，TCPy在顶侧室和基底侧室中以相等浓度达到平衡。在较高的TCPy剂量下，观察到未结合的TCPy增加，并且顶室和基底侧室中的TCPy浓度比较低剂量更快地达到平衡，表明仅未结合的TCPy能够穿过细胞单层。在生理实验中，TCPy转运比非生理条件下慢，并且在顶室和基底侧室中以与先前在TCPy给药的大鼠中测量的比率（0.034）相当的比率（唾液：血液比率：0.049）在不同浓度下实现平衡。基于TCPy蛋白结合动力学开发了细胞转运计算模型，并使用2种实验条件下的不同渗透系数（非生理和生理实验分别为1.14与0.4 cm/h）合理地模拟了所有转运实验。将计算模型整合到基于生理学的药代动力学模型中，并准确预测TCPy给药大鼠唾液中的TCPy浓度。总的来说，这项研究证明了一种预测唾液中化学物质转运的方法，可能会在未来增加唾液生物监测的实用性。
A combination experimental and computational approach was developed to predict chemical transport into saliva. A serous-acinar chemical transport assay was established to measure chemical transport with nonphysiological (standard cell culture medium) and physiological (using surrogate plasma and saliva medium) conditions using 3,5,6-trichloro-2-pyridinol (TCPy) a metabolite of the pesticide chlorpyrifos. High levels of TCPy protein binding were observed in cell culture medium and rat plasma resulting in different TCPy transport behaviors in the 2 experimental conditions. In the nonphysiological transport experiment, TCPy reached equilibrium at equivalent concentrations in apical and basolateral chambers. At higher TCPy doses, increased unbound TCPy was observed, and TCPy concentrations in apical and basolateral chambers reached equilibrium faster than lower doses, suggesting only unbound TCPy is able to cross the cellular monolayer. In the physiological experiment, TCPy transport was slower than nonphysiological conditions, and equilibrium was achieved at different concentrations in apical and basolateral chambers at a comparable ratio (0.034) to what was previously measured in rats dosed with TCPy (saliva:blood ratio: 0.049). A cellular transport computational model was developed based on TCPy protein binding kinetics and simulated all transport experiments reasonably well using different permeability coefficients for the 2 experimental conditions (1.14 vs 0.4 cm/h for nonphysiological and physiological experiments, respectively). The computational model was integrated into a physiologically based pharmacokinetic model and accurately predicted TCPy concentrations in saliva of rats dosed with TCPy. Overall, this study demonstrates an approach to predict chemical transport in saliva, potentially increasing the utility of salivary biomonitoring in the future.