Purpose

To advance physiologically-based pharmacokinetic modelling of xenobiotic metabolism by integrating metabolic kinetics with percutaneous absorption.

Method

Kinetic rate equations were proposed to describe the metabolism of a network of reaction pathways following topical exposure and incorporated into the diffusion-partition equations of both xenobiotics and metabolites. The published ex vivo case study of aromatic amines was simulated. Diffusion and partition properties of xenobiotics and subsequent metabolites were determined using physiologically-based quantitative structure property relationships. Kinetic parameters of metabolic reactions were best fitted from published experimental data.

Results

For aromatic amines, the integrated transdermal permeation and metabolism model produced data closely matched by experimental results following limited parameter fitting of metabolism rate constants and vehicle:water partition coefficients. The simulation was able to produce dynamic concentration data for all the dermal layers, as well as the vehicle and receptor fluid.

Conclusion

This mechanistic model advances the dermal in silico functionality. It provides improved quantitative spatial and temporal insight into exposure of xenobiotics, enabling the isolation of governing features of skin. It contributes to accurate modelling of concentrations of xenobiotics reaching systemic circulation and additional metabolite concentrations. This is vital for development of both pharmaceuticals and cosmetics.

中文翻译：

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同时经皮吸收和异生物质代谢的计算机模拟：模型开发和芳香胺的案例研究

目的

通过将代谢动力学与经皮吸收相结合，推进基于生理学的异生物质代谢药代动力学建模。

方法

提出了动力学速率方程来描述局部暴露后反应途径网络的代谢，并将其纳入异生物质和代谢物的扩散分配方程。模拟了已发表的芳香胺离体案例研究。使用基于生理学的定量结构特性关系确定外源性物质和后续代谢物的扩散和分配特性。代谢反应的动力学参数最符合已发表的实验数据。

结果

对于芳香胺，综合透皮渗透和代谢模型产生的数据与代谢速率常数和赋形剂：水分配系数的有限参数拟合后的实验结果密切匹配。该模拟能够产生所有真皮层以及载体和受体液的动态浓度数据。

结论

这种机械模型提高了硅胶功能的真皮。它提供了对异生物质暴露的改进的定量时空洞察力，从而能够隔离皮肤的控制特征。它有助于准确模拟达到体循环的异生物质浓度和额外代谢物浓度。这对于药物和化妆品的开发都至关重要。