In Silico Simulation of Simultaneous Percutaneous Absorption and Xenobiotic Metabolism: Model Development and a Case Study on Aromatic Amines.
In Silico Simulation of Simultaneous Percutaneous Absorption and Xenobiotic Metabolism: Model Development and a Case Study on Aromatic Amines.
复制标题
同时经皮吸收和异生物质代谢的计算机模拟：模型开发和芳香胺案例研究。
DOI：
10.1007/s11095-020-02967-w
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发表时间：
2020
影响因子：
3.7
通讯作者：
Coleman L
中科院分区：
文献类型：
--
作者：
Coleman L
目的将代谢动力学与经皮吸收相结合，建立基于生理的外源代谢药代动力学模型。方法建立动力学速率方程来描述局部暴露后反应通路网络的代谢，并将其纳入外源物和代谢物的扩散-分配方程。对已发表的芳香胺的活酶研究进行了模拟。利用基于生理学的定量结构性质关系来确定外源物和随后代谢物的扩散和分配特性。代谢反应的动力学参数与已发表的实验数据最吻合。结果芳香胺的透皮渗透代谢综合模型对代谢速率常数和载水分配系数进行了有限参数拟合，得到的数据与实验结果吻合较好。该模拟能够生成所有真皮层以及载体和受体液体的动态浓度数据。结论该机制模型提高了真皮硅功能。它提供了改进的定量空间和时间洞察暴露的异种生物，使控制特征的皮肤的隔离。它有助于准确模拟达到体循环的外源药物浓度和额外的代谢物浓度。这对药品和化妆品的发展都是至关重要的。
PurposeTo advance physiologically-based pharmacokinetic modelling of xenobiotic metabolism by integrating metabolic kinetics with percutaneous absorption.MethodKinetic 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 publishedex vivocase 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.ResultsFor 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.ConclusionThis mechanistic model advances the dermalin silicofunctionality. 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.