In Silico Simulation of Simultaneous Percutaneous Absorption and Xenobiotic Metabolism: Model Development and a Case Study on Aromatic Amines

• Published in: Pharmaceutical research 2020-12, Vol.37 (12), p.241-241, Article 241
• Main Authors: Coleman, Lucy, Lian, Guoping, Glavin, Stephen, Sorrell, Ian, Chen, Tao
• Format: Article
• Language: English
• Subjects: Amines; Analysis; Aromatic amines; Biochemistry; Biomedical and Life Sciences; Biomedical Engineering and Bioengineering; Biomedicine; Case studies; Cosmetics; Medical Law; Metabolism; Metabolites; Pharmacokinetics; Pharmacology/Toxicology; Pharmacy; Physiological aspects; Research Paper; Skin; Xenobiotics
• ISSN: 0724-8741; 1573-904X
• DOI: 10.1007/s11095-020-02967-w

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.