In Silico Simulation of Simultaneous Percutaneous Absorption and Xenobiotic Metabolism: Model Development and a Case Stu
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RESEARCH PAPER
In Silico Simulation of Simultaneous Percutaneous Absorption and Xenobiotic Metabolism: Model Development and a Case Study on Aromatic Amines Lucy Coleman 1
&
Guoping Lian 1,2 & Stephen Glavin 2 & Ian Sorrell 2 & Tao Chen 1
Received: 22 June 2020 / Accepted: 27 October 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
ABSTRACT 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. Supplementary Information The online version contains supplementary material available at https://doi.org/10.1007/s11095-020-02967-w. * Tao Chen [email protected] 1
Department of Chemical and Process Engineering, University of Surrey, Guildford GU2 7XH, UK
2
Unilever, Colworth Science Park, Sharnbrook, Bedfordshire MK44 1LQ, UK
KEY WORDS bioavailability . diffusion . in silico modelling . metabolism . xenobiotic
ABBREVIATIONS HaCaT PBPK QSPR SC VE
Immortalised human keratinocytes Physiologically-Based Pharmacokinetics Quantitative Structure-Property Relationship Stratum Corneum Viable Epidermis
INTRODUCTION Quantitative understanding of xenobiotic metabolism due to dermal exposure is crucial for safety and efficacy assessment of dermatological drugs and cosmetic products (1). The subject is also important to environmental exposure (2). Much of the research conducted has been through in vivo, ex vivo or in vitro experimentation. Assessment of transdermal xenobiotic metabolism using in vivo methodology produces results from overall metabolic transformations. This means separating dermal metabolic transformations from those present in other organ
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