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

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 incorpor...

Full description

Saved in:
Bibliographic Details
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
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:0724-8741
1573-904X
DOI:10.1007/s11095-020-02967-w