In Silico Simulation of Simultaneous Percutaneous Absorption and Xenobiotic Metabolism: Model Development and a Case Study on Aromatic Amines.
bioavailability
diffusion
in silico modelling
metabolism
xenobiotic
Journal
Pharmaceutical research
ISSN: 1573-904X
Titre abrégé: Pharm Res
Pays: United States
ID NLM: 8406521
Informations de publication
Date de publication:
11 Nov 2020
11 Nov 2020
Historique:
received:
22
06
2020
accepted:
27
10
2020
entrez:
11
11
2020
pubmed:
12
11
2020
medline:
5
8
2021
Statut:
epublish
Résumé
To advance physiologically-based pharmacokinetic modelling of xenobiotic metabolism by integrating metabolic kinetics with percutaneous absorption. 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. 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. 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.
Identifiants
pubmed: 33175239
doi: 10.1007/s11095-020-02967-w
pii: 10.1007/s11095-020-02967-w
doi:
Substances chimiques
Amines
0
Xenobiotics
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
241Subventions
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/P504415/1
Pays : United Kingdom
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