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Xenobiotic Metabolism Integrated into an in Silico Dermal Pharmacokinetic Model for Exposure Assessment
Lucy Ann Coleman, MChem.
Tao Chen1, Guoping Lian1,2, Stephen Glavin2,Ian Sorrell21Department of Chemical and Process Engineering, University of Surrey, Guildford, Surrey, GU2 7XH, UK.
2Unilever, Colworth Science Park, Sharnbrook, Bedfordshire, MK44 1LQ, UK.
Intentional contact
Consumer health
Topical medicine/personal care products
Consumer health
Personal care products
What comes into contact with skin?
https://www.nhs.uk/medicines/hydrocortisone-skin-cream/
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https://www.healthline.com/health/washing-hands
Unitentionalcontact
Consumer health
Household products
Occupational health
Agricultural chemicals
Occupational health
Personal care products
https://www.healthline.com/health/bleach-on-skin
http://www.hsesolutions.co.za/our-company/markets/
http://sciencenordic.com/hairdressers-troubled-respiratory-problems
What comes into contact with skin?
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https://tissupath.com.au/medical-student-subjects-skin/ 4
What do we want to know?
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METHODS
https://www.petmd.com/exotic/conditions/skin/c_ex_rt_ringtail_syndrome
http://www.episkin.com/frequently-asked-questions
https://www.mattek.com/store/p96gc-1-5-5-f-case/
https://www.qacslab.com/our-services/cosmetics/patch-testing-for-cosmetics/
https://extherid.com/porcine-skin/
https://doi.org/10.1038/labinvest.2011.184
Animal testing
Ex vivo animal skin
In vivo human/ clinical trials
In chemico
Ex vivo human skin
In vitro / skin equivalents
How can we get this information?
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Ex vivo human
skin
In vitro / skin
equival-ents
QSPR Models
PBPK Models
http://doi.org/10.3390/pharmaceutics9040041R. Potts et al. Pharmaceutical Research, vol. 9, pp. 663-669, 1992.
What can we find out? Model comparison
7T. Chen et al. Pharmaceutical Research, vol. 33, pp. 1602-1614, 2016.
𝜕𝐶𝐴𝜕𝑡
+ 𝑉𝑥𝜕𝐶𝐴𝜕𝑥
+ 𝑉𝑦𝜕𝐶𝐴𝜕𝑦
+ 𝑉𝑧𝜕𝐶𝐴𝜕𝑧
= 𝐷𝐴𝐵𝜕2𝐶𝐴𝜕𝑥2
+𝜕2𝐶𝐴𝜕𝑦2
+𝜕2𝐶𝐴𝜕𝑧2
+ 𝑅𝐴
Mass species conservation equation (Mass transfer equation)
Transient Convection Diffusion Generation
https://www.microscopyu.com/gallery-images/scar-tissue-at-10x-magnification-1
In silico approach and details
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• Mechanistic in silico methods, utilising a combination of:
• Semi-empirical models describing permeation
• Mechanistic understanding
Model set-up
9Adapted from: https://en.wikipedia.org/wiki/Drug_metabolism
PHASE I
PHASE II
R
R RR
OOR NH₂R OH R SH
R SO₂HR GIR Ac R SG
Hydrolysis reduction
Oxidation
Glutathione conjugation
Glu
curo
nid
atio
n
Ace
tyla
tio
n
Sulp
hat
ion
Xenobiotic metabolism pathways
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V
SC
VE
D
RF
Add a source term
• Quantitatively determine concentration of metabolites
−𝑘𝑟𝑎𝑡𝑒 × 𝐶𝐴 𝑘𝑟𝑎𝑡𝑒 × 𝐶𝐴
Consumption term
concentration of substrate
Generation term
concentration of product
𝑘𝑟𝑎𝑡𝑒S P
𝜕𝐶𝐴𝜕𝑡
+ 𝑉𝑥𝜕𝐶𝐴𝜕𝑥
+ 𝑉𝑦𝜕𝐶𝐴𝜕𝑦
+ 𝑉𝑧𝜕𝐶𝐴𝜕𝑧
= 𝐷𝐴𝐵𝜕2𝐶𝐴𝜕𝑥2
+𝜕2𝐶𝐴𝜕𝑦2
+𝜕2𝐶𝐴𝜕𝑧2
+ 𝑅𝐴
Mass species conservation equation (Mass transfer equation)
Diffusion Generation
P P P P P P PP
Introducing metabolism
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https://www.personneltoday.com/hr/occupational-health-research-round-january-2016/
A B
Y XVIABLE EPIDERMIS
STRATUM CORNEUM
DERMIS
VEHICLE
RECEPTOR FLUID
HAPTEN-PROTEIN COMPLEX
+ Protein
KEY EVENT 1PROTEIN BINDING
HAPTENS
Pro-hapten route Direct hapten route
Skin Sensitisation implementation
12https://www.verywellhealth.com/do-hair-dyes-cause-cancer-2223739
J. Manwaring et al. Toxicology and Applied Pharmacology, vol. 287, pp. 139-148, 2015.
Aromatic Amine + Ac-CoA Ac-Aromatic Amine + CoANAT1
PHASE II
Ex vivo experimentation
In vitro experimentation
Case study 1 – Aromatic amines
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Case study 1 – Aromatic amines
14https://www.graceplacewellness.org/simple-spiritual-wellness-four-words/pitcher-pouring-water-4/
https://www.allure.com/story/what-does-a-conditioner-do-why-should-you-use-it
𝑘𝑟𝑎𝑡𝑒
Case study 1 – Aromatic amines
15https://universityhealthnews.com/daily/nutrition/triclosan-dangers-why-you-should-avoid-products-with-triclosan/ https://www.stemcell.com/mem-with-earles-neaa.html
Ex vivo experimentation
T. Moss et al. Food and Chemical Toxicology,
vol. 38, pp. 361-370, 2000.
Case study 2 - Triclosan
16https://universityhealthnews.com/daily/nutrition/triclosan-dangers-why-you-should-avoid-products-with-triclosan/
Case study 2 - Triclosan
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Cheap to run
Quick to run
Replicate exposure scenarios
Accurate probing of data
Determining safety of exposure
Determining efficacy of exposure
Summary - How could it be used?
Thank you for your attention
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Any questions?
