Transport Through The Skin- Judy Madden

Question 1

State ficks law of diffusion

Answer 1

The rate of diffusion is proportional to both the surface area and concentration difference and is inversely proportional to the thickness of the membrane

Question 2

What is bioavailability

Answer 2

The fraction of a compound applied that reaches the systemic blood circulation unchanged

Question 3

What is systemic exposure determined by

Answer 3

The conc of ingredient in the product

Amount of product used

Dermal bioavailability eg if low then no predicted systemic effects

Question 4

Explain the bricks and mortar model of routes of absorption

Answer 4

Appendageal- through hair glands in a straight path

Intracellular - the most common pathway taken and occurs through small spaces between the cells of the skin, this route is the more tortous one.

Question 5

How can you measure transport through the skin

Answer 5

By flux (J) - depends on concentration grad and thickness of the barrier 
Permeability (kp)- can use a franz cell to measure IN VITRO using a skin layer could be artificial human or animal 
Extent absorption (%abs)

Can use tape stripping method to see how much has permeated the skin by seeing how much ingredient is left on the skin
Values available in journals both in vitro and in Vivo

TEWL can be used as a measure of barrier function and how much topical products can retain water

Question 6

Sources of variability in skin permeability data from in vitro and in Vivo experiments

Answer 6

Temp
Conc
Type of skin

In vitro
Origin of skin
Temp
Ph
Buffer
Timing 
Exposure pattern 
Metabolic competency 

In Vivo 
Site of application
Age of skin 
Hydration status 
Occlusion 
Vol. of formulation applied

Question 7

How does in silico testing work

Answer 7

The behaviour of a chemical eg toxicity and skin permeability is a function of its molecular properties therefore knowledge of the molecular properties enables skin permeability to be predicted from structure

Question 8

Lipinski rule of 5 for oral absorption

Answer 8

Compounds classed as low or high oral absorption based on simple physio chemical properties

This can be applied to dermal absorption

Question 9

What are qsars

Answer 9

A technique where a molecules reactivity, activity and properties are predicted based on the analysis of an equation that connects the structure of molecules to their respective measured reactivites and properties

Question 10

Dancik model

Answer 10

A spreadsheet based model that stimulates penetration through skin layers

Question 11

Absorption

Answer 11

ONE WAY OF DETERMINING BIOAVAILABIKITY EG AMOUNT THAT REACHES SYSTMEIC BLOOD CIRCULATION UNCHANGED

Metabolism is another way

Question 12

Define bioavailability

Answer 12

The fraction of a compound applied that reaches systemic blood circulation

Question 13

Internal exposure is driven by

Answer 13

Absorption, distribution, metabolism and excretion / toxicokinetics

Question 14

Explain 2 phases of metabolism

Answer 14

Phase 1- induce and expose functional groups to make molecule more polar - using enzymes eg CYP P450s
This may produce more reactive metabolites

Phase 2- conjugation to increase water solubility
Includes glucuronidation, methylation and Sulfation
And used enzymes such as glutathione reactive metabolites
This phase can detoxify reactive metabolites

Question 15

How can you measure metabolites in skin

Answer 15

Can use software packages eg toxtree or qsar toolbox which are based on liver studies -

Question 16

Skin vs liver metabolism

Answer 16

There’s absence of P450s in skin
Less enzymes in skin
Existing data is mostly liver data like the predicted models rely on this data but there’s a lot of difference between skin and liver metabolism

Issues comparing skin and liver enzymes
Eg levels in skin much lower and sometimes lower than limit of detection and need an inducer to be able to see
Differential expression in skin layers eg looser protease
The epidermal basal later has more aldehyde dehydrogenase