Transcript Percutaneous Absorption

Percutaneous Absorption
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Transdermal absorption/percutaneous
absorption
Toxicants pass through the cell layers before
entering the small blood and lymph
capillaries in the dermis
A complex event with many key factors
relating to the physical, chemical, and
biochemical constitution of the skin overlaid
with the vast range of physicochemical
behavior of the penetrant
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Transdermal control
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Local or systemic pharmacological response
using dermally applied drugs
Current research is divided
– restraint (slow release technology) and
– enhancement (occlusion, permeation enhancers)
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Toxicological hazard
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Accidental or deliberate (chemical warfare)
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commercial and home and garden pesticides
polymer and paint chemicals
detergents and cleaning chemicals
a broad range of heavy industrial chemicals
unscheduled exposures to environmental
accidents and
– mishandling of toxic waste disposal
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Percutaneous Absorption
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With the exemption of highly volatile
chemicals, the principal organ exposed to
these hazards is skin
Research in this area is directed towards
understanding transdermal flux rates and the
toxicological consequences of penetration
At the practical end, such data contribute to
risk assessment
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1. Factors Affecting Percutaneous Absorption
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Biological factors
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skin age
skin condition
anatomical site
skin metabolism
circulatory effects
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1. Factors Affecting Percutaneous Absorption
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Physicochemical factors
– hydration
– drug-skin binding
– temperature
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1. Factors Affecting Percutaneous Absorption
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Physical factors
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drug concentration
surface area
exposure time
occlusion
vehicle
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2. Mechanisms of Percutaneous Absorption
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Mechanisms by which chemicals cause
visible effects on the skin differ from
chemical to chemical
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disruption of lipids and membranes
protein denaturation
keratolysis
cytotoxicity
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2. Mechanisms of Percutaneous Absorption
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The rate-determining barrier is Stratum
Corneum (nonviable epidermis), which is
densely packed keratinized cells (nuclei lost,
biologically inactive)
SC contains 75-80% lipophilic materials
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very little triglycerids (0%)
cholesterol (27%)
cholesterol esters (10%)
various ceramides (41%; amides and/or esters of
saturated and unsaturated fatty acids)
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Figure 5. The sequential steps involved in
percutaneous absorption
1. Partitioning
2. Diffusion
3. Partitioning
4. Diffusion
5. Capillary uptake
Mukhtar, H., 1992. Pharmacology of the Skin. CRC Press, Inc., Boca Raton, FL.
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Figure 6. The putative pathways of penetration
across the Stratum Corneum
Mukhtar, H., 1992. Pharmacology of the Skin. CRC Press, Inc., Boca Raton, FL.
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2. Mechanisms of Percutaneous Absorption
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Appendageal transport makes a negligible
contribution to the overall percutaneous flux
across human skin.
– however, transport through the appendageal route
has been shown to be significant during the initial
(non-steady-state) period of percutaneous
absorption
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Appendageal transport remains controversial
– resent research has again raised the question of
the participation of the hair follicles in
percutaneous absorption
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2. Mechanisms of Percutaneous Absorption
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Permeation pathways
– Polar (hydrophilic)
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Path through corneocytes with their desmosomal
connections
– Nonpolar (lipophilic)
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Agents dissolve in and diffuse through the lipid matrix
between the protein filaments
Regional variations in skin permeability are
correlated with quantitative differences in
lipid content rather than SC thickness or cell
number
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3. Percutaneous Transport
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Molecules traverse membranes either by
– passive diffusion
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solute flux is linearly dependent on the solute
concentration gradient
– active transport
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typically involves a saturable mechanism
Percutaneous flux is directly proportional to
the concentration gradient and, therefore,
transport across the skin occurs primarily by
passive diffusion
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3. Percutaneous Transport
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At steady state, the flux due to passive diffusion
may be described by Fick’s 1st law
J = kp  a
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J = flux of the permeant (moles/cm2s)
kp = permeability coefficient of the permeant through the
membrane (cm/s)
∆a = activity gradient across the membrane (moles/cm3)
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3. Percutaneous Transport
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kp is the inverse of the “resistance”, which the
membrane offers to solute transport, and is
defined by
kp = KD / h
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K = membrane-aqueous phase partition coefficient of
the solute
D = diffusion coefficient of the solute in the membrane
(cm2/s)
h = diffusion path length through the membrane
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3. Percutaneous Transport
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The flux rate is a rate process
rate = (driving force) / (resistance)
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The driving force for diffusion is the activity
gradient (concentration gradient across the
permeability barrier)
Molecular flux across the membrane can be
determined by the solute’s size and
lipophilicity if the driving force remains the
same
Octanol/Water partition coefficient (Ko/w) has
been chosen to be used as the index of
lipophilicity
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Laboratory Human Volunteer Study
Exposure study
was done inside a
fume-hood to
prevent inhalation
exposure
1.0 ml of jet fuel is
applied at two sites
Surface area of
exposure is 20 cm2
Tenax® tubes were used
to measure evaporation
from arm
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Study Population
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5 male and 5 female adult volunteers
Breathing-zone, dermal tape-strip, breath, urine, and blood
samples
Exclusion criteria
– occupational exposure to chemicals in JP-8 (e.g., auto
mechanics)
– cardiovascular disease
– atopic dermatitis
– smoking
– use of prescription medication for illness
– alcohol consumption during the study
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How to estimate permeation of JP-8
components across the skin
Fick’s Law of Diffusion
L1
L2
x0, C(x0)
C
J = -D
x
x1, C(x1)
Permeability Coefficient Kp (cm/h)
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Calculation of Kp
Cumulative mass per area (ng/cm2)
5000
4000
3000
Kp 
J
C
2000

1000
0
0
60
120
180
240
Time (min)
naphthalene
decane
1-methyl naphthalene
undecane
2-methyl naphthalene
dodecane
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Human Skin Permeability Coefficients (x 10-5)
Subject
naphthalene
1-methyl naphthalene
2-methyl naphthalene
decane
undecane
dodecane
1
16.0
1.3
5.3
0.85
0.021
0.13
2
3.4
2.8
3.1
0.86
0.036
0.15
3
3.2
3.1
3.0
0.76
0.023
0.30
4
3.7
2.7
3.2
1.2
0.025
0.20
5
5.4
2.8
2.9
0.33
0.067
0.13
6
5.7
3.3
3.0
0.80
0.048
0.15
7
4.1
3.1
3.0
0.71
0.033
0.15
8
4.1
2.9
3.1
0.56
0.041
0.13
9
3.3
3.1
3.0
0.22
0.076
0.11
10
4.2
3.5
2.8
0.20
0.083
0.12
mean
5.3
2.9
3.2
0.65
0.045
0.16
SD
3.8
0.59
0.74
0.33
0.023
0.56
minimum
3.2
1.3
2.8
0.20
0.021
0.11
maximum
16.0
3.5
5.3
1.2
0.083
0.30
rat Kp
51.0
16.0
16.0
5.5
2.5
1.4
Rat Kp from McDougal et al. (2000)
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Estimation of the Internal Dose
hands ≈ 840 cm2
3 mg/ml
1 hr
M = Kp  CJP-8  A  t
rat, pig, human
4
Mrat = 1.29 mg
Mpig = 0.53 mg
Mhuman = 0.13 mg
10 
Rat Kp from McDougal et al. (2000)
Pig Kp from Muhammad et al. (2004)
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Metabolism of Xenobiotics
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Most foreign compounds are lipophilic and
able to penetrate lipid membranes and to be
transported by lipoproteins in the blood
These lipophilic compounds are substrates for
biotransforming enzymes
Epidermis is the major site in the skin for
metabolism of xenobiotics, steroids, and
vitamins
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Metabolism of Xenobiotics
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After invasion, the xenobiotic substance is
first chemically activated (usually by
oxidation)
– phase I metabolic reaction, where a polar reactive
group is introduced into the molecule, rendering it
a suitable substrate for phase II metabolism
– cytochrome P-450 isoenzymes
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localized mainly in the endoplasmic reticulum
(microsomal fraction)
activities about 1-5% of those in the liver
Pre-carcinogenic chemicals can be converted
to carcinogenic metabolites
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Cytochrome P-450 isozy mes expressed in the skin and their
corresponding catalytic activities.
Isozyme Catalytic
1A1
1A2
1B1
2A
2B
2B12
2E1
3A4
3A5
AHH
7-EROD
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T-7-OH
7-ECOD
7-PROD
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p-NPH
EMDM
Protein
mRNA
Species
All so far investigated
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Mouse
Human
Rat
Rat
Human
Rat
Mouse
Human
Human
Mouse
AHH, arylhydrocarbon hydroxylase; 7-EROD, ethoxyresorutin o-deethylase;
T-7-OH, testosterone 7-hydroxylase; 7-ECOD, 7-ethoxycoumarin o-deethylase;
Marzulli, F.N. and Maibach, H.I., 1996. Dermatotoxicology, 5th ed. Taylor & Francis, Washington, DC.
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Figure 7. Schematic of metabolism of xenobiotics
Drug
Or
Xenobiotic
P-450
Active Xenobiotic
(e.g., epoxides)
Transferases,
Epoxyhydrase,
NQR
Elimination
Binding to Macromolecules
(e.g., membranes, proteins,
DNA, RNA)
Chemocarcinogenesis, Mutagenesis,
Teratogenesis, Sensitization
Marzulli, F.N. and Maibach, H.I., 1996. Dermatotoxicology, 5th ed. Taylor & Francis, Washington, DC.
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Metabolism of Xenobiotics
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Activated metabolite is transformed by phase
II enzymes (transferases, reductases)
– all major transferases are found in the skin (about
10% of hepatic activities)
– NAD(P)H-quinone reductase (NQR)
– epoxide hydrolase
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Formation of highly hydrophilic metabolites,
which are more readily excreted (e.g.,
mercapturic acids)
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Metabolism of Xenobiotics
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Some foreign compounds (e.g., electrophiles
that undergo nuclear substitution) are not
transformed by phase I enzymes but react
directly at the site of contact; ultimately
eliminated by phase II enzymes
– e.g., mono- and multifunctional acrylates
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Skin metabolizing enzymes differ both
quantitatively and qualitatively from those in
the liver, particularly by their relative
proportions, composition, and interactions
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