TOXICOLOGICAL SCIENCES 92(2), 349–355 (2006)
doi:10.1093/toxsci/kfl010
Advance Access publication May 10, 2006
A Single Oral Dose of Ethanol Can Alter Transdermal Absorption of
Topically Applied Chemicals in Rats
Rhonda M. Brand,1 Jessica L. Jendrzejewski, Eric M. Henery, and Anna R. Charron
Division of Emergency Medicine and Department of Internal Medicine, Evanston Northwestern Healthcare and
Feinberg School of Medicine at Northwestern University, Evanston, Illinois 60201
Received November 7, 2005; accepted December 25, 2005
Topical ethanol is used as a dermal penetration enhancer in
some commercial products. Previous studies have demonstrated
that chronic ethanol consumption can also disrupt skin barrier
function, leading to increased transdermal penetration. This
observation becomes much more relevant if a single drinking
episode induces similar changes. The purpose of this study was
thus to examine the transdermal penetration of three model chemicals after acute ethanol consumption. Wistar rats were gavaged
with either 10, 6, 4.3, 3, 1.5 g/kg ethanol or saline and allowed to
recover for 2 or 24 h. Blood and skin ethanol levels were
determined and in vitro penetration experiments performed. The
herbicide paraquat, industrial solvent N,N-dimethylformamide
(DMF), and insect repellent N,N-diethyl-m-toluamide (DEET)
were used as is model chemicals. Absorption was determined and
directly compared between ethanol- and saline-treated skin by
calculating enhancement ratios. Blood ethanol levels range from
0.25 to 0.015% at 2 h with skin levels at 12–18% of blood values.
Ethanol enhances the absorption of paraquat, DMF, and DEET in
a dose-dependent fashion. Paraquat and DEET showed no appreciable reduction in enhancement between 2 and 24 h postgavage
for the 10-g/kg dose, but DMF did. Enhancement ratios were
higher at 24 h for 10 than for 6 g/kg animals, demonstrating
a dose-response relationship for recovery time. These studies
imply that increased absorption of topical chemical occurs after
alcohol ingestion. Both acute and chronic ethanol consumption
can compromise the dermal barrier.
Key Words: ethanol; transdermal; topical; DEET; paraquat; DMF.
INTRODUCTION
Ethanol is well known as a topical penetration enhancer
which has been successfully used to increase permeability for
numerous chemicals. It acts by disrupting the dermal barrier, as
well as by increasing the solubility of a penetrating chemical
1
To whom correspondence should be addressed at Division of Emergency
Medicine and Department of Internal Medicine, Evanston Northwestern
Healthcare and Feinberg School of Medicine at Northwestern University,
Walgreen’s Building SB521, 2650 Ridge Avenue, Evanston, IL 60201. Fax:
(847) 570-8011. E-mail: [email protected].
(Cornwell and Barry, 1995; Stinecipher and Shah, 1997;
Walters et al., 1997). This enhancement is beneficial if the
chemicals involved are being used for therapeutic purposes;
however, exposure to potentially toxic chemicals, which occurs
both in the workplace and at home, make increased absorption
less desirable.
The effect of chronic alcohol consumption on the dermal
absorption of herbicides has been examined in a previous study.
Six to 8 weeks of feeding rats with ethanol (36% of calories)
enhances transdermal penetration of small hydrophilic and
moderately hydrophobic molecules. When the animals were
given a control diet for a week after termination of ethanol
feeding, their skin partially recovered from the adverse effects
of ethanol consumption (Brand et al., 2004). Furthermore, an
additional study demonstrated that rat skin is more permeable
to both tritiated water as well as the tobacco carcinogen
nitrosonornicotine after 120 days of ethanol consumption
(Squier et al., 2003). The number of people subject to dermal
barrier alteration due to ethanol consumption greatly increases
if continuous alcohol exposure is not required to induce
changes in the skin, but instead occurs after a single drinking
episode. The effect of a single, low dose of ethanol consumption (0.30–0.52 g/kg) resulted in measurable amounts of
ethanol evaporating from the skin surface but did not influence
the stratum corneum absorption of the UV filter substance butyl
methoxydibenzoylmethane (Jacobi et al., 2005). The lack of
ethanol-induced changes in penetration found for this highly
hydrophobic compound as defined by its octanol water
partition coefficient (log Kow ¼ 4.5) was not surprising based
on earlier studies that demonstrated that ethanol induces
dermal penetration the most for hydrophilic molecules and
can actually inhibit the absorption of the highly lipophilic
herbicide trifluralin (log Kow ¼ 5.1) (Brand et al., 2004).
In the studies described here, blood and skin ethanol levels
were determined after a single ingestion of alcohol with doses
ranging from 1.5–10 g/kg in rats. The influence of this ethanol
consumption on in vitro transdermal absorption was also
examined. Three model compounds, the herbicide paraquat (MW ¼ 257 g/mol, log Kow ¼ 4.5), the industrial
solvent N,N-dimethylformamide (DMF) (MW ¼ 73.1 g/mol,
Ó The Author 2006. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved.
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350
BRAND ET AL.
log Kow ¼ 1.0), and the commonly used insect repellant N,Ndiethyl-m-toluamide (DEET) (MW ¼ 191 g/mol, log Kow ¼ 2.2),
representing exposure both in a work and home environment,
were used to compare penetration between skin from rats that
had been gavaged with either ethanol or saline using an in vitro,
flow-through system. The duration of ethanol enhancement
was examined by testing both alcohol levels and penetration
enhancement at both 2 and 24 h after ingestion.
HBSS passed to a fraction collector for 120-min fractions. Eluent was assayed
for radioactivity by liquid scintillation counting (Beckman Coulter Model
LS6500 Fullerton, CA).
Each herbicide was tested between four and eight times. The enhancement
ratio (amount through ETOH skin at 24 h/amount through control skin at 24 h)
was used to compare penetration between control- and ethanol-fed rats. The
enhancement ratio was then analyzed to determine if it was statistically
different from 1.0 (which would indicate no enhancement) using a two-tailed,
one-sample t-test with significance set at p < 0.05 (GraphPad Prism, GraphPad,
San Diego, CA).
MATERIALS AND METHODS
Chemicals. Buffer chemicals, radiochemicals, and liquid scintillation fluid
were obtained from Sigma Chemicals (St Louis, MO) and Fisher Scientific
(Pittsburg, PA). The chosen radiochemicals were 14C-paraquat—methyl 14Cdichloride (specific activity 125.7 lCi/mg), 14C-DMF (specific activity 752.4
lCi/mg), and 14C-DEET (specific activity 209.1 lCi/mg). Paraquat, in the
commercial formulation Gramoxone Extra, which is 37% paraquat (ZenecaAg/
Syngenta, Wilmington, DE), was diluted in water 1:40 for a final donor of
0.93%, DEET was diluted to 19% in acetone (since it is insoluble in water), and
DMF was diluted to 3% in water. Each concentration was chosen because it
reflects common usage of the product.
Animal model. All procedures followed the National Institutes of Health
Guide for the Care and Use of Laboratory Animals. Male Wistar rats were
anesthetized by isoflurane inhalation just to effect and gavaged with either 10,
6, 4.3, 3, or 1.5 g/kg ethanol or the equivalent saline control. After 2 h, the
animals were anesthetized again, and blood was sampled through the tail vein.
The rats were then euthanized, and the skin was shaved with dog-grooming
clippers (Oster, blade #40, McMinnville, TN). A 15-mg piece was isolated and
immediately used for skin ethanol–level determination. Both blood and skin
ethanol was determined using an ethanol assay kit (#229-29, Diagnostics
Chemicals Limited, Oxford, CT). This assay uses stabilized NAD analog in
conjunction with alcohol dehydrogenase to metabolize any ethanol present to
acetaldehyde and a photometrically active cofactor. The reaction is quantitated
by measuring absorbance at 340 nm. Blood assays were performed according to
manufacturer’s directions. Skin alcohol levels were determined by pulverizing
a 15-mg piece of skin with a Bessman tissue pulverizer precooled with liquid
nitrogen. In order to eliminate any potentially interfering compounds in the
skin, the absorbance readings obtained from the control skin were subtracted
from the ethanol readings. The effect of skin on the assay was also accounted
for by spiking control tissue with ethanol to develop the standard curve. These
studies were then repeated for animals euthanized 24 h after being gavaged with
either 10 or 6 g/kg ethanol. A third study examined the effect of 24 h in the
diffusion system on the skin ethanol level. Rats were gavaged with 10 g/kg
ethanol or saline and euthanized 2 h after treatment. The skin was removed and
one piece immediately assayed for ethanol levels. A second piece was placed in
the diffusion system for 24 h and then assayed for ethanol as described above.
No donor was used to reduce the chance that a metabolite or interfering
substance would give a false positive in the alcohol assay. This enabled a direct
comparison between any alcohol remaining in the skin after 24 h in vivo and
in vitro.
Diffusion studies. A second piece of skin from the ethanol- and controltreated animals was placed in an in vitro flow-through diffusion cell system
maintained at 32°C (PermeGear, Riegelsville, PA). The epidermal side was
exposed to 100 ll of test compound (paraquat, DMF, or DEET) and 50,000 dpm
14
C-labeled chemical. The chemical was allowed to remain on top of the skin
for the course of the experiment. The dermal side was in contact with the
receiver fluid comprising Hanks Balanced Saline Solution (HBSS). The barrier
function of the skin should be maintained without degradation under these
conditions (Bronaugh and Stewart, 1984; Moody and Nadeau, 1994; Moody
et al., 1994). The receiver chamber was continuously perfused and then the
RESULTS
Ethanol Levels
Blood ethanol levels were determined 2 h after gavage (Fig.
1). A dose dependency exists between the quantity of ethanol
administered and blood levels with values of 0.25 ± 0.03, 0.12 ±
0.02, 0.073 ± 0.003, 0.024 ± 0.004, and 0.015 ± 0.002% for
gavages of 10, 6, 4.3, 3, and 1.5 g/kg respectively. Skin ethanol
was determined for the highest three doses with 10 g/kg equal
to 0.031 ± 0.004%, 6 g/kg at 0.021 ± 0.08%, and 4.3 g/kg
measuring 0.012 ± 0.002% (Fig. 2). Skin ethanol levels are thus
12–18% of blood values. In a second study, the animals were
not euthanized until 24 h after gavage. By 24 h, ethanol levels
are reduced to 0.006 ± 0.005% for blood and 0.004 ± 0.002%
for skin after a 10-g/kg dose. At 6 g/kg, all alcohol had left the
blood, and just a trace amount remained in the skin, 0.001 ±
0.001%. Skin ethanol levels were not tested at lower doses
because the assay limit of detection was reached, and the values
would be zero. The effect of 24 h in the diffusion system on the
skin ethanol level was determined for skin from an animal
gavaged with 10 g/kg ethanol or saline control and euthanized
2 h later. The in vitro experiment confirmed the in vivo data that
shows small amounts of ethanol remaining in the skin at 24 h
with the skin alcohol level at 0.025 ± 0.003% when it was
placed in the chamber and 0.001 ± 0.000% after 24 h.
Penetration Studies
Animals were paired, with one receiving ETOH by gavage
and the other saline. Two hours after treatment, the in vitro
transdermal penetration of paraquat, DMF, and DEET was
determined for each pair of animals. Figure 3 shows the data
generated from animals treated with either 6 g/kg ethanol or
saline control. The animals were euthanized 2 h after treatment;
their skin was removed and placed in the diffusion system.
Similar figures were generated for each ethanol dose for skin
taken from animals, 2 and 24 h after ethanol treatment (data not
shown). Transdermal absorption is enhanced for each of the
compounds tested. The linearity of the data indicates that
the barrier properties of the skin have remained intact during
the 24-h in vitro study. Furthermore, the enhancement
ratios remain relatively constant throughout the course of the
experiment. The increased transdermal absorption after ethanol
351
ALCOHOL INGESTION AND SKIN BARRIER
0.30
Cumulative Transdermal
Absorption (%)
20
Blood Ethanol (%)
0.25
0.20
0.15
0.10
15
10
5
0.05
0
0.00
1.5
3
4.3
6
10
Dose (g/kg)
FIG. 1. Blood alcohol levels as a function of dose at 2 h.
ingestion is not a result of equal amounts partitioning into the
skin, but more remaining within the skin for the saline-treated
group nor differential partitioning between the treatments.
There were no significant differences (p > 0.05) for any of the
three test compounds when comparing the amount left in the
control versus ethanol skin at the end of the 24-h diffusion
studies with 3.35 ± 0.55% versus 3.72 ± 1.12% remaining in
the skin for paraquat, 2.46 ± 0.52% versus 3.19 ± 0.45% for
DMF, and 8.40 ± 1.11% versus 7.10 ± 1.20% DEET. Similar
results were found for skins from animals treated for both 2 and
24 h with other doses of ethanol prior to penetration studies
(data not shown).
The relationship between cumulative absorption levels for
alcohol- and saline-treated animals was quantitated for each
condition by calculating the enhancement ratio. Ethanol
increases the absorption of paraquat at all five doses tested as
demonstrated by enhancement ratios greater than 1.0 (Fig. 4a).
Statistical significance (p < 0.05) is found for the highest three
doses. Interestingly, at 1.5 g/kg, DMF penetration is inhibited
0.04
Skin ETOH (%)
0.03
0.02
0.01
0.00
4.3
6
10
Dose (g/kg)
FIG. 2. Skin ethanol levels as a function of dose at 2 h.
0
5
10
15
20
25
Time (Hours)
FIG. 3. Representative sample of cumulative absorption graphs for paraquat, DMF, and DEET. Skin is from animals gavaged with 6 g/kg ethanol or
saline that were euthanized at 2 h. n ¼ paraquat control, h ¼ paraquat ethanol,
: ¼ DMF control, n ¼ DMF ethanol, ; ¼ DEET control, and P ¼ DEET
ethanol.
by ethanol consumption (p < 0.05, Fig. 4b). As greater
quantities of ETOH were ingested, there was a corresponding
increase in DMF absorption with statistical significance at 6
and 10 g/kg (p < 0.05). Ethanol also induced penetration
enhancement of DEET (Fig. 4c) at 4.3 g/kg (p < 0.05), 6 g/kg,
and 10 g/kg (p < 0.05).
The duration of the ETOH-induced enhancement was
examined by waiting 24 h after ingestion before performing
penetration experiments. The two highest doses were selected
for testing to increase the likelihood that penetration enhancement would be observed. Overall, there were no statistically
significant (p > 0.05) increases in absorption when compared to
the no-effect enhancement ratio of 1.0 (Figs. 4d–4f). However,
enhancement ratios were higher in all cases for animals treated
with 10 g/kg than for those exposed to 6 g/kg, indicating that
there is a dose-response relationship for recovery time of the
dermal barrier from ethanol consumption. Furthermore, comparing the 24-h results with those from 2 h provides interesting
information. In the case of both paraquat (1.93 ± 0.7 vs 1.89 ±
0.39) and DEET (1.61 ± 0.20 vs 1.43 ± 0.26) there was no
appreciable reduction in the enhancement ratio between 2 and
24 h postgavage for the 10-g/kg dose. DMF, however, does
show a marked decrease from 1.81 ± 0.17 at 2 h to 1.28 ± 0.29
at 24 h. The 6-g/kg dose led to a more rapid recovery of the
skin’s barrier capacity with paraquat going from a 2.79 ± 0.56–
fold enhancement ratio at 2 h to an actual inhibition of 0.63 ±
0.22 at 24 h. DMF and DEET also renormalized to control with
enhancement ratios of 1.62 ± 0.28 to 1.17 ± 0.18 and 1.38 ±
0.39 to 1.16 ± 0.24, respectively.
The correlation between penetration enhancements triggered
by ethanol consumption and molecular lipophilicity was
examined for the 10- and 6-g/kg doses at the 2-h time point
(Fig. 5). Enhancement is greatest for the most hydrophilic
compound paraquat and the smallest for the most hydrophobic
352
BRAND ET AL.
2 Hours Post Ethanol
24 Hours Post Ethanol
a) Paraquat
d) Paraquat
3.5
*
3.0
2.5
*
*
2.0
1.5
1.0
0.5
0.0
1.5
3
4.3
6
Paraquat Enhancement
Ratio
Paraquat Enhancement
Ratio
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0.0
10
6
b) DMF
e) DMF
3.5
3.5
3.0
3.0
2.5
*
2.0
*
1.5
1.0
0.5
0.0
*
2.5
2.0
1.5
1.0
0.5
1.5
3
4.3
6
0.0
10
6
c) DEET
f) DEET
3.5
3.5
3.0
3.0
2.5
2.0
*
1.5
10
Dose (g/kg)
*
1.0
0.5
DEET Enhancement
Ratio
DEET Enhancement
Ratio
Dose (g/kg)
0.0
10
Dose (g/kg)
DMF Enhancement
Ratio
DMF Enhancement
Ratio
Dose (g/kg)
2.5
2.0
1.5
1.0
0.5
1.5
3
4.3
6
10
Dose (g/kg)
0.0
6
10
Dose (g/kg)
FIG. 4. Enhancement ratios 2 h after gavage for (a) paraquat, (b) DMF, and (c) DEET and 24 h after gavage for (d) paraquat, (e) DMF, and (f) DEET; *p < 0.05.
DEET. Linear regression analysis adequately described the
relationship with a slope of 0.21 (r2 ¼ 0.97) for 6 g/kg and
0.04 (r2 ¼ 0.91) for 10 g/kg. Since only three points were
available for performing regressions, the results may not be
reliable, but they are consistent with results found previously
for skin from chronically treated animals (Brand et al.,
2004) and indicate that the hydrophilicity/hydrophobicity of
a chemical will impact its penetration enhancement in response
to ethanol ingestion.
DISCUSSION
The data demonstrate that a single drinking episode can lead
to changes in barrier function as evidenced by increased
ALCOHOL INGESTION AND SKIN BARRIER
6 g/kg
10 g/kg
3.5
ER
3.0
2.5
2.0
1.5
-5
-4
-3
-2
-1
0
1
2
3
log Kow
FIG. 5. Inverse correlation between enhancement ratios defined as penetration across ethanol-fed animal skin/penetration across control-fed animal
skin as a function of lipophilicity. The slope is 0.21 (r2 ¼ 0.97) for 6 g/kg
and 0.04 (r2 ¼ 0.91) for 10 g/kg.
penetration of each of the model chemicals tested. The
response is dose dependent, with insignificant effects at the
lowest doses tested. Recovery from this enhancement also
occurs in a dose dependent fashion.
In order to assess transdermal absorption, we chose three
compounds with small molecular weights with a range of
lipophilicities and penetration rates through the skin. Furthermore, they have widespread worldwide usage either occupationally or as a consumer product and have some form of
interaction with ethanol. Paraquat (1,1#-dimethyl-4,4#-bipyridylium dichloride) is a contact herbicide that is useful as an
effective nonselective weed eliminator. Interactions between
alcohol and paraquat have been reported as combined ingestion
of both ethanol (2 or 3.8 g/kg) and paraquat (200 mg/kg) led to
increases in blood paraquat levels when compared to animals
receiving just paraquat (Kuo and Nanikawa, 1990), demonstrating an interaction between the two compounds. We have
previously shown that paraquat penetration is significantly
increased by 5.3-fold after 6–8 weeks of chronic alcohol
consumption. The lower level of enhancement seen here
indicates that additional effects on the skin occur with chronic
alcohol use.
DEET is the most widely used topical insect repellent,
typically found in commercial products in concentration
ranging from 5 to 95% (Stinecipher and Shah, 1997). Many
of these formulations use ethanol as a cosolvent for DEET
(Proniuk et al., 2002), and topically applied ethanol has been
shown to significantly increase its transdermal absorption
(Stinecipher and Shah, 1997). The studies presented here
demonstrate that orally consumed ethanol also enhanced DEET
penetration in a dose-dependent manner and that this enhancement remains even 24 h after ethanol exposure when blood
levels have been reduced.
353
DMF is a hydrophilic solvent used in manufacturing (Twiner
et al., 1998). It acts as a penetration enhancer that promotes
polar route absorption by raising diffusivity and partitioning
(Southwell and Barry, 1983). The effect of alcohol consumption on the transdermal absorption of DMF is dose dependent.
Interestingly, after ingesting 1.5 g/kg ethanol, DMF penetration
is significantly inhibited. Furthermore, unlike paraquat and
DEET, the penetration enhancement seen for DMF after 10
g/kg ingestions is reversed after 24 h.
A previous study examining the relationship between
animals fed a chronic ethanol containing diet for 6–8 weeks
and penetration enhancement of chemicals with varying
degrees of lipopholicity found that enhancement was inversely
related to log Kow (Brand et al., 2004). After chronic ethanol
consumption, a linear relationship with a slope of 0.46 was
found. In the case of 2 h after acute ethanol consumption, the
slopes are of 0.21 for 6 g/kg and 0.04 for 10 g/kg. The
decrease in slope for the higher acute concentration is due in
part to increased enhancement of the less hydrophilic compounds, indicating that a higher concentration will modify the
skin to a greater extent, permitting more penetration. Furthermore, the enhancement induced by ethanol for paraquat was
greater for the 6-g/kg dose than the 10-g/kg dose. The reason
for this differential is unclear.
While there are significant differences between rat and
human skin, we feel that our data can be extrapolated to
humans. Rat skin is known to be more permeable than human
skin by an average of approximately threefold (Barber et al.,
1992; Priborsky and Muhlbachova, 1990; van de Sandt et al.,
2000). Differences in penetration enhancement between rat and
human skin vary depending on the chemicals involved. Ratios
induced across rat skin after topical application of chemical
enhancers have been reported to be slightly higher for
verapamil hydrochloride in the presence of Azone (Agrawala
and Ritschel, 1988) or lower for naproxen in the presence of the
surfactants sodium lauryl sulfate, sodium laurate, and methyldecyl sulfoxide (Chowhan and Pritchard, 1978) than for human
skin. It has been proposed, however, that one can predict
transdermal absorption through human skin from rat studies
based on the equation (van Ravenzwaay and Leibold, 2004):
% Human dermal penetration
¼ ½ð% rat in vivo dermal penetrationÞ
* ðrate of in vitro human dermal penetrationÞ
= rate of in vitro rat dermal penetration:
The trends found in this study on the effect of ethanol on
transdermal absorption through rat skin are expected to be
similar for humans, but the magnitude of compound crossing
the skin and the ethanol-induced enhancement will likely be
different.
Gavaging is a standard technique used in ethanol research
and has been used to model binge drinking. In these studies,
blood ethanol levels after gavage range from 0.015 to 0. 25%.
354
BRAND ET AL.
In humans, a blood concentration of 0.05% (¼ 50 mg/dl blood
or 10mM) is achieved when a 150-lb (68 kg) person consumes
two average-sized drinks. Concentrations of 0.05–0.08% can
trigger psychomotor impairment, and blood levels of 0.4–0.5%
can be fatal (Cohen, 1978). Therefore, the doses that we have
used reflect values that would be seen with human consumption. Experiments were performed at 2 h based on the work of
Donohue et al. (1988), who found that peak ethanol levels
occurred between 0.5 and 2 h in rats after a 6-g/kg gavage.
This study examined ethanol levels that remained in the skin
2 and 24 h after ingestion. Skin alcohol is approximately
12–18% of blood levels at 2 h. The blood ethanol levels at 24 h
were reduced to just 2.5% of their 2-h postgavage values;
however, the skin values remained at approximately 13% of the
2-h value. The continuation of enhancement ratios greater than
1 for the 24-h penetration studies indicates that increased blood
ethanol alone is not the only factor responsible for this
observation but that skin levels more likely impact it. Others
have also demonstrated that consumed alcohol can reach the
skin. When ethanol is ingested, a small amount (< 1%)
penetrates completely through the skin and is excreted in
sweat. Skin vapor levels have also been correlated with blood
ethanol concentrations (Giles et al., 1987). Skin evaporation
rates increase as early as 5 min after alcohol consumption, and
peak values can be reached between 5 and 150 min depending
on the individual (Jacobi et al., 2005).
The mechanism by which orally ingested ethanol enhances
transdermal delivery of topically applied compounds was not
examined for this study but is the subject of future work.
Several potential mechanisms include alterations in tissue
solubility, biophysical alterations in the barrier, and changes
in the skin due to alcohol metabolism. Increased solubility of
paraquat and DMF in the skin due to the presence of ethanol is
an unlikely method for the penetration enhancement observed
as both the compounds are only sparingly soluble in ethanol.
Furthermore, no differences in skin levels of any of the three
chemicals tested in these studies were found between ethanoland saline-treated skin.
Topically applied ethanol alters the polar head group region
of the lipid bilayers, by inducing lipid fluidity near the polar
interface by as much as 70% (Marjukka Suhonen et al., 1999).
This would increase in the effective interfacial area of the
bilayer, leading to greater diffusivity and partitioning especially for hydrophilic permeants (Kim et al., 1992; Krill et al.,
1992). At high concentrations, ethanol can extract stratum
corneum lipids and proteins as well as alter the protein
conformation to include more b-sheet–like conformations
(Goates and Knutson, 1994). These observations are consistent
with our results, demonstrating that enhancement from consumed ethanol is greatest for hydrophilic molecules.
While dramatic effects on the stratum corneum occur when
ethanol is applied topically, the doses achieved in the skin are
much higher than for orally ingested ethanol. In the case of
hydrophilic chemicals, no changes were seen in the perme-
ability coefficient unless the topically applied ethanol concentration is greater than 25% (Ghanem et al., 1992). The fact that
skin levels after gavage are only 0.03% but are able to induce
penetration enhancement of topically applied chemicals indicates that there are some differences in the skin’s response to
alcohol after oral ingestion versus topical application.
This study demonstrates that a single drinking episode can
increase transdermal absorption of topically applied chemicals.
Both the changes in absorption and recovery are dose dependent as ethanol does not clear as rapidly from skin as from
blood. The mechanism by which these changes occur was not
examined in this work but is the subject of future studies.
ACKNOWLEDGMENTS
The authors would like to acknowledge the assistance of Nirmita Kumar,
Jennifer Koestier, and Hemant Roy. This work was supported by National
Institutes of Health grant number 1 R21 AA015199-01.
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