Veterinary Dermatology 2003, 14, 83 89

Comparison of serum dexamethasone concentrations in cats after

oral or transdermal administration using Pluronic Lecithin
Organogel (PLO): A pilot study

Blackwell Publishing Ltd.

HEATHER S. WILLIS-GOULET*, BILL A. SCHMIDT*, CONSTANCE F. NICKLIN*,

ROSANNA MARSELLA*, GAIL A. KUNKLE* and IAN R. TEBBETT
*Blanche Saunders Dermatology Laboratory, Department of Small Animal Clinical Sciences, College of
Veterinary Medicine, University of Florida, Gainesville, FL, USA
University of Florida Racing Laboratory, University of Florida, Gainesville, FL, USA
(Received 17 October 2002; accepted 5 December 2002)

Abstract The objective of this study was to measure and compare the serum concentrations of dexamethasone
after oral and transdermal administration using pluronic lecithin organogel in six healthy cats. The study was
designed as a crossover, in which the cats were randomly assigned to two groups. The cats received a single dose
(0.05 mg kg1) of dexamethasone either orally or transdermally on the inner pinna. Blood samples were taken
at 0, 5, 15, 30, 60, 90 and 120 min, and 3, 4, 6, 8, 12 and 24, 48 and 72 h post dexamethasone administration.
A mean peak serum concentration of 30.1 ng mL1 was detected 15 min after oral administration. Serum
concentrations were below detection limits by 24 h. In contrast, there was no significant increase in serum
concentrations of dexamethasone after transdermal administration. In cats, transdermal administration of a single
dose of dexamethasone did not result in significant serum concentrations compared to oral administration.
Keywords: cats, dexamethasone, penetration enhancer, PLO, pluronic lecithin organogel, transdermal.

INTRODUCTION
Transdermal (TD) drug administration is becoming
increasingly popular in both human and veterinary
medicine.14 The primary challenge of developing TD
delivery systems is overcoming the barrier function of
the skin, which resides mainly in the stratum corneum.47
Attempts to overcome this barrier involve combining
the drug with a vehicle (penetration enhancer) that
is intended to modify the skin to enhance drug
penetration.1,4 This study refers to those formulations
administered with the intent of achieving effective
systemic concentrations and clinical responses similar to those achieved with other routes of systemic
administration.24
The superior advantages of TD delivery of drugs to
animals compared with traditional methods include:
(i) an alternative route of drug administration in animals
that are too difficult to dose orally; (ii) avoidance of the
gastrointestinal tract and, thus, vomiting of medications and absorption inconsistencies; (iii) ease of application resulting in increased compliance; (iv) no need

This project was funded by the University of Florida, College of

Veterinary Medicine 2001 Resident Grant Competition.
Correspondence: Dr Willis-Goulet.
Present address: Department of Small Animal Clinical Sciences,
College of Veterinary Medicine; University of Florida, PO BOX
100126, Gainesville, FL 32610-0126, USA.
2003 European Society of Veterinary Dermatology

to clip fur in cats; and (v) potentially faster acting,

especially for drugs metabolized by the liver.2 4 This
method of drug administration is popular in cats
because they can be particularly difficult animals for
owners and veterinarians to medicate. The TD route
would be an easier and more reliable method of administration in this species.
Problems that may be encountered when using penetration enhancers and TD delivery include absorption
through the owners or childrens skin, variable efficacy,
unknown safety or toxicity and irritation.24 Also, the
skin is an effective barrier that prevents absorption of
many substances.4,6 This barrier protects individuals
from the penetration of environmental insults such
as bacteria and toxic chemicals.4,9 Scientific data, especially in veterinary species, is lacking in regard to which
drugs are actually absorbed through the skin or what
the dose should be. A compounding pharmacy in the
USA can legally make up any formulation of a drug as
long as there is an order from a veterinarian.3 There is
no assurance that formulating a drug into a TD gel will
result in systemic absorption or that it is safe. If a drug
that is necessary for a life-threatening disease, such as
heart failure, is applied in this manner without evidence
that it will be absorbed, the result could be harmful.
The compounding of medications using pluronic
lecithin organogel (PLO) as the vehicle is becoming a
standard practice for compounding pharmacies in
both human and veterinary medicine, however, studies
with PLO in animals are lacking.14 PLO is formed by
83

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H. S. Willis-Goulet et al.

combining lecithin, water, isopropyl palmitate and

pluronic acid.1,2 No studies have been performed in
animals to determine if PLO alone has the ability to
penetrate the skin. Available evidence regarding the
effectiveness of these formulations in animals is
anecdotal and without objective measurement of
systemic drug concentrations. The mechanisms by which
penetration enhancers are thought to improve drug
diffusion through the skin have been reviewed in detail
elsewhere.4,5,7 Information regarding efficacy has been
extrapolated from studies performed in humans,1 or from
subjective evaluations made by owners and veterinarians.
In general, for a drug to be a candidate for TD delivery
it should be highly hydrophobic and oil-soluble, have a
low molecular mass and crystallinity (melting point),
and not need to be given at high doses.8,9 Only a small
fraction of existing drugs have these properties and
fewer than 10 have been successfully administered
transdermally in humans.8
Dexamethasone is administered to cats by veterinarians using the TD route with PLO (B. Hall and B.
Biolchini, personal communication). Dexamethasone
is a lipophilic (hydrophobic), neutral compound with a
low molecular mass (392.47 Da).8,10 It has been shown
in humans and dogs that topically applied steroids
used for local treatment are absorbed systemically to
some degree.4,8,1012 Therefore, dexamethasone was
considered to be a good candidate for TD administration using a penetration-enhancing vehicle such as
PLO. The objective of this study was to determine if
dexamethasone, administered at a dose commonly
used to decrease inflammation in cats, could be
detected in the blood after TD administration using
PLO. The serum concentrations obtained transdermally with a single dose were compared with those
achieved following a single oral (PO) dose.

MATERIALS AND METHODS

Animals
Six female, young adult research cats were selected. All
were found to be healthy based on history and physical
examination. Acclimatization was not necessary as
the cats had been housed at the University of Florida,
College of Veterinary Medicine. The cats remained
housed in groups until the day of sample collection
when they were housed individually, under controlled
lighting and temperature, according to the principles
outlined in the NIH Guide for the Care and Use of
Laboratory Animals. All procedures were approved by
the Institutional Animal Care and Use Committee at
the University of Florida.
Experimental design
This pilot study was designed as a crossover study, so that
each of the cats received both treatments in a random
order. A washout period of 3 weeks was used between
treatments. This length of time was considered adequate
based on the elimination half-life of dexamethasone in

other species (range 53335 min).1315 Treatments

included administration of a single dose (0.05 mg kg1)
of either oral dexamethasone (Dexamethasone SP,
Hawkins Chemical Inc, Minneapolis, MN) or TD
dexamethasone (Dexamethasone USP micronized,
Professional Compounding Centers of America,
Houston, TX) in PLO (provided by B. Hall, The Animal
Pharmacy, Rochester, NY) rubbed on the inside of the
pinna. Sixteen hours prior to sample collection, all cats
were anaesthetized using isoflurane for placement of a
jugular catheter (Arrow central venous catheterization
kit, 20 gauge 5, Arrow International, Inc., Reading,
PA).
The dose of dexamethasone and method of administration were selected based on that used clinically
to treat for inflammation.16,17 For oral administration,
dexamethasone was compounded into a 0.5-mg mL1
solution to ensure accuracy in dosing (Westlab Pharmacy,
Gainesville, FL). The dexamethasone used on the ear
was prepared for TD administration into the PLO gel by
a compounding pharmacist (B. Hall, The Animal
Pharmacy) at a concentration of 0.25 mg 0.05 mL1.
The investigators wore gloves while applying the gel (range
0.070.1 mL) to the skin of the inner pinna for 30 s, as
this is how owners are instructed by their pharmacists
(B. Hall & B. Biolchini, personal communication).
Cats did not wear Elizabethan collars because the
collar is not deemed necessary in the clinical setting
(B. Hall & B. Biolchini, personal communication).
Blood samples were collected from each cat at 0, 5,
15, 30, 60, 90, 120 min, 3, 4, 6, 8, 12, 24, 48 and 72 h
post treatment administration.18 Prior to each blood
sample, 2 mL of blood was withdrawn through the
catheter to ensure that the sample was not diluted or
contaminated. An additional 1 mL of whole blood was
then collected and placed into a serum separator tube
(Vacutainer, Becton Dickinson, Franklin Lakes, NJ).
This volume was selected based on the amount of
serum required for the assay. Following each time
point, the original 2 mL of blood was returned to the
cat, along with 1 mL of fluid volume replaced with
normal saline, then the catheters were flushed with
0.5 mL of heparinized saline. The serum separator tubes
were centrifuged (3500 g, 20 min, 8 C) to obtain
serum, which was collected and stored in microcentrifuge
tubes (polypropylene, Fisherbrand, Fisher Scientific,
Pittsburg, PA) at 20 C until analysis.
Measurement of serum concentrations of
dexamethasone
Serum concentrations of dexamethasone were measured using an enzyme-linked immunosorbent assay
(ELISA) (Enhanced dexamethasone kit, Neogen
Corp, Lexington, KY) as described previously.1921
Samples were run in duplicate with positive and negative
controls. This kit has been validated for use in canine
urine, and equine urine, serum and plasma (data not
shown). The smallest quantity of dexamethasone
detected by this kit is 0.25 ng mL1 in equine serum.
Pooled serum from three of the six cats was used to

2003 European Society of Veterinary Dermatology, Veterinary Dermatology, 14, 83 89

Transdermal dexamethasone concentrations in cats

85

Figure 1. Mean (+SEM) serum dexamethasone (Dx) concentrations over time after
oral (PO) (j) and transdermal (TD) (h)
administration of a single dose of Dx
(0.05 mg kg1) to five cats. Concentrations
adjusted so that any value < 1 ng mL1 = 0.5.
*Statistically significant difference between
groups.

validate the ELISA for use with feline serum (data not
shown). A 1:10 dilution was necessary in order to
quantify serum dexamethasone concentrations up to
100 ng mL1. A standard curve was generated and
dexamethasone concentrations in the samples measured. The ELISA did not cross-react with endogenous
cortisol, as the blank cat serum had undetectable levels.
The limit of detection of the ELISA for feline serum
was re-examined under the study conditions, after
addition of three standard deviations to the apparent
concentration of dexamethasone in serum samples
obtained before treatment (0.6 0.13 ng mL1). A
limit of 1 ng mL1 was established. This result is similar
to that seen in other studies performed with this
assay.19,20 Concentrations < 1 ng mL1 were reported
as 0.5 ng mL1 in an attempt to prevent over or under
estimation of the actual value.
Statistics
Data were analysed using least squares analysis of variance (LS) with all main effects and interactions
included in the model. Differences among groups and
times were analysed using orthogonal contrast analysis.
If no differences were detected between periods, indicating that order of treatment did not have an effect,
data were pooled and reanalysed. Prior to analysis,
tests for heterogeneity of regression were conducted to
evaluate trends over time within groups. The analysis
was performed at the highest significant order of
regression. All analyses were performed using the
statistical software, SAS (version 8.2, SAS Institute,
Cary, NC). A value of P 0.05 was considered significant. All data are presented as mean SEM, unless
otherwise indicated.

RESULTS
No differences were detected between periods for all
variables, indicating that order of treatment did not
have an effect, so data were pooled and reanalysed.

Animals
A total of five cats, 13 years old, weighing 36 kg,
were used for serum collection in the final study. One
cat was excluded because of blood sampling difficulties
before any medications were administered.
Serum dexamethasone concentrations
Over all times, there was a statistically significant difference in dexamethasone serum concentrations between
the two treatments (P = 0.0196). Significantly more dexamethasone was absorbed in the PO group than the
TD group at 0.25, 0.5, 1, 1.5 and 2 h post treatment
(P 0.0215) (Fig. 1). There was no clinically significant absorption in the TD group; all values were
below the detection limit of the assay (1 ng mL1) (Fig. 1).
After oral administration, serum concentrations peaked
at 15 min (mean 30.1 3.5 ng mL1. Maximum serum
concentrations ranged from 3.8 to 84.4 ng mL1. Two
cats did not retain the administered dose of the oral
dexamethasone that they were given, resulting in lower
serum concentrations, particularly in one of the cats.
Of interest to note, at 3 h after oral administration
there was a decrease in serum concentrations (Fig. 1)
followed by a sudden increase at 4 h for each of the cats
in the study. However, this event was not significantly
different statistically compared with the next time
point.

DISCUSSION
In this study, TD administration of a single dose of
dexamethasone did not result in statistically significant
serum concentrations in cats compared with that seen
with oral administration. After oral administration,
serum concentrations varied considerably among cats.
The maximum serum concentration ranged from 3.8 to
84.4 ng mL1. The lower concentrations were most
likely due to the cats expectorating some of the dose, as
this was noted during the study in those individuals
with the lower values.

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86

H. S. Willis-Goulet et al.

No studies have been published on dexamethasone

pharmacokinetics in the cat and in this study great
variation in concentration was found. Wide interindividual variation in dexamethasone concentrations with
oral administration has also been reported in humans.2224
OSullivan et al.24 reported a mean dexamethasone
oral bioavailability of 60.7% with a standard deviation
of 13.9 (range 33.789.2%) in 19 people. Variation
in serum concentrations can result from variable
ingestion (regurgitating drug, licking regurgitated drug
from the fur), absorption, metabolism, binding, distribution and elimination.25 The shoulder that was evident in our data (although not statistically significant)
at 4 h in the serum concentration vs. time curve was
also seen in a study by Duggan et al.23 Reasons for the
apparent increase in concentrations were attributed
either to redistribution of drug, enterohepatic re-entry
or to the appearance of metabolites.23
Currently, without objective information on systemic
drug concentrations, veterinarians and pet owners are
evaluating the efficacy of PLO transdermal drug
administration subjectively. The placebo effect can be
as high as 30%,26 and all reports of improvement are
anecdotal and not controlled. Recent studies have
been conducted in cats to evaluate the effectiveness
of PLO as a vehicle for the systemic absorption of
fentanyl and methimazole by measuring systemic drug
concentrations.2,27 Similar to the findings of the current
investigation, these prior studies have failed to detect
significant concentrations of the target drug in systemic
circulation after TD application with PLO. It is
unknown whether problems with absorption are due to
the gel, the drug, the properties of the cat skin or a
combination thereof.
PLO has been shown, through in vitro studies, to
improve drug permeability through the stratum corneum
in humans and is considered compatible with many
different types of drugs.1,8,2830 None of these studies
determined systemic drug concentrations after TD
application with PLO. Furthermore, except for patient
testimony and a few subjective studies, there is limited
empirical data on the efficacy of these formulations in
people, and additional research is clearly needed.2830
One study even touts the benefit of using PLO for local
application of drugs when little or no systemic distribution is warranted.28 No studies have been performed
in animals to determine whether PLO can function
effectively as a penetration-enhancing agent.
The PLO vehicle could be implicated as the responsible variable for the poor absorption of all three drugs.
The question as to why significant concentrations of
fentanyl were not found in the study using PLO27 while
the patch system is effective, has no readily available
answer. Multiple studies in animals, including cats,
have shown that fentanyl is absorbed into the blood
through the skin at safe and effective concentrations
when using the patch system designed for use in
humans.3134 As mentioned previously, the rate of TD
drug absorption for a penetration enhancer formulation is controlled by diffusion through the stratum

corneum. At this time, the primary difference when

using a patch is that the rate is controlled by release
from the system itself.4 In other words, the gel formulation is used to enhance the TD uptake of the drug
while the patch actually decreases the rate of delivery to
maintain serum concentrations at safe and effective
levels.
There are important differences in the barrier functions of varied mammalian species.4,3538 Therefore, a
drug that has been proven to be efficacious for TD use
in one species may be toxic or not absorbed at all in
another. Studies on fentanyl reveal that there is significant variability in TD systemic absorption between
species.3134 Other factors that may effect TD absorption include: vehicle, body size (concentration per unit
of applied surface area), different rates of cutaneous
blood flow, body region, occlusion, relative humidity,
temperature or abrasions.4 Reviews of TD drug delivery indicate that the drug can also be sequestered in
the penetration enhancer because of physiochemical
properties of the compound (e.g. partition coefficient)
and never be released into the skin.4,5,8 Further
investigation of the interaction of PLO with the skin of
different animal species, as well as with different drugs,
is needed.
It is also hypothesized that other histological differences may be responsible for the variability in systemic
absorption after TD administration between species.4,7
There is a controversial debate regarding the absorption or shunt of drugs through the appendages including hair follicles, sebaceous and sweat glands bypassing
the stratum corneum barrier.4,5 Atrichial sweat glands
are located over the entire body surface of humans but
found only in the footpads of cats and other carnivores.6
This may be an important anatomical difference
resulting in variability in TD absorption between
species. More studies to determine the importance of
appendageal absorption vs. intercellular and transcellular absorption are needed, particularly in companion
animals.
Although, no studies have been carried out to evaluate
systemic absorption of topically applied corticosteroids in cats, studies in dogs and humans show that
topical corticosteroids are readily absorbed into the
systemic circulation.4,8,1012,39 The PLO vehicle should
enhance this penetration and enable larger concentrations to enter into the systemic circulation. Studies are
warranted to investigate whether dexamethasone, as
well as other corticosteroids, in any formulation is
absorbed into the systemic circulation of cats after
being applied topically.
There are two studies measuring the efficacy of TD
methimazole with PLO in cats. Hoffmann et al.40
found that total thyroid hormone concentrations were
significantly decreased in 50% of the cats within
4 weeks of receiving methimazole in PLO applied once
to twice daily. Total thyroid hormone concentrations
were rechecked at 4 weeks and 6 months.40 Systemic
concentrations of methimazole were not assessed.
Hoffman et al.2 found that the systemic absorption of

2003 European Society of Veterinary Dermatology, Veterinary Dermatology, 14, 83 89

Transdermal dexamethasone concentrations in cats

methimazole was low to undetectable after a single TD
dose. Several reasons for the contrasting results
between these studies were suggested: (i) cats that
clinically responded did not have TD absorption, but
rather oral ingestion through grooming; (ii) TD absorption
is more efficient in hyperthyroid cats because of an
increased blood flow and thinner stratum corneum;
and (iii) differences in the formulations.2
However, one of the six cats had apparent TD
absorption equal to that seen with the oral dose (100%
bioavailability), and another had low but detectable
concentrations of methimazole.2 Owing to this latter
finding and the results of the study assessing thyroid
hormone levels, Hoffman et al. are conducting a
controlled, prospective study to evaluate the efficacy
of this formulation using a chronic dosing schedule.
It was proposed that absorption may be enhanced
after repeated applications of PLO as a result of a
decreased penetration barrier due to stratum corneum
exfoliation and inflammation from the lecithin
compound.2,41 If this is true, a chronic dosing
schedule may result in more significant systemic concentrations of the target drug, but also potentially
more topical adverse effects. Anecdotal clinical success
in animals with TD drugs formulated in PLO may
be due to the fact that they are administered in this
manner.
In conclusion, this study demonstrated that a single
dose of dexamethasone in PLO applied transdermally
to normal cats does not result in significant serum
concentrations compared with that observed with oral
administration. Mechanisms of TD absorption are
complex and are species-, drug- and vehicle specific.
Further studies are necessary to determine whether
PLO is effective at crossing the epidermal barrier in
cats and other species in a consistent and reproducible
manner. The effectiveness of other penetration enhancers should also be evaluated. Effective penetration
enhancers that would allow for reliable TD absorption
of drugs would be a useful addition to the routes of
administration available to veterinarians. This was further exemplified in this study by the extreme variability
in serum dexamethasone concentrations in cats that
failed to retain the prescribed oral dose.

ACKNOWLEDGEMENTS
The authors would like to thank Nancy Maynard for
standardizing and performing the dexamethasone
assays, Dr Sheilah Robertson and Wendy Davies for
placing the jugular catheters and technical assistance,
Jennifer Lopez and Sarah Fansher for technical assistance, Bob Hall for supplying the dexamethasone in
PLO, and Julie Levy for the use of the research cats.
The dexamethasone was prepared for transdermal
administration into the PLO gel by Bob Hall, compounding pharmacist, Rochester, NY, USA. Serum
concentrations of dexamethasone were measured at
the University of Florida Racing Laboratory.

87

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Zasshi 2000; 120: 32838.

Rsum Lobjectif de cette tude tait de mesurer et de comparer les concentrations sriques de dexamthasone
aprs administration orale et transdermique chez 6 chats. Ltude a t ralise en crossover, les chats tant dirigs
au hasard dans chacun des deux groupes. Les chats ont reu une dose unique (0.05 mg kg1) de dexamethasone
soit oralement soit par voie transdermique sur la face interne du pavillon auriculaire. Des prlvement sanguins
ont t raliss 0, 5, 15, 30, 60, 90, 120 minutes et 3, 4, 6, 8, 12 et 24, 48 et 72 hours aprs administration de
dexamethasone. Le pic moyen de concentration (30.1ng mL1 ) a t dtect 15 minutes aprs administration
orale. Les concentrations sriques taient en dessous des limites de detection aprs 24 heures. Au contraire, aucune
augmentation des concentrations sriques de dexamthasone na t observe aprs administration transdermique. Chez le chat, ladministration transdermique de dexamthasone ne provoque pas daugmentation des concentrations sriques, par rapport ladministration orale.
Resumen El objetivo de este estudio fue medir y comparar las concentraciones sricas de dexametasona tras la
administracin oral y transdrmica, utilizando un organogel plurnico de lecitina en seis gatos sanos. Fue diseado como un estudio de cruce (crossover) donde los gatos fueron asignados al azar a dos grupos. Los gatos
recibieron una dosis nica de dexametasona (0.05 mg kg1) oral o transdrmica en la cara interna de la oreja.
Las muestras de sangre fueron tomadas a los 0, 5, 15, 30, 60, 90, 120 minutos y a las 3, 4, 6, 8, 12, 24, 48 y 72
horas tras la administracin de dexametasona. Un pico medio en la concentracin srica de 30.1ng mL1 fue
detectado quince minutos tras la administracin oral. Las concentraciones sricas estaban por debajo de los
2003 European Society of Veterinary Dermatology, Veterinary Dermatology, 14, 83 89

Transdermal dexamethasone concentrations in cats

89

lmites de deteccin a las 24 horas. En contraste, no hubo un incremento significativo en la concentracin srica
de dexametasona tras la administracin transdermal. En gatos, la administracin transdermal de una nica dosis
de dexametasona no dio lugar a la presencia de concentraciones sricas significativas, comparado con la
administracin oral.
Zusammenfassung Das Ziel dieser Studie war die Messung und der Vergleich von Dexamethasonserumkonzentrationen nach oraler und transdermaler Gabe von Pluronic Lecithin Organogel bei sechs gesunden Katzen.
Die Studie war eine berkreuzte Studie, bei der Katzen randomisiert zwei Gruppen zugeteilt wurden. Die Katzen
erhielten entweder eine orale oder transdermale Dexamethasoneinzeldosis (0.05 mg kg1) auf der Innenflche
der Ohrmuschel. Blutproben wurden 0, 5, 15, 30, 60, 90, 120 Minuten und 3, 4, 6, 8, 12 und 24, 48 und 72 Stunden
nach der Dexamethasongabe genommen. Eine durchschnittliche Spitzenserumkonzentration von 30.1ng mL1
wurde 15 Minuten nach der oralen Gabe festgestellt. Im Gegensatz dazu war keine signifkante Erhhung
der Dexamethasonkonzentrationen nach transdermaler Gabe vorhanden. Bei Katzen resultierte die transdermale Gabe einer Dexamethasoneinzeldosis verglichen mit der oralen Gabe nicht in signifikant erhhten
Serumkonzentrationen.

2003 European Society of Veterinary Dermatology, Veterinary Dermatology, 14, 8389