DOI: 10.1111/j.1365-3164.2011.00985.
Terbinafine pharmacokinetics after single dose oral
administration in the dog
Mary R. Sakai*, Elizabeth R. May*, Paula M.
Imerman, Charles Felz*, Timothy A. Day,
Steve A. Carlson and James O. Noxon*
*Department of Veterinary Clinical Sciences, Veterinary Diagnostic
Laboratory and Department of Biomedical Sciences, Iowa State
University, Ames, IA, USA
Correspondence: Mary R. Sakai, Iowa State University, Lloyd Veteri-
nary Medical Center, 1600 South 16th Street, Ames, IA 50011, USA.
E-mail: msakai@iastate.edu
Sources of Funding
This study was funded by the Department of Veterinary Clinical
Sciences, Iowa State University, Ames, IA and research start-up
funds provided by Iowa State University, Ames, IA, USA.
Conflict of Interest
No conflicts of interest have been declared.
Abstract
Terbinafine is an allylamine antifungal prescribed for
the treatment of mycoses in humans. It is increasingly
being used in veterinary patients. The purpose of this
study was to evaluate the pharmacokinetic properties
of terbinafine in dogs after a single oral dose. Ten
healthy adult dogs were included in the study. A
single dose of terbinafine (3035 mg/kg) was admin-
istered orally, and blood samples were periodically
collected over a 24 h period during which dogs were
monitored for adverse effects. Two of 10 dogs devel-
oped transient ocular changes. A high-performance
liquid chromatography assay was developed and
used to determine plasma terbinafine concentrations.
Pharmacokinetic analysis was performed using PK
Solutions computer software. Area under the curve
(AUC) from time 0 to 24 h was 15.4 lgh/mL
(range 527), maximal plasma concentration (Cmax)
was 3.5 lg/mL (range 34.9 lg/mL) and time to Cmax
(Tmax) was 3.6 h (range 26 h). The time above mini-
mal inhibitory concentration (T > MIC) as well as
AUC/MIC was calculated for important invasive fun-
gal pathogens and dermatophytes. The T > MIC was
1718 h for Blastomyces dermatitidis, Histoplasma
capsulatum and dermatophytes (Microsporum spp.
and Trichophyton mentagrophytes), while the MIC
for Sporothrix schenckii and Coccidioides immitis
was exceeded for 9.511 h. The AUC/MIC values ran-
ged from 9 to 13 lg h/mL for these fungi. Our results
provide evidence supporting the use of terbinafine as
an oral therapeutic agent for treating systemic and
subcutaneous mycoses in dogs.
Accepted 28 March 2011
528
Introduction
Allylamine antifungals, such as terbinafine, are fungicidal
and act through inhibition of squalene epoxidase, the
enzyme catalysing the synthesis of ergosterol from squa-
lene.1,2 The allylamines possess a dual mode of action as
a consequence of the requirement for ergosterol in fungal
cell membrane synthesis and the toxic accumulation of
squalene resulting from squalene epoxidase inhibition.1,2
Until recently, terbinafine was marketed only as Lamisil
(terbinafine hydrochloride; Novartis Pharmaceuticals, East
Hanover, NJ, USA) and was under patent protection
(patent expiration date December 2006). Availability of
generic formulations has dramatically decreased the cost
of terbinafine, leading to increased usage in veterinary
medicine. Terbinafine may provide an effective, afford-
able and safe alternative to traditional systemic antifungal
therapies.
Currently, most cases of subcutaneous and systemic
mycoses are treated with azole antifungals (itraconaz-
ole, ketoconazole and fluconazole), amphotericin B,
iodides (against sporotrichosis) or combination drug
therapy. At typical therapeutic doses (e.g. 510 mg kg)
itraconazole and fluconazole are less hepatotoxic and
have less effect on steroidogenesis than ketoconaz-
ole.39 Itraconazole is recommended as the treatment
of choice for many subcutaneous and systemic myco-
ses because of its superior efficacy against filamentous
fungi (including Aspergillus spp.) and the dimorphic
pathogenic fungi,36,10 but the cost of treatment is usu-
ally prohibitive in all but the smallest patients. The
azole antifungals are fungistatic drugs and their use is
considered most appropriate in immunocompetent
patients. Polyene antifungals, such as amphotericin B,
are fungicidal drugs and can be used regardless of
patient immune status; however, the necessity for par-
enteral administration and potential for nephrotoxicity
are important limitations of therapy with amphoteri-
cin B, even with the newer liposomal formulations.1113
The liposomal formulations are significantly more costly
than conventional amphotericin B, and when the addi-
tional expense of frequent laboratory monitoring is
considered, treatment with this drug is often prohibited
by cost.
There are several published studies and case reports
documenting the efficacy of terbinafine for treatment of
dermatophytosis in cats at doses ranging from 30 to
40 mg kg,1418 but fewer published reports regarding
the use of terbinafine in dogs. Reports in dogs focus on
treatment of Malassezia spp. dermatitis and dermato-
phytosis.1820 Further unpublished reports and clinical
experiences suggest that terbinafine may be an option for
2011 The Authors. Veterinary Dermatology
2011 ESVD and ACVD, Veterinary Dermatology, 22, 528534.

treatment of subcutaneous and systemic mycoses as
either an adjunctive or primary therapy. Current dosing
recommendations have been extrapolated from terbina-
fine use in humans, success in various clinical veterinary
cases, and studies in cats. The purpose of the present
study was to describe the pharmacokinetics of terbinafine
in the dog after administration of a single oral dose and to
use these data [along with reported minimal inhibitory
concentration (MIC) data for fungal pathogens] to form a
basis for recommendation of future clinical investigations
and uses of terbinafine for treatment of select subcutane-
ous or systemic fungal diseases in dogs.
Materials and methods
The procedures performed in this study were approved by the Institu-
tional Animal Care and Use Committee at Iowa State University (pro-
tocol #6983). Informed consent was obtained from the owners of all
dogs enrolled in the study.
Animals and housing
Twelve adult dogs were used in this study. All dogs were owned by
veterinary students and employees of the Iowa State University
Lloyd Veterinary Medical Center. In order to be included in the study,
dogs had to weigh at least 23 kg, be healthy and of good tempera-
ment, and could not have received any medications or supplements
within 2 weeks of the study. Larger dogs were selected for this
study to ensure the safe collection of multiple blood samples. The
dogs ranged in age from 2 to 9 years old. Prior to inclusion in the
study, a complete physical examination, complete blood count,
serum chemistry profile panel and urine specific gravity was per-
formed on each dog. Exclusion criteria included evidence of systemic
disease, medication administration other than routine heartworm and
flea and tick control, pregnancy or lactation, or behavioural problems.
Dogs were hospitalized for a 24 h period during the study and housed
in wire-sided plastic-bottomed dog crates or holding cages, routinely
walked, allowed free access to water and fed a diet similar to the one
they ate at home at t = 0 h and t = 8 h.
Haematological and serum biochemical analysis
Blood samples were obtained from dogs via jugular venipuncture and
urine samples were collected via a voided sample. Complete blood
counts were performed using an Advia 120 Hematology System
(Bayer Diagnostics, Pittsburgh, PA, USA). Serum biochemical analy-
sis was conducted using a Hitachi 921 Analyzer (Boehringer Mann-
heim Roche, Indianapolis, IN, USA). Urine specific gravity was
evaluated via refractometry.
Terbinafine administration and sample collection
Upon admission to the hospital, a repeat physical examination was
performed and an 18-gauge, 5.08 cm intravenous catheter was asep-
tically placed in the cephalic or accessory cephalic vein. A single oral
dose of terbinafine hydrochloride (NorthStar Rx Orchid Healthcare;
Princeton, NJ, USA), 3040 mg kg was administered with a meal at
t = 0 in order to enhance absorption from the gastrointestinal tract.21
The dose range was selected based upon previously published rec-
ommendations.14,18 Blood samples (35 mL) were collected from
each dog at times 0, 15 and 30 min and 1, 1.5, 2, 3, 4, 6, 8, 12 and
24 h postadministration. Blood samples were collected from the
intravenous catheter at time points t = 0 through t = 8 h.22 Approxi-
mately 0.2 mL of blood was removed and discarded prior to each
sample collection (twice the flush volume of the catheter), and the
catheter was flushed with heparinized saline after each collection.
Blood samples were collected via jugular venipuncture at times
points t = 12 h and t = 24 h, due to the fact that in preliminary trials,
catheters did not reliably retain patency allowing for blood collection
after t = 8 h. Blood samples were collected in sterile glass blood col-
lection tubes with EDTA anticoagulant. Samples were centrifuged for
2011 The Authors. Veterinary Dermatology
2011 ESVD and ACVD, Veterinary Dermatology, 22, 528534.
Terbinafine pharmacokinetics in the dog
10 min at 503 g. Plasma was removed and placed in plastic test
tubes for storage at )20C until analysis. Blood was collected for
post-treatment complete blood count and serum chemistry panel at
the 24 h time point.
Measurement of plasma terbinafine concentration
High-performance liquid chromatography assay
High-performance liquid chromatography (HPLC) with ultraviolet
detection was used for the terbinafine analysis in canine plasma sam-
ples. The method was a modification of the protocol previously
described by Denouel et al.23 A terbinafine reference standard
was obtained from Sigma-Aldrich Corp. (St Louis, MO, USA). The
terbinafine standard was dissolved in methanol to make 0.12 and
0.012 lg lL standard solutions. These were stored at 4C in tightly
sealed glass vials. The standard solutions were used to produce
various dilutions of terbinafine in water and in control canine plasma
(obtained from three study participants prior to the start of the study).
These dilutions were used for calibration curves and assay develop-
ment. The assay was validated in house by one of the (PMI)
using pooled canine plasma spiked with the terbinafine reference
standard. The limit of detection of terbinafine in canine plasma was
0.01 lg mL. A standard calibration curve within the negative control
canine plasma was created, with concentrations of 0.1, 0.2, 0.5, 1
and 5 lg mL. The mobile phase consisted of A = 0.012 M triethyl-
amine plus 0.02 M orthophosphoric acid and B = acetonitrile at A:B,
50:50 (v v). The HPLC system used was a Waters 2695 separations
module with a Waters 996 photodiode array detector (Waters
Corporation, Milford, MA, USA). The analytical column was an Axiom
5 lm C18 150 mm 4.6 mm column. The ultraviolet detection was
set at 222 nm with a flow rate of 1 mL min. The area of the peak
was integrated, and samples were quantified against the control
pooled canine plasma standard curve. The percentage recovery after
ethyl acetate extraction was 80 8%.
Sample preparation
All plasma samples, calibration curve samples and negative control
(blank) plasma samples were prepared in a similar manner. A 500 lL
volume of sample was added to a clean glass 15 mL screw-cap tube.
Next, 1 mL of 0.2 M borate buffer (pH 9.0) was added and the tube
was vortexed for 5 s; 5 mL ethyl acetate was then added and the
tube was vortexed for 30 s. Next, the tube was centrifuged for
10 min at 626 g. The ethyl acetate (top layer) was removed, placed
into a clean glass 7 mL vial, and was evaporated under nitrogen to
dryness. Vial contents were reconstituted with 200 lL of methanol,
100 lL of this reconstituted solution was placed in an autosampler
vial, and 20 lL was injected onto the analytical column. For samples
in which a higher concentration of terbinafine was expected, analysis
was performed with 10 lL injection volume. Each time samples
were run, a new set of calibration and blank samples were prepared.
Pharmacokinetic analysis
Analysis of plasma terbinafine concentration curves and pharmaco-
kinetic modelling was performed without compartmental bias using
PK Solutions computer software (Summit Research Services, Mont-
rose, CO, USA). Area under the curve (AUC), maximal plasma con-
centration (Cmax) and time to reach Cmax (Tmax) were calculated for
each dog. Terbinafine MIC values for important invasive fungal patho-
gens (Blastomyces dermatitidis,24 Histoplasma capsulatum,24 Sporo-
thrix schenkii,2426 Pythium insidiosum27 and Coccidioides immitis28)
were examined in conjunction with the terbinafine plasma concentra-
tion versus time curve. Select dermatophytes (Microsporum canis,
M. gypseum and Trichophyton mentagrophytes)24,29,30 were also
examined for their relevance in deep dermatophyte infections
(dermatophyte pseudomycetoma, granuloma or kerion).3133 The
time that terbinafine plasma concentration remained greater than the
MIC (T > MIC) and the AUC over MIC (AUC MIC) were also calcu-
lated for each fungal organism. Statistical software (SPSS 19; IBM
Corp., Somers, NY, USA) was used to perform descriptive and infer-
ential analysis, which included a series of Students paired t-tests.
529
Sakai et al.

Results potential adverse reproductive or gestational effects of

terbinafine in dogs. One dog had a grade 2 6 systolic
Ten dogs were ultimately included in the study. Dogs ran- heart murmur on physical examination. The dog was
ged in age from 36 months to 9 years and in weight from evaluated by a veterinary cardiologist and diagnosed with
24 to 43 kg. There were six castrated males, one intact asymptomatic early degenerative valve disease with no
male and three spayed female dogs; the breeds included functional impairment; therefore, this dog was allowed to
golden retriever (n = 1), Labrador retriever (n = 3) and be used in the study.
mixed breed (n = 6). One of the original 12 dogs was Initial haematological and biochemical analyses did not
excluded for behavioural problems. Another dog under- reveal results that excluded any dog from the study. One
went artificial insemination the week prior to the study dog had a serum creatinine measuring slightly above the
and so was withdrawn owing to the lack of data regarding upper limit of the reference interval (150.3 lmol L; refer-
ence interval 44.2132.6 lmol L); however, urine con-
centration was within normal limits and no evidence of
renal insufficiency was diagnosed. This dogs urine was
well concentrated (specific gravity 1.032) and it had no
accompanying clinical signs of renal insufficiency. Since
the dogs haemogram was within normal limits and there
were no additional changes on the chemistry panel to
suggest renal insufficiency, the serum creatinine mea-
surement in this dog was considered to be normal for that
individual and not an indication of disease.
Throughout the 24 h study period, two of the dogs
experienced periocular swelling, chemosis and conjuncti-
val erythema. This appeared in both dogs approximately
8 h after administration of the terbinafine dose, and disap-
peared within 2436 h of terbinafine administration.
Throughout the study period, there was no evidence of
ocular discomfort in the dogs, they were nonpruritic and
Figure 1. Mean plasma terbinafine concentrations in dogs (n = 10) had normal menace and pupillary light reflexes. Physical
after oral administration of a single dose (mean dose 32.8 mg kg; examination was performed on both dogs and no other
range 3035 mg kg); error bars depict SEM. abnormalities were noted. The two dogs experiencing
ocular changes were examined by a veterinary ophthal-
mologist after study completion. The dogs had normal
Table 1. Pharmacokinetic parameters of terbinafine in dogs after vision and ophthalmological examination was within
oral administration of a single dose (3035 mg kg)
normal limits aside from minor incidental findings consid-
AUC Cmax Tmax ered to be unrelated to drug administration. No other
Dog no. (lg h mL) (lg mL) (h) adverse effects were noted throughout the study. Post-
1 18 4.3 3 study haematological and biochemical evaluations did not
2 10 1.3 6 reveal significant abnormalities in any dogs.
3 21 4.3 3 The terbinafine plasma concentration versus time curve
4 13 4.6 2
is shown in Figure 1. Pharmacokinetic analysis revealed
5 11 1.7 6
6 15 2.9 3 that the mean Cmax was 3.48 lg lL (range 1.34.9
7 15 4.9 3 lg lL) and mean Tmax was 3.59 h (range 26 h). The
8 5 1.5 2 mean AUC from time 0 to 24 h was 15.4 lgh mL.
9 19 4.7 4 Table 1 summarizes the data for each individual dog. Pair-
10 27 4.6 3.9 wise t-tests showed no significant difference between
AUC, area under the curve; Cmax, maximal plasma concentration; and individual dogs in terms of AUC, Cmax or Tmax, given a
Tmax, time to Cmax. confidence interval of 95%. The reported MIC values,

Table 2. Pathogen-specific terbinafine pharmacokinetic analysis and proposed dosing intervals (3035 mg kg)
Organism Reported MIC (lg mL) T > MIC (h)* AUC MIC (lg h mL) Proposed dosing interval
Blastomyces dermatitidis 0.0818 18.8 13 Twice daily
Histoplasma capsulatum 0.0618 17.6 13 Twice daily
Sporothrix schenckii 0.250.518,20,21 9.5 9 Three times daily
Coccidioides immitis 0.631 11 9 Three times daily
Pythium insidiosum 3223 0 Not assessed Not recommended
Microsporum spp. 0.0117 17.6 13 Twice daily
Trichophyton mentagrophytes 0.0117 17.6 13 Twice daily
*T > MIC data exhibited approximately 5% intersubject variability.
AUC MIC data exhibited approximately 10% intersubject variability.
For deep dermatophyte infections.

2011 The Authors. Veterinary Dermatology

530 2011 ESVD and ACVD, Veterinary Dermatology, 22, 528534.

T > MIC and AUC MIC values, as well as recommended
terbinafine dosing interval for fungal pathogens are
shown in Table 2. Dosing intervals recommended herein
are made on the basis of maintaining plasma concentra-
tion greater than the MIC for 100% of the dosing interval.
Discussion
Results of this study show that oral terbinafine is rapidly
absorbed when given with food, reaching Tmax within
approximately 3.5 h. This is slightly longer than the Tmax
described in humans (2 h) after oral administration of a
single dose of terbinafine.34 In our study, terbinafine was
administered with a meal because studies in humans
have found that higher Cmax is achieved when terbinafine
is taken with food compared with on an empty stom-
ach.21
Most reported adverse effects of terbinafine adminis-
tration in humans are manifested via the gastrointestinal
system; rarely, adverse effects involving the hepatobiliary
or cutaneous tissues are reported.2,35 No such adverse
effects were observed in our study; however, since only
a single dose of terbinafine was administered, the possi-
bility of adverse effects following multiple doses cannot
be excluded. An unexpected finding in our study was the
occurrence of periocular swelling and erythema in two
dogs. These two dogs were also enrolled in a subsequent
investigation that was continuous with the presently
described study, in which they received terbinafine daily
for an additional 13 days; no recurrence of ocular changes
was noted after an additional 13 days of terbinafine. Rare
ocular adverse effects have been reported in monkeys
and in humans, including white spots on the retina,36 a
single report of green vision along with pruritus and urti-
caria,37 and a single report of anterior uveitis.38 All of
these described effects were reversible upon discontinu-
ation of terbinafine.
The cause of the transient periocular swelling and ery-
thema noted in two of 10 dogs in our study is unknown.
Both dogs were from the same household; however,
there was a third dog from the same household (also
enrolled in the study) that did not exhibit these changes.
Whether the ocular changes were drug related or due to
an unknown trigger from something that occurred during
hospitalization cannot be determined. The observed ocu-
lar adverse effects may be related to administration of
terbinafine; however, the possibility that this occurrence
was unrelated to terbinafine administration must be
considered as well.
A recent study described oral terbinafine pharmaco-
kinetics in greyhound dogs (n = 6) after administration of
a single dose (30 mg kg) of terbinafine orally with food.39
The mean Cmax we report in the present study
(3.48 lg mL) is slightly lower than that reported in grey-
hounds (4.01 lg mL). Additionally, we report a mean
Tmax of 3.48 h and AUC of 15.4 lg h mL, compared with
2 h and 17.253 lg h mL, respectively, reported in grey-
hounds. In comparing these studies, Tmax seems to
exhibit the most variation between greyhounds and
nongreyhound dogs. Differences in drug metabolism are
unlikely to explain this phenomenon because eventual
Cmax and AUC values did not appear to be significantly
2011 The Authors. Veterinary Dermatology
2011 ESVD and ACVD, Veterinary Dermatology, 22, 528534.
Terbinafine pharmacokinetics in the dog
different between greyhounds and nongreyhounds.
Additionally, terbinafine is not subjected to the first-pass
effect (i.e. hepatic or gastrointestinal metabolism prior to
reaching the systemic circulation). Although the grey-
hound breed is well known to have some singularities in
drug metabolism and distribution,4044 we conclude that
the pharmacokinetics of terbinafine in greyhounds and
nongreyhound dogs are equivocal. The kinetics of absorp-
tion may be slightly accelerated in greyhounds, but this
phenomenon appears to be saturable.
Several studies have confirmed that terbinafine has
good in vitro efficacy against organisms including
dermatophytes,24,29,30 S. schenckii,2426 B. dermatitidis,24
H. capsulatum24 and P. insidiosum (as part of a combina-
tion therapy).30,45 There is also evidence that a synergistic
effect is produced against pathogenic moulds and yeasts
(including Aspergillus spp. and Candida spp.) and against
P. insidiosum when terbinafine is co-administered with
fluconazole, itraconazole, ketoconazole or amphoteri-
cin B.2,27,45 This has proved useful in the treatment of
rare or refractory systemic and cutaneous mycoses in
humans46,47 and may be advantageous in veterinary
patients as well.48
To the best of our knowledge, the pharmacodynamic
properties of terbinafine remain incompletely described.
The pharmacodynamic parameter (T > MIC, AUC MIC or
Cmax MIC) most predictive of drug efficacy has not been
established. As such, we were unable to consider the
issue of time-dependent versus concentration-dependent
action when recommending dosing intervals for terbina-
fine therapy. Our recommendations were made using
the most conservative approach, assuming a required
T > MIC for 100% of the dosing interval.
Our pharmacokinetic analysis demonstrated that thera-
peutically significant plasma concentrations were reached
and maintained for 17.618.8 h (T > MIC) for fungal
pathogens including B. dermatitidis, H. capsulatum and
all dermatophytes examined after a single oral dose of
terbinafine at 3035 mg kg. This indicates that terbina-
fine administered at a dosing interval of every 12 h should
maintain appropriate plasma drug concentrations for
treatment of blastomycosis, histoplasmosis and dermato-
phyte pseudomycetoma. For S. schenkii and C. immitis,
the T > MIC was 9.511 h, indicating that administration
of terbinafine dosed at 3035 mg kg every 8 h would be
necessary to sustain therapeutic plasma drug concentra-
tions. Therapeutic plasma concentrations of terbinafine
were not reached at any time in the 24 h period for
P. insidiosum. As a result, terbinafine administered at
3035 mg kg as a sole therapeutic agent cannot be
recommended for treatment of pythiosis. As synergy
between terbinafine and the azole or polyene antifungals
has been proposed, future investigation into the possibil-
ity of combination therapy for pythiosis or other fungal
infections that are refractory to single agent therapy may
be beneficial.
Although the T > MIC for dermatophytes seems to
suggest appropriate use of terbinafine for superficial
dermatophyte infections, the authors hesitate to make
dosing recommendations solely based on the data pro-
duced in this study. Tissues infected by dermatophytes
in superficial infections are avascular components of the
531
Sakai et al.
skin and adnexa (hair shafts and stratum corneum). Sys-
temically administered drugs reach the stratum corneum
and hair follicle via diffusion from superficial dermal
vessels through the lower layers of the epidermis, incor-
poration into basal keratinocytes and subsequent differ-
entiation and migration, or in glandular secretions.49
Therefore, the time to attain therapeutic concentrations
in the hair follicle and stratum corneum may differ greatly
from the time to achieve therapeutic concentrations in
the plasma. Additionally, it is likely that in dogs, as has
been demonstrated in humans and cats, terbinafine con-
centrations may persist in these tissues for a period of
time after drug administration is discontinued.49,50 This
could potentially allow the use of a longer dosing interval
or even pulsed dosing regimens when treating superficial
dermatophytosis.
The main limitations of this study stem from the fact
that although pharmacokinetic modelling attempts to
predict clinical outcomes, there are sometimes biological
factors that cannot be represented through this approach
and that may affect therapeutic outcome. For example,
serum peaktrough relations were not evaluated in this
single dose study. There is strong evidence from studies
in humans and cats that once daily dosing will achieve
therapeutic concentrations. Studies in humans have
shown that therapeutically significant concentrations of
terbinafine are rapidly achieved in serum, skin and sebum
with once daily oral dosing.49,51 Additionally, a veterinary
study demonstrated therapeutic concentrations of terbi-
nafine in cat hairs after once daily oral dosing.50 Future
studies to examine alternative dosing protocols in dogs
may be warranted.
In this study, we have described the pharmacokinetic
properties of terbinafine after single dose oral administra-
tion in the dog. Based on our results, we propose that
terbinafine may present an alternative to traditionally used
systemic antifungals for the treatment of blastomycosis,
histoplasmosis, coccidioidomycosis, sporotrichosis and
deep dermatophyte infections. Although isolated pub-
lished and anecdotal reports of clinical success can be
found in support of this, expanded clinical trials should be
performed in the future to document clinical efficacy and
safety.
Acknowledgements
The authors would like to thank Richard Stone for his
assistance with statistical analysis and Pfizer Animal
Health for their generous donation of incentive products
for owners of dogs in the study.
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Resume La terbinafine est un antifongique de la famille des allylamines prescrit dans le traitement des
mycoses de lhomme. Elle est de plus en plus utilisee en medecine veterinaire. Lobjectif de cette etude
etait devaluer les proprietes pharmacocinetiques de la terbinafine chez les chiens apres une seule dose
orale. Dix chiens adultes ont ete inclus dans letude. Une dose unique de terbinafine (3035 mg kg) a ete
administree oralement et des echantillons sanguins ont ete preleves periodiquement sur une periode de
24 heures au cours de laquelle les chiens ont ete suivis pour deventuels effets indesirables. Deux des 10
chiens ont developpes des changements oculaires transitoires. Un test HPLC a ete developpe et utilise
pour determiner les concentrations de terbinafine plasmatique. Une analyse pharmacocinetique a ete rea-
lisee par le logiciel informatique PK Solutions. Laire sous la courbe (AUC) entre 0 et 24 h etait de 15.4
lg mL (moyenne 527), la concentration plasmatique maximum (Cmax) etait de 3.5 lg mL (moyenne
34.9), et le temps de Cmax (Tmax) etait de 3.6 h (moyenne 26). Le temps au dessus de la concentration
minimale inhibitrice (T > CMI) aussi bien que le rapport AUC MIC etait calcule pour les pathogenes invasifs
fongiques importants et les dermatophytes. Le T > CMI etait de 1718 h pour Blastomyces dermatitidis,
Histoplasma capsulatum et les dermatophytes (Microsporum spp. et Trichophyton mentagrophytes) alors
que la CMI pour Sporothrix schenckii et Coccidioides immitis etait depassee pour 9.511 h. Les valeurs de
AUC MIC variaient de 9 a 13 lg h mL pour ces champignons. Nos resultats fournissent des preuves sup-
portant lutilisation de la terbinafine comme agent therapeutique oral dans le traitement des mycoses
canines sous-cutanees et systemiques.

Resumen La terbinafina es un antifungico del tipo alilamina prescrita para el tratamiento de micosis en
seres humanos. Se esta utilizando cada vez mas en pacientes veterinarios. El proposito de este estudio
era evaluar las caractersticas farmacocineticas de la terbinafina en perros despues de una sola dosis oral.
Diez perros sanos adultos fueron incluidos en el estudio. Se administro una sola dosis de terbinafina
(30-35 mg kg) por va oral y se tomaron muestras de sangre periodicamente durante un periodo de 24

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Sakai et al.

horas durante el cual los perros fueron supervisados por posible efectos nocivos. Dos de los 10 perros
desarrollaron cambios oculares transitorios. Se realizo un analisis mediante HPLC para determinar las
concentraciones de terbinafina en plasma. El analisis farmacocinetico se realizo usando el programa PK
Solutions. El area debajo de la curva (AUC) del tiempo 0 a las 24 h fue de 15,4 lg mL (rango de 527), la
concentracion maxima del plasma (Cmaxima) fue de 3,5 lg mL (rango de 34,9), y el tiempo para la Cmaxima
(Tmaximo) fue de 3,6 h (rango 26). El tiempo para exceder la concentracion inhibitoria mnima (T > MIC) as
como el AUC MIC se calculo para agentes patogenos fungicos de importancia y para dermatofitos. T >
MIC fue de 1718 h para Blastomyces dermatitidis, Histoplasma capsulatum, y dermatofitos (Micro-
sporum spp. y Trichophyton mentagrophytes) mientras que la MIC para Sporothrix schenckii y Cocci-
dioides immitis fue sobrepasada a las 9,511 h. Los valores de AUC MIC oscilaron entre 913 lg h mL
para estos hongos. Nuestros resultados proporcionan evidencia que apoya el uso de terbinafina como
agente terapeutico oral para tratar micosis sistemicas y subcutaneas en perros.

Zusammenfassung Terbinafine ist ein Allylamin Antimykotikum, welches fur die Behandlung von Myko-
sen beim Menschen verschrieben wird. Es wird zunehmend bei Tierpatienten angewendet. Das Ziel dieser
Studie war es, die pharmakokinetischen Eigenschaften von Terbinafine bei Hunden nach einer einzigen
oralen Dosis zu evaluieren. Es wurden zehn gesunde Hunde in diese Studie aufgenommen. Eine einzelne
Dosis Terbinafine (3035 mg kg) wurde per os verabreicht und Blutproben wurden periodisch uber eine
Dauer von 24 Stunden, wahrend der die Hunde auf Nebenwirkungen uberpruft wurden, entnommen. Zwei
von 10 Hunden entwickelten vorubergehende Augenveranderungen. Ein HPLC Assay wurde entwickelt
und zur Bestimmung von Terbinafine-Konzentrationen im Plasma verwendet. Eine pharmakokinetische
Analyse wurde mittels PK Solutions Computer Software durchgefuhrt. Die Flache unter der Kurve (AUC)
vom Zeitpunkt 0 bis 24 h betrug 15,4 lg ml (Breite 5-27), die maximale Plasmakonzentration (Cmax) betrug
3,5 lg mL (Breite 34,9) und die Zeit bis zu Cmax (Tmax) betrug 3,6 h (Breite 26). Die Zeit oberhalb der mini-
malen inhibitorischen Konzentration (T > MIC) sowie AUC MIC wurde fur wichtige invasive pathogene
Pilze und Dermatophyten kalkuliert. T > MIC fur Blastomyces dermatitidis, Histoplasma capsulatum und
Dermatophyten (Microsporum spp. und Trichophyton mentagrophytes) betrug 1718 h wahrend die MIC
fur Sporothrix schenckii und Coccidioides immitis bei mehr als 9,511 h lag. AUC MIC Werte reichten bei
diesen Pilzen von 9.13 lg h ml. Unsere Ergebnisse liefern Evidenz dafur, dass Terbinafine als orales Thera-
peutikum fur die Behandlung von systemischen und subkutanen Mykosen bei Hunden eingesetzt werden
kann.

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534 2011 ESVD and ACVD, Veterinary Dermatology, 22, 528534.