Full text of DOI:10.1111/j.1751-0813.2000.tb10349.x

Clinical
Effect of phenobarbitone on the low-dose dexametha-
sone suppression test and the urinary corticoid:
creatinine ratio in dogs
SF FOSTER, DB CHURCH and ADJ WATSON
Department of Veterinary Clinical Sciences, The University of Sydney, New South Wales, 2006
Objectives
To investigate potential effects of phenobarbitone on the low-dose dexamethasone suppression (LDDS)
test and urinary corticoid to creatinine ratio in dogs in a controlled prospective study and in a clinical setting.
Animals Ten crossbreed experimental dogs and 10 client-owned dogs of mixed breeds treated chronically with
phenobarbitone to control seizures.
Procedures
Experimental dogs were allocated to treatment (6 mg/kg oral phenobarbitone, n = 6) and control (n = 4)
groups. LDDS tests (dexamethasone 0.01 mg/kg intravenously, cortisol concentration determined at 0, 2, 4, 6 and 8 h)
were conducted repeatedly over a 3-month period. Urinary corticoid to creatinine ratios were measured before LDDS
tests. A single LDDS test was performed on 10 epileptic dogs.
Results
LDDS and urinary corticoid to creatinine ratios in dogs were not affected by treatment with phenobarbitone.
Conclusions Phenobarbitone does not interfere with LDDS testing regardless of dosage or treatment time. Urinary
corticoid to creatinine ratios are also unaffected.
Aust Vet J 2000;78:19-23
Key words: Dog, phenobarbitone, anticonvulsant, dexamethasone suppression test, urinary corticoid: creatinine ratio, human.
ACTH
DST
HA
Adrenocorticotrophic hormone
Dexamethasone suppression test
Hyperadrenocorticism
IV
LDDS
UCCR
Intravenous/ly
Low-dose dexamethasone suppression
Urinary corticoid: creatinine ratio
an abnormal result after 6 and 12
months of treatment despite normal
endogenous ACTH concentrations and
normal ACTH response tests.11 It was
not known whether this was due to
phenobarbitone.
those of HA, namely polyuria, poly-
dipsia, lethargy, hepatomegaly and
increased liver enzyme values.11 As the
LDDS test is generally regarded as the
screening test of choice for canine HA
the effect of phenobarbitone on the
LDDS test in dogs requires investiga-
tion. UCCRs are simple, inexpensive
screening tests for HA and if unaffected
by phenobarbitone could be useful in
dogs treated with phenobarbitone.
STs were developed in the
1960s and the single dose DST
became the screening test for
D
human HA.1,2 It soon became apparent
that dexamethasone failed to produce
normal adrenocortical suppression in
patients treated chronically with the
anticonvulsants phenytoin and primi-
done.3-5 Dexamethasone clearance was
increased in human patients treated with
The UCCR test is based on the
premise that corticoids measurable in a
single, random, voided urine sample
reflect the average blood corticoid
concentration in the period during
which the urine was formed. It readily
distinguishes between healthy dogs and
those with hyperadrenocorticism but it
is also increased in stressed dogs with
other diseases.12,13 The test has also been
considered unreliable in dogs with
polyuria and polydipsia but it is not
known whether this reflects the under-
lying disease process or the specific
effects of polydipsia and polyuria.12 The
effect of phenobarbitone, a drug known
to cause polyuria and polydipsia in some
dogs, on UCCRs has not been reported.
Diagnosis of HA in dogs receiving
phenobarbitone can be difficult.
Phenobarbitone can produce clinical
signs and laboratory findings mimicking
6
phenytoin and biliary excretion and
hepatic conjugation of dexamethasone
were enhanced in rats.5 Increased clear-
ance of dexamethasone due to hepatic
enzyme induction was subsequently
demonstrated with phenobarbitone
therapy in humans.7 It was concluded
that failure of cortisol suppression in
response to dexamethasone in humans
on long-term anticonvulsants was due to
increased hepatic metabolism of
dexamethasone.5,8
This has led to concern about inter-
preting LDDS tests in dogs treated with
anticonvulsants.9,10 An uncontrolled
study concluded that LDDS tests were
unaffected by phenobarbitone adminis-
tration although one of five dogs showed
Materials and methods
Experimental study
Animals - Ten healthy crossbreed dogs,
five entire males and five entire females,
weighing 12.3 to 23.8 kg, were used in
the experiment. They were housed indi-
vidually in converted stables, walked
once daily for 20 to 30 min, between
0600 h and 0900h and also allowed a 5
to 10 min run at feeding time. They
were fed nutritionally complete, dry dog
food (Eukanuba Premium, Iams) once
daily, between 1600 h and 1800 h.
Water was provided ad libitum.
All dogs were vaccinated, treated with
anthelminthics (Drontal Allwormer,
Aust Vet J Vol 78, No 1, January 2000
19

Clinical
Clinical study
Bayer) and acclimatised to housing,
feeding and handling for 3 weeks prior
to commencing the study. As trichuriasis
was diagnosed during the study,
anthelminthics (Drontal Allwormer,
Bayer; Popantel Allwormer, Dover
Urine was refrigerated for 24 h then 50
µL was mixed with 450 µL of distilled
water and stored frozen for later creati-
nine measurement, the remainder being
frozen for corticoid assays. Phenobarbi-
tone assays were performed by a
commercial laboratory (Macquarie
Vetnostics). Cortisol assays were batched
at the end of the study to avoid inter-
assay variations for an individual dog’s
results.
Ten dogs (numbered 1 to 10) of
various breeds aged between 1.5 and 9
years, receiving phenobarbitone for
epilepsy, were recalled for the study. The
dogs had been treated with oral pheno-
barbitone for 14 to 92 months at doses
of 3.9 to 14.4 mg/kg/d (mean 8.6, SD
3.6, median 7.9). The daily dose was
divided and administered twice or thrice
daily. Four dogs (1, 2, 3 and 10) were
also receiving potassium bromide
(Epibrom, Equisci International), which
is not reported to induce or inhibit
hepatic drug metabolising enzymes or to
compete for protein binding sites with
other anticonvulsants.14
The dogs were fasted from 2000 h
until testing the following morning at
0830 h. All dogs were examined thor-
oughly and weighed before having blood
taken at 0900 h for measurement of
serum phenobarbitone and basal plasma
cortisol concentrations. The dogs were
then given 0.01 mg/kg dexamethasone
sodium phosphate IV and their morning
dose of phenobarbitone. Blood for
cortisol assays was taken 4 and 8 h later.
Sample handling, phenobarbitone
measurements and cortisol assays were
done as previously.
Laboratories)
were
administered
monthly throughout. One dog required
surgery for an intestinal foreign body
during week 6 of the study thus pheno-
barbitone was not administered between
day 4 of week 6 and day 2 of week 7 in
this dog and sampling due on week 6
was postponed one week. Another dog
sustained a fight wound during week 6
which necessitated surgery on week 6,
after its LDDS test.
Plasma cortisol and urinary corticoid
concentrations were measured using a
commercially
available
radioim-
munoassay kit (Coat-A-Count, Cortisol
Radioimmunoassay Kit, Diagnostic
Products) according to the manufac-
turer’s directions. The assay sensitivity,
estimated as the lowest cortisol concen-
tration required to displace 10% of
bound tracer, was 5.4 nmol/L.
Specificity was demonstrated by parallel
competitive binding curves for serial
dilutions of pooled dog plasma and
human standards. The intra- and inter-
assay coefficients of variation were 7.7
and 10.5% respectively.
Statistics - Serum phenobarbitone
concentrations and UCCR results were
each subjected to a one - way analysis of
variance with repeated measures design.
Plasma cortisol concentrations during
LDDS tests were analysed using a
multiple analysis of variance with
repeated measures design. Statistical
significance was accepted at the 5%
level.
Dogs were distributed randomly into
treatment (n = 6) and control (n = 4)
groups. No phenobarbitone was admin-
istered during weeks
1
and 2.
Phenobarbitone treatment commenced
on day 1 of week 3 and continued for 12
weeks. The treated dogs were dosed with
oral phenobarbitone at 6 mg/kg once
daily at 0900 h. Phenobarbitone tablets
(Phenobarbitone 30 mg, Sigma
Pharmaceuticals) from a single batch
were divided as necessary to give the
closest approximation to 6 mg/kg. The
range of calculated doses was 5.9 to 6.4
mg/kg but accuracy was limited by
tablet divisions into quarters. Dosage
adjustments because of weight changes
were made after sampling trough pheno-
barbitone concentrations.
Samples and assays - Blood for serum
phenobarbitone concentrations was
collected at 0900 h on day 5 of weeks 1,
2, 4, 6, 8, 10, 12 and 14. Urine for
measurement of UCCR was collected by
free catch, catheterisation or cystocen-
tesis between 0600 h on day 6 and 0900
h on day 7 of weeks 1, 2, 4, 6, 10 and
14. On day 7 of these weeks, blood was
taken at 0900 h for plasma cortisol assay
then dexamethasone sodium phosphate
solution (Dexadreson, Intervet) was
administered at 0.01 mg/kg IV. Blood
samples for cortisol determination were
then taken at 2 h intervals for 8 h. All
blood was collected by jugular
venipuncture.
Results
Experimental study
Serum phenobarbitone concentrations
in treated dogs did not change over
time. The means for weeks 6, 8, 10 and
Samples for measuring cortisol and
phenobarbitone concentrations were
collected into heparinised tubes and
plain tubes respectively. Samples for
cortisol were placed on ice then
centrifuged and the supernatant was
frozen immediately after separation.
Figure 1. Log mean cortisol (nmol/L) at 0, 2, 4, 6 and 8 h after dexamethasone (0.01 mg/kg
IV) for control dogs and treated dogs at weeks 2 and 14.
20
Aust Vet J Vol 78, No 1, January 2000

Clinical
Table 1. LDDS test results and phenobarbitone dose, serum concentration, and treatment duration for
10 epileptic dogs.
14 were lower than the laboratory’s
suggested therapeutic range of 65 to 194
µmol/L.15 There was a significant
decrease in UCCR between weeks 1 and
2, before phenobarbitone treatment
commenced. After week 1, all UCCRs
except one were below the reference
limit (20 x 10-6 ). The one abnormal
UCCR noted at week 6 (22 x 10-6) was
attributed to stress due to a fight wound
in that dog.
Plasma cortisol concentrations during
LDDS tests showed no differences over
time except between weeks 1 and 2, that
is, before phenobarbitone treatment
commenced. LDDS results were all
normal when assessed on absolute
values. However, suppression was diffi-
cult to assess in some dogs, as baseline
cortisol concentrations were very low,
often below the threshold considered
consistent with suppression. If suppres-
sion of baseline cortisol concentration
by 50% or more was used as the crite-
rion, then some LDDS results for
treated and control dogs would be
considered abnormal. Baseline cortisol
concentrations for these tests range from
0.5 nmol/L to 22 nmol/L, all except one
below the 20 nmol/L normally observed
after suppression. However, there was no
significant difference between treated
and untreated groups and no change
over time in phenobarbitone-treated
dogs (Figure 1).
Dog
Phenobarbitone
dose
Serum
phenobarbitone
µmol/L
Treatment time
months
Cortisol nmol/L
4 h
0 h
31
8 h
mg/kg
1
2
3
4
5
6
7
8
9
10
9.3
7.9
135
86
92
65
35
15
15
50
16
18
32
14
0
4
2
4
70
52
14.4
3.9
171
102
101
99
4
3
205
190
72
17
13
25
6
10
9
5.0
10.2
6.0
56
6
72
53
9.4
89
71
10
8
7
13.8
5.6
119
127
112
70
13
3
8
may reflect variation in dexamethasone
metabolism and clearance.9 In dogs with
non-adrenal illness, specificity is much
lower with 38% and 56% of dogs failing
to demonstrate cortisol suppression at 4
Discussion
Phenobarbitone did not affect LDDS
testing in experimental dogs in this
study. The decrease in cortisol concen-
trations between weeks 1 and 2 in the
pre-treatment period were attributed to
the dogs becoming more accustomed to
blood sampling. UCCR results
decreased similarly between weeks 1
and 2 and phenobarbitone had no
effect.
13
and 8 h respectively. Dog 6 had no
clinical or biochemical findings
suggesting HA but was very nervous, as
were most of the clinical patients
studied. Unlike the other dogs, this dog
defaecated voluminously and frequently
(six times over 24 h), possibly indicating
gastrointestinal disease (one of the
disease categories in the study of
Kaplan);13 dietary modification has
since led to resolution of this problem.
It is possible that the abnormal LDDS
in dog 6 was caused by phenobarbitone.
Dexamethasone at 0.01 mg/kg
suppresses plasma cortisol for at least 16
h in normal dogs.19 Plasma dexametha-
sone concentrations vary greatly in
healthy dogs after 0.01 mg/kg and 0.1
mg/kg IV.9 Whether this variability
affects the response of the hypothalamic-
pituitary axis to dexamethasone is
unknown.9 If plasma dexamethasone
concentration was lower in dog 6 than
in the other dogs, increased dexametha-
sone metabolism induced by phenobar-
bitone could have lead to inadequate
cortisol suppression.
The effect of stress and excitement on
plasma cortisol concentrations in dogs
should not be underestimated. Resting
cortisol concentrations became very low
in many of the experimental dogs and,
given the assay sensitivity, the LDDS
responses were occasionally difficult to
assess. This would not affect clinical
interpretation but hindered assessment
of effects of phenobarbitone on indi-
vidual results. Many baseline cortisol
concentrations were as low as those seen
in dogs with hypoadrenocorticism.
These dogs had bonded with the first
author and, in essence, were being
handled and sampled by their owner in
their home environment. Our reference
range for baseline cortisol concentra-
tions was established on dogs brought
into the hospital by clients and may
reflect the additional stress and excite-
ment involved. Low baseline cortisol
concentrations (21 to 34 nmol/L) have
been noted previously in well-condi-
tioned dogs.17
In these dogs, 36 of 60 baseline
cortisol concentrations were less than or
equal to the lowest end of our reference
range (25 to 75 nmol/L). Some dogs
had concentrations that would more
commonly be noted with hypoadreno-
corticism. One dog had baseline cortisol
concentrations of 5, 10, 1 and 5 nmol/L
at weeks 4, 7, 10 and 14 respectively but
was active, healthy and had normal
responses to ACTH in subsequent
studies.16
Clinical study
The phenobarbitone doses, serum
concentrations, duration of therapy and
LDDS results for each dog are listed in
Table 1. Mean serum phenobarbitone
concentration was 110 µmol/L (range
72 to 171 µmol/L). All concentrations
were in the suggested therapeutic range
of 65 to 194 µmol/L. Results of LDDS
tests in 9 of 10 dogs were consistent
with normal adrenal function; one dog
(dog 6) showed inadequate suppression.
Phenobarbitone increases the rate of
dexamethasone metabolism in humans,
altering DST results. The normal LDDS
results in 15 of 16 dogs in this study
suggest that a comparable effect in dogs
does not occur or is insufficient to influ-
ence the LDDS test. The standard
human DST procedure is to administer
1 mg dexamethasone orally at 2300 h,
The one abnormal LDDS result in the
epileptic dog 6 may reflect the test’s
specificity. Specificity was greater than
0.95 in one study13 but only 0.73 in
another.18 False positives in normal dogs
Aust Vet J Vol 78, No 1, January 2000
21

Clinical
Medicine 1981;60:25-35.
when endogenous cortisol secretion is
normally low and to collect samples for
serum cortisol assays the next day at
tions in 4 of the 6 weeks tested; the
maximum phenobarbitone concentra-
tion was 96 µmol/L. All 10 clinical
cases, however, had serum phenobarbi-
tone concentrations within the thera-
peutic range; four of these dogs were
receiving daily doses of phenobarbitone
equal to or less than that of the experi-
mental dogs and had serum phenobarbi-
tone concentrations of 72 to 127
µmol/L.
3. Asfeldt VH. Simplified dexamethasone suppres-
sion test. Acta Endocrinol 1969;61:219-231.
4. Werk EE, Choi Y, Sholiton L et al. Interference in
the
effect
of
dexamethasone
by
0800 h and sometimes at later periods
1,20
diphenylhydantoin. N Engl J Med 1969;281:32-34.
5. Jubiz W, Meikle AW, Levinson RA et al. Effect of
diphenylhydantoin on the metabolism of dexam-
ethasone. N Engl J Med 1970;283:11-14.
6. Haque N, Thrasher K, Werk EE et al. Studies on
dexamethasone metabolism in man: effect of
diphenylhydantoin. J Clin Endocrinol 1972;34:44-50.
7. Brooks SM, Werk EE, Ackerman SJ et al.
Adverse effects of phenobarbital on corticosteroid
metabolism in patients with bronchial asthma. N
Engl J Med 1972;286:1125-1128.
8. Meikle AW, Stanchfield JB, West CD, Tyler FH.
Hydrocortisone suppression test for Cushing
syndrome. Arch Intern Med 1974;134:1068-1071.
9. Kemppainen RJ, Peterson ME. Circulating
concentration of dexamethasone in healthy dogs,
dogs with hyperadrenocorticism, and dogs with
nonadrenal illness during dexamethasone
suppression testing. Am J Vet Res 1993;54:1765-
1769.
such as 1600 h and 2300 h.
The
elimination half-life of intravenous
dexamethasone in humans is similar to
that in dogs.21,22 The 1 mg dose of
dexamethasone is 0.01 to 0.02 mg/kg
for body-weights of 50 to 100 kg,
comparable to the standard canine dose
of 0.01 mg/kg. Dexamethasone
metabolism in humans is sufficiently
increased by phenobarbitone to affect
results of the 9h sample. The effect of
phenobarbitone at 4 h is unknown.
Two factors that differ between the
DST in humans and the LDDS test in
dogs are the route of administration and
the lack of circadian rhythm for corti-
costeroid secretion in dogs.23,24 The
route of administration may be a critical
difference. Plasma concentration
following a single oral dose of dexam-
ethasone, as used in humans, is depen-
dent on volume of distribution and rate
and extent of drug absorption (bioavail-
ability) as well as drug clearance.21 The
reported bioavailability of dexametha-
sone in normal humans is approximately
80%25 but, due to presystemic clearance
(first-pass effect), it may be only 10 to
25% in some patients.26 Interestingly, all
patients with dexamethasone bioavail-
ability below 50% were receiving pheny-
toin whereas two of three patients with
good bioavailability were not. As pheny-
toin did not impair gastrointestinal
absorption of dexamethasone in rats,5
possible effects of the oral route of
dexamethasone administration on the
human DST have not been examined.
Hypothalamic-pituitary-adrenal axis
The discrepancy was surprising as,
although there is a poor correlation
between
dose
and
serum
concentrations,28,29 one would assume
that with longer treatment duration,
phenobarbitone tachyphylaxis would
necessitate increasing phenobarbitone
doses to maintain therapeutic serum
concentrations.30,31 Frey30 reported
lengthened phenobarbitone half-lives in
some individual dogs and it is possible
this could have occurred in the clinical
cases. A more likely explanation is that
dividing the dose eliminates the effect of
a shortened half-life and enables thera-
peutic concentrations to be maintained.
Routine clinical recommendations
have been to divide the phenobarbitone
dose, despite pharmacokinetic studies
that suggest once daily dosing should be
sufficient.31,32 The findings in this study
provide some support for the current
recommendations that divided dosing is
more likely to produce therapeutic
concentrations of phenobarbitone.
Pharmacokinetic studies examining the
effects of dose frequency on serum
phenobarbitone concentrations would
be required to investigate this further.
10. Feldman EC, Nelson RW. Canine and feline
endocrinology and reproduction. 2nd edn.
Saunders, Philadelphia, 1996:187-265.
11. Chauvet AE, Feldman EC, Kass PH. Effects of
phenobarbital administration on results of serum
biochemical analyses and adrenocortical function
tests in epileptic dogs. J Am Vet Med Assoc
1995;207:1305-1307.
12. Feldman EC, Mack RE. Urine cortisol:creati-
nine ratio as a screening test for hyperadrenocorti-
cism in dogs.
1992;200;1637-1641
J
Am Vet Med Assoc
13. Kaplan AJ, Peterson ME, Kemppainen RJ.
Effects of disease on the results of diagnostic tests
for use in detecting hyperadrenocorticism in dogs.
J Am Vet Med Assoc 1995;207:445-451.
14. Woodbury DM, Pippenger CE. Other
antiepileptic drugs. In: Woodbury DM, Penry JK,
Pippenger CE, editors. Antiepileptic drugs. Raven
Press, New York, 1982:791-801.
15. Foster SF, Church DB, Watson ADJ. Effects of
phenobarbitone on serum biochemical tests in
dogs. Aust Vet J 2000;78:23-26.
16. Watson ADJ, Church DB, Emslie DR, Foster
SF. Plasma cortisol responses to three corti-
cotrophic preparations in normal dogs. Aust Vet J
1998;76:255-257.
17. Toutain PL, Alvinerie M, Ruckebusch Y.
Pharmacokinetics of dexamethasone and its effect
on adrenal gland function in the dog. Am J Vet Res
1983;44:212-217.
18. Rijnberk A, van Wees A, Mol JA. Assessment
of two tests for the diagnosis of canine hypera-
drenocorticism. Vet Rec 1988;122:178-180.
19. Kemppainen RJ, Sartin JL. Effects of single
intravenous doses of dexamethasone on baseline
plasma cortisol concentrations and responses to
synthetic ACTH in healthy dogs. Am J Vet Res
1984;45:742-746.
20. APA Task Force on Laboratory Tests in
Psychiatry. The dexamethasone suppression test:
an overview of its current status in psychiatry. Am
J Psychiatry 1987;144:1253-1262.
21. Guthrie SK, Heidt M, Pande A et al. A longitu-
dinal evaluation of dexamethasone pharmacoki-
netics in depressed patients and normal controls. J
Clin Psychopharmacol 1992;12:191-196.
Acknowledgments
The senior author was supported by a
Lionel Lonsdale Clinical Fellowship. We
thank Dr David Snow and Macquarie
Vetnostics for the phenobarbitone
assays, Dr Chris Holland for assistance
with dog 10 and the Animal Ethics
Committee for granting permission to
home experimental dogs as pets at the
end of the experiment. The study would
not have been possible without the co-
operation of the owners of the epileptic
dogs.
suppression correlates with plasma
dexamethasone concentration and is
thus influenced by pharmacokinetic
variations.27 Although dexamethasone
metabolism is increased by anticonvul-
sants, reduced bioavailability because of
an enhanced first-pass effect may be the
main cause of problems with the DST in
humans. Further studies into the effects
of phenobarbitone on dexamethasone
pharmacokinetics in humans, including
trials with oral and IV DSTs, would be
necessary to investigate this.
References
It was interesting that the mean
22. Greco DS, Brown SA, Gauze JJ et al.
Dexamethasone pharmacokinetics in clinically
normal dogs during low- and high-dose dexam-
ethasone suppression testing. Am J Vet Res 1993;
54:580-585.
1. Nugent CA, Nichols T, Tyler FH. Diagnosis of
serum phenobarbitone concentrations
in the six experimental dogs failed to
reach suggested therapeutic concentra-
Cushing’s
syndrome.
Arch
Intern
Med
1965;116:172-176.
2. Aron DC, Tyrrell JB, Fitzgerald PA et al.
Cushings syndrome: problems in diagnosis.
22
Aust Vet J Vol 78, No 1, January 2000

Clinical
23. Takahashi Y, Ebihara S, Nakamura Y,
Takahashi K. A model of human sleep-related
growth hormone secretion in dogs: effects of 3,6,
and 12 hours of forced wakefulness on plasma
growth hormone, cortisol and sleep stages.
Endocrinology 1981;109:262-272
24. Kemppainen RJ, Sartin JL. Evidence for
episodic but not circadian activity in plasma
concentrations of adrenocorticotrophin, cortisol
and thyroxine in dogs.J Endocrinol 1984;103:219-226.
26. Brophy TRO’R, McCafferty J, Tyrer JH, Eadie
MJ. Bioavailability of oral dexamethasone during
high dose steroid therapy in neurological patients.
Eur J Clin Pharmacol 1983;24:103-108.
27. Lowy MT, Meltzer HY. Dexamethasone
bioavailability: implications for DST research. Biol
Psychiatry 1987;22:373-385.
control of canine seizures. Vet Rec 1988;122:346-
349.
30. Frey H-H, Kampmann E, Nielsen CK. Study on
combined treatment with phenobarbital and
diphenylhydantoin. Acta Pharmacol Toxicol
1968;26:284-292.
31. Ravis WR, Pedersoli WM, Wike JS.
Pharmacokinetics of phenobarbital in dogs given
multiple doses. Am J Vet Res 1989;50:1343-1347.
32. Thurman GD, McFadyen ML, Miller R. The
pharmacokinetics of phenobarbitone in fasting and
non-fasting dogs. J S Afr Vet Assoc 1990;61:86-89
(Accepted for publication 21 June 1999)
28. Farnbach GC. Serum concentrations and effi-
cacy of phenytoin, phenobarbital, and primidone in
canine epilepsy.
J
Am Vet Med Assoc
25. Duggan DE, Yeh KC, Matalia
N
et al.
1984;184:1117-1120.
29. Morton DJ, Honhold N. Effectiveness of a ther-
apeutic drug monitoring service as an aid to the
Bioavailability of oral dexamethasone. Clin
Pharmacol Therap 1975;18:205-209.
Effects of phenobarbitone on serum biochemical tests
in dogs
SF FOSTER, DB CHURCH and ADJ WATSON
Department of Veterinary Clinical Sciences, The University of Sydney, New South Wales 2006
Objectives To investigate effects of phenobarbitone on serum activities of alanine aminotransferase, alkaline
phosphatase and gamma-glutamyl transferase and concentrations of bilirubin, albumin, cholesterol and total protein
in dogs.
Animals
Ten crossbreed experimental dogs and 10 client-owned dogs of mixed breeds treated chronically with
phenobarbitone to control seizures.
Procedures Experimental dogs were allocated to treatment (6 mg/kg oral phenobarbitone, n = 6) and control (no
treatment, n = 4) groups in which serum biochemical tests were performed at intervals during a 3-month period.
Biochemical tests were performed once on the 10 epileptic dogs.
Results
Phenobarbitone caused increased serum alkaline phosphatase activity but did not affect gamma-
glutamyl transferase activity or bilirubin, cholesterol, albumin and total protein concentrations. Phenobarbitone had
minimal effect on alanine aminotransferase activity.
Conclusions
Individual dogs treated with phenobarbitone may have small increases in serum alanine amino-
transferase activity and variable increases in alkaline phosphatase activity but are unlikely to have alterations in
gamma-glutamyl transferase activity or bilirubin, cholesterol, albumin or total protein concentrations.
Aust Vet J 2000;78:23-26
Key words: Dog, phenobarbitone, alanine aminotransferase, alkaline phosphatase, gamma-glutamyl transferase, hypertriglyceridaemia.
ALP
ALT
Alkaline phosphatase
Alanine aminotransferase
GGT
TP
Gamma-glutamyl transferase
Total protein
have, until recently,11 been based on a
study using only two dogs and effects
on GGT have not been investigated.
been reported and these changes have
been attributed to drug-induced enzyme
synthesis and low-grade hepatocellular
injury, with larger increases possibly
associated with morphologic evidence of
liver injury.4,5 Most of the information
about effects of anticonvulsants on the
liver has been based on data for primi-
done and anticonvulsant combinations6-8
or on studies with few dogs receiving
henobarbitone and primidone are
the most effective drugs for long
term anticonvulsant therapy in
9
P
dogs.1,2 As there is a greater potential for
behavioural side-effects and hepatotoxi-
city with primidone, phenobarbitone is
widely regarded as the drug of choice for
chronic therapy.1,2 However, phenobar-
bitone has also been reported to cause
hepatotoxicosis in dogs.3
Materials and methods
Animals
Dogs from a study of the effects of
phenobarbitone on adrenocortical func-
tion tests14 were used in this study.
There were 10 experimental dogs (6
dosed with phenobarbitone, 4 controls)
and 10 client-owned epileptic dogs
(numbered 1 to 10) receiving phenobar-
la
rge doses of phenobarbitone.9-11
Anticonvulsants may affect results of
laboratory tests commonly used to assess
hepatic abnormalities. Increased serum
activities of ALT, ALP and GGT have
Evidence exists for phenobarbitone-
induced increases in ALP activity 10-13
but effects of phenobarbitone on ALT
bitone
to
prevent
seizures.
Aust Vet J Vol 78, No 1, January 2000
23