Pharmacokinetics of Phenobarbital in the Cat Following

Intravenous and Oral Administration

Susan M. Cochrane, William D. Black, Joane M. Parent, Dana G. Allen and John H. Lumsden

ABSTRACT

RESUME

INTRODUCTION

Phenobarbital was administered to

eight healthy cats as a single intravenous dose of 10 mg/kg. Serum phenobarbital concentrations were deter-

Du phenobarbital (10 mg/kg) a ete

injecte en une seule dose par voie
intraveineuse a huit chats sains. Les
concentrations seriques de phenobarbital ont ete determinees par immunoessais. Les donnees ont tente d'etre
ajustees selon des modeles 'a un, deux
ou trois compartiments; le modele 'a
deux compartiments a ete celui
decrivant le mieux la cimetique du
produit. Suite a l'injection intraveineuse, le medicament s'est rapidement
disperse (demi-vie de la distribution,
0,046 0,007 h) dans un volume
apparent de distribution de 931 45
mL/kg. Par la suite, l'elimination
corporelle du produit a ete lente
(demi-vie, 58,8 4,2 h).
Trois semaines plus tard, une seule
dose orale de phenobarbital (10 mg/
kg) a ete donnee aux memes animaux. Un modele a un compartiment
avec une composante ajoutee s'est
revele comme celui decrivant le
mieux les resultats obtenus. Apres la
phase d'absorption rapide (demi-vie,
0,382 0,099 h), les concentrations
seriques (13,5 0,1 ,g/mL) ont
atteint un plateau pendant pres de dix
heures. De son cote, la demie-vie de la
phase d'e'limination (76,1 6,9 h) n'a
pas e
't significativement differente de celle observee lors de
l'injection intraveineuse. La biodisponibilite du produit administre per
os a ete elevee (F = 1,20 0,12).
Selon l'etude de la pharmococinetique du phenobarbital chez le chat, il
semble que ce produit pourrait etre
employe avantageusement comme
anticonvulsivant chez le chat.

Seizure disorders represent one of

the most common problems in small
animal neurology (1). Seizure activity
is reported to occur in approximately
0.5-1% of feline and canine patients
(2,3). This is similar to the incidence
reported in humans (4,5). In contrast
to the dog, where idiopathic epilepsy is
a common cause of seizures (6,7), in
the cat convulsions are more likely to
reflect a structural, and often intracranial disease such as neoplasia,
inflammation or degeneration (8,9).
Limited information is available on
the use of anticonvulsants in the cat
(2). Neither phenytoin nor primidone
have been recommended in this
species because of their potential
toxicity and difficulty in establishing a
safe dosage regimen (3,10,11).
Authors have recommended phenobarbital (PB), and more recently
diazepam, as the anticonvulsants of
choice for long-term therapy in the cat
(8,12). Despite these recommendations, minimal pharmacokinetic data
are available. Frey (2) reported a halflife of 34-43 h following chronic PB
treatment in cats.
The objectives of this study were to
select the appropriate model and to
determine the pharmacokinetics of PB
after administration of a single
intravenous and oral dose in the cat.

mined

using

an

immunoassay

technique. The intravenous data were

fitted to one-, two- and threecompartment models. After statistical
comparison of the three models, a
two-compartment model was selected.
Following intravenous administration, the drug was rapidly distributed
(distribution half-life = 0.046 0.007
h) with a large apparent volume of
distribution (931 44.8 mL/kg).
Subsequent elimination of phenobarbital from the body was slow (elimination half-life = 58.8 4.21 h).
Three weeks later, a single oral
dose of phenobarbital (10 mg/kg)
was administered to the same group
of cats. A one-compartment model
with an input component was used to
describe the results. After oral
administration, the initial rapid
absorption phase (absorption halflife = 0.382 0.099 h) was followed by
a plateau in the serum concentration
(13.5 0.148 Ag/mL) for approximately 10 h. The half-life of the
terminal elimination phase (76.1 +
6.96 h) was not signifilcantly different
from the half-life determined for the
intravenous route. Bioavailability of
the oral drug was high (F = 1.20 +
0.120).
Based on the pharmacokinetic
parameters determined in this study,
phenobarbital appears to be a suitable
drug for use as an anticonvulsant in
the cat.

MATERIALS AND METHODS

EXPERIMENTAL ANIMALS

Eight mixed breed cats (6 male, 2

female) ranging in age from approxi-

Department of Clinical Studies (Cochrane, Parent, Allen), Department of Biomedical Sciences (Black) and Department of Pathology (Lumsden),
Ontario Veterinary College, University of Guelph, Guelph, Ontario NIG 2W1.
This study was funded by the Ontario Veterinary College Pet Trust.
Submitted June 13, 1989.

132

Can J Vet Res 1990; 54: 132-138

mately one to three years were used in and 96 h after injection. To avoid ORAL PHENOBARBITAL STUDY
this experiment. The cats weighed collecting the residual volume of the
Three weeks following the IV
from 2.6 to 6.0 kg (mean weight 4.35 catheter, 0.5 mL of blood was drawn blood samples were drawn fromstudy,
kg). Prior to the study, physical and discarded prior to sampling. To cat for hematological evaluation each
and
examination, hematological evalua- maintain patency, 0.5 mL of heparin serum
biochemistry
analysis.
A
tion, serum biochemistry analysis solution (100 U/mL) was injected into
jugular
catheter
was
placed
under
(Coulter Dacos, Coulter Electronics the catheter following each of the last
general anesthesia as previously
of Canada, Burlington, Ontario) and five samples.
fecal parasite egg count were perTo evaluate the effect of sampling, described (13). Two days later, the oral
formed to demonstrate that each cat hemoglobin, total protein level and PB study was initiated.
Phenobarbital tablets (Phenobarbiwas healthy. Throughout the experi- hematocrit were determined at the 10,
ment the cats were housed in individ- 24 and 96 h intervals. Following the tal acid USP, Parke-Davis, Scarual metal cages in a room isolated final sample, the catheter was borough, Ontario) were administered
orally as a single dose of 10 mg/kg.
from other cats and were fed commer- removed.
cial dry cat food (Meow Mix,
Ralston Purina, Mississauga, Ontario) and water ad libitum. The cats
were fasted of food for 12 h prior to
and following drug administration.
The guidelines of the Guide to the
Care and Use of Experimental Anim- 0O 20*
als of the Canadian Council on
0
L.
Animal Care were followed.

%..%

SURGICAL PROCEDURES

10-

To facilitate blood collection with

minimal stress to the cat during the .O.
intravenous (IV) and oral studies, an 0
indwelling jugular catheter (16 or 19 Igauge, 20.3 cm Intracath, Deseret Co., -oO 2.
Sandy, Utah) was placed as previously C0
4)
described (13).
-C
To induce anesthesia, the cats were
placed in a 5 L airtight plexiglass box
)
containing isoflurane (AErrane,
Anaquest, Pointe Claire, Quebec) and o
oxygen. They were then intubated and CL
maintained at a light surgical plane of 4-5
anesthesia during catheterization.
The catheter was removed after the
IV study and another catheter placed 0) 30
in the opposite jugular vein prior to 0
the oral experiment.

.......................

20

lo

*;;w99-@@B1

: ...................................

30
Time (min)

50

40

60

INTRAVENOUS PHENOBARBITAL
STUDY

Two days following placement of

the jugular catheter a single dose of 10
mg/kg of phenobarbital sodium USP
(Luminal, Abbott Laboratories,
Toronto, Ontario) was administered
into the cephalic vein using a butterfly
apparatus (Venisystems Butterfly-23,
Abbott Ireland Ltd., Ireland), followed by flushing with sterile saline
(1.0 mL). The PB dose was selected to
allow for sufficient points on the curve
to be measured accurately by the assay
procedure. Blood samples (0.5 mL)
were collected at 0, 1, 2, 3, 4, 5, 10, 15
and 30 min, 1, 2, 3,4,6, 10,24, 48, 72

a)qj
C

10

't
ff

-0L-0
C

CD

-C

I tl

ib

24

48

72

Time (h)
Fig. 1. Serum concentrations of phenobarbital (T mean SEM) following administration of a
single intravenous dose of 10 mg/kg in eight cats; A) 0-60 min, B) 0-96 h.
Predicted Curves:
One-compartment model ( . )
Two-compartment model (--------)
Three-compartment model (
I

133

During cross-reactivity studies, the

major metabolite p-hydroxyphenobarbital did not cross-react or interfere with the assay (Technical Information, Seralyzer Aris, Ames
Division, Miles Laboratories Inc.,
Elkhart, Indiana).

-i

DATA ANALYSIS

cn

_ 30

0
4-

20-

o 10

'LI

Logarithmic

~0
2
5

Time (h

analysis (14).
The intravenous PB

serum levels
fitted to one-, two- and threecompartment models (15) and the

2-

were

20

0)
0

o3

serum concentra-

tions of PB were plotted against time

(linear) for both IV and oral studies
(Figs. 1 and 2). The terminal
elimination slope of each graph was
8#-,-.- lanalyzed by least squares regression
analysis (14). The remaining components of the curve were isolated using
the method of residuals (15) and
analyzed by least squares regression

predicted

curves were plotted (Fig.

1). Selected pharmacokinetic
parameters obtained for each model
were compared (Table I) using oneway analysis of variance (ANOVA)

.0

03
41

-c0

and least significant differences

(LSD) (14).
The two-compartment model (Cp =
Ae- at + Be- bt) was chosen for detailed
I1
24
48
72
pharmacokinetic
analysis.were
The calcupharmacokinetic parameters
Time (h)
Fig. 2. Serum concentrations of phenobarbital ( Tmean SEM) following a single oral dose of 10 lated using standard equations ( 15,
16). These parameters are defined in
mg/kg in eight cats; A) 0-24 h, B) 0-120 h.
Table II. The maintenance dose was
Predicted curve: one-compartment model ( _
)
calculated using the formula:
Maintenance dose QB)
x desired
F
The tablets were cut and weighed to ries IInc., Elkhart, Indiana). To serum concentration x T, where T =
ensure an accurate dose. Blood validaLte this procedure for the cat, dosing interval (17).
samples were collected as described samplies of known PB concentration
Pharmacokinetics of PB adminisfor the IV study at 0, 5, 10, 15, 30 and (0, 7.5 , 15, 30, 60 and 120 Ag! mL) in tered orally were determined using a
45 min, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, normail cat serum were analyzed in one-compartment model with an
48, 72, 96 and 120 h after PB duplic ,ate to establish a standard input component (15). The pharmacoadministration. Heparin solution was curve. The equation of the line for the kinetic parameters were calculated as
injected as previously described for the PB st tandard curve was -0.0958 + previously described (15,16) and are
IV study, following each of the last six 0.98577(X) and the correlation coeffi- defined in Table III.
The half-life data for IV and oral
samples. Hematological evaluation cient ( r) was 0.9993.
Landr)
wastrol
administration
were compared for
and serum biochemistry analysis was
Ast andardized control (30,Mg! mL)
animals
using a paired
repeated following the 120 h sample providled by the manufacturer was individual
Student's t-test (14).
collection.
assaye d prior to each group of
Statistical analyses were performed
es. If the calculated concentra- at a confidence level of 95%. All data
samplh
PHENOBARBITAL ASSAY
17

izd

The blood sample was allowed to

clot. The serum was separated by
centrifugation (15 min at 1239 g) and
the serum analyzed within I h of
collection.
Analysis was performed by an
immunoassay technique (Seralyzer
Aris, Ames Division, Miles Laborato-

134

.g/

tion f(or the control was outside the

range4of 28-32 Mug/ mL, the instrument
nAVs. *...cm A1- using
_ D
was reca1iUraLea
Known IB
standards of 10 and 50 ,ug/mL
supplied by the manufacturer. The
coefficient of variation (CV) for the
appropriately calibrated 30 Ag/ mL
control for the entire experimental
-,al;ls

o;

period was 3.75%.

are presented as mean standard

error of the mean (SEM).

RESULTS

Hematological and serum biochemical data determined prior to the IV

and oral studies and at completion of
the oral study were within normal

TABLE I. Comparison between pharmacokinetic parameters determined by one-, two- and threecompartment models following a single IV dose of phenobarbital in the cat*
B
Model
I-C

n
8

(Mg/ mL)
13.6a

0.560
2-C

10.9b

0.500
3-C

7+

10.6b

0.602

b
(h-')
0.016a

(jg/ mL)

(h-')

18.6a

17.3a
2.21

P
(#g/ mL)

p
(h')

0.001
0.013b

0.001
0.012b

0.001

1.91
4.50b

1.17

2.58b

15.3

25.9

0.615

2.73

4.50

*Values expressed as mean SEM

a,bDifferent superscripts in vertical columns indicate significant difference between derived
parameters
+One cat did not fit a three-compartment model
n = number of cats
C = compartment
B = y-intercept elimination curve
b = overall elimination rate constant
A = y-intercept distribution curve
a = distribution rate constant (peripheral compartment)
P = y-intercept distribution curve
p = distribution rate constant (peripheral compartment)

ANOVA and LSD (14) (Table I). The

y-intercept of the terminal elimination
curve (B) and the slope of the
elimination phase (b) for the two- and
three-compartment models were
significantly less than for the onecompartment model. However, when
the y-intercept and elimination slope
of the two- and three-compartment
models were compared, they were not
significantly different.
The y-intercept (A) and distribution
slope (a) for the two- and threecompartment models were significantly different (Table I). P and p
values were reported for the threecompartment model.
The pharmacokinetic parameters of
PB following a single IV dose
determined by the two-compartment
model are presented in Table II.
ORAL PHENOBARBITAL STUDY

ranges as established at the Ontario

Veterinary College. When values for
the individual cats were compared
during the experiment using a paired
Student's t-test, no significant differences were present, suggesting that
sample collection did not alter blood
parameters.
The correlation coefficient of the
standard curve indicated that the
assay was linear over the concentration range used in the study. The low
CV for the standard control (30 ,g!
mL) indicates that the repeatability of
the analytical procedure between
sample runs was high.
INTRAVENOUS PHENOBARBITAL
STUDY

The logarithmic serum drug concentrations measured following IV

administration of PB were plotted
against time (linear) (Fig. 1).
When the curves predicted for the
one-, two- and three-compartment
models were plotted (Fig. 1), the curve
for the three-compartment model
appeared to best describe the serum
PB data. The difference between the
two- and three-compartment models
was most evident at the 10 to 30 min

points.
When the terminal elimination
slope was evaluated, the correlation
coefficient (r) for data points indicated
a better fit of the data to the curves of
the two-compartment (0.976) and
three-compartment (0.983) models

than for the one-compartment model

(0.848)
To further assess selection of an
appropriate model, the y-intercepts
(A,B,P) and slopes of the curves
(a,b,p) determined for each model
were compared using one-way

The logarithmic serum drug concentrations following oral administration of PB were plotted against time
(linear) (Fig. 2). The data were fitted to
a one-compartment model with an
input component. The pharmacokinetic parameters of PB following

TABLE II. Pharmacokinetic parameters following a single intravenous dose of phenobarbital

(10 mg/kg) in eight cats based on two-compartment model

Parameter
Cp (,ug/mL)
A (,ug/mL)

B(Ag/mL)

a (h-I)
b (h-')

t2a (h)

t'/2b (h)
k,2 (h-)
k21 (h-')
kel (h-I)
Vc(mL/kg)
V'd(area) (mL/kg)

Mean
29.5
18.6
10.9
17.3
0.013
0.046
58.8
10.7
6.58
0.033
351.0
931.1
11.3
918.9
4.35

SEM
1.92
1.91
0.50
2.21
0.001
0.007
4.21
1.56
0.966
0.002
26.8
44.8
0.76
69.3
0.388

Cl(B)(mL/kg/h)
AUC (,ug h/mL)
Weight (kg)
CO p = theoretical serum level immediately after injection
A
= y-intercept distribution curve
B
= y-intercept elimination curve
a
= distribution rate constant
b
= overall elimination rate constant
t/2a = half-life distribution
t /2b = half-life elimination
k12 = transfer constant (central to peripheral)
k2, = transfer constant (peripheral to central)
= elimination rate constant from central compartment
kel
= apparent volume of distribution central compartment
Vc
V'd = apparent volume of distribution at equilibrium (area method)
Cl(B) = total body clearance from plasma
AUC = area under plasma concentration-time curve (0 to infinity)

Range
21.1 - 35.4
9.22 - 23.9
8.77- 12.7
8.76 - 26.8
0.009 - 0.017
0.026 - 0.079
41.3 - 77.0
5.92 - 18.6
2.81 - 10.5
0.022 - 0.039
282.4 - 467.3
784.2- 1138.9
7.68 - 14.4
656.9 - 1301.5
2.6 - 6.0

135

TABLE III. Pharmacokinetic parameters following oral administration of phenobarbital (10 mg/kg)
in eight cats
Parameter

Mean
SEM
13.9
0.711
Kab (h-')
2.56
0.581
b (h-1)
0.010
0.0001
0.382
0.099
t/2ab (h)
76.1
t/2b (h)
6.96
V'd(area)(mL/ kg)
727.6
37.9
Cl(B)(mL/kg/h)
6.97
0.598
AUC(ugh/mL)
1518.07
139.3
F
1.69
0.172
F*
1.20
0.120
Wt (kg)
4.94
0.438
B'
= y-intercept elimination curve
Kab = rate of absorption
b
= overall elimination rate constant
tl/2ab = half-life absorption
tI / 2b = half-life elimination
V'd
= apparent volume of distribution at equilibrium (area method)
CI(B) = total body clearance from plasma
AUC = area under plasma concentration-time curve (0 to infinity)
F
= fraction absorbed
F*
= F corrected for drug form and intraindividual variation
Wt
= body weight of animal

B'(pg/mL)

Range
11.0- 16.6
0.672 - 5.04
0.007 - 0.015
0.157 - 1.03
46.2 - 96.3
598.7 - 904.5
4.66 - 9.10
1151.7 - 2145.2
1.28 - 2.51
0.82- 1.79
3.0 - 6.0

administration of a single oral dose are compartment model appeared to best

presented in Table III.
describe the data (Fig. 1). However,
The duration of the initial rapid when the parameters B and b, which
absorption phase was approximately 1 are both important in determining a
to 1.5 h. The serum PB concentration therapeutic regime, were calculated by
then remained relatively constant for the two- and three-compartment
approximately 10 h. The mean serum models, they were virtually the same
drug concentration calculated during (Table I). Therefore, it was decided
this time interval from 2-12 h was 13.5 that the simpler two-compartment
+ 0.148 ug/ mL (Fig. 2).
model could be used for detailed
The bioavailability of oral PB was pharmacokinetic analysis.
high (F = 1.69 0.172). This value was
The elimination half-life following
reduced to 1.20 0.120 when IV administration of PB in cats was
corrections were made for intraindi- within the range reported for dogs [32
vidual variability in the overall h (23) to 92.6 h (19)], and shorter than
elimination rate from the body (16), one report in humans [99 h (22)]. In
and for differences in the molecular contrast, the t2b for adult horses was
weight of the PB sodium salt (IV) and 18.3 h (21) and for neonatal foals was
PB acid (oral) (18).
12.8 h (24).
The high V'd suggests a wide
distribution of PB within the body
DISCUSSION
(16). This value is larger than reported
for dogs (631.0 mL/kg) (25) but
Previous reports have described the similar to humans (700-1000 mL/kg)
disposition kinetics of PB after IV (26) and horses (803 mL/kg) (21). The
administration using a one- high lipid solubility of PB and low
compartment model in dogs (19), a level of ionization at physiological pH
two-compartment model in horses (pKa 7.3) probably contribute to the
(20,21) and humans (22) or a one- and high V'd observed (27). These charactwo-compartment model in dogs (23). teristics allow the drug to readily
In the present study, sample collection diffuse across body membranes such
at 1 min intervals for the first 5 min as the blood-brain barrier (27). In fact,
after IV drug administration and sequestration of PB within brain tissue
frequently thereafter enabled detec- has been demonstrated (28).
tion of three compartments. The
Phenobarbital administered orally
predicted curve of the three- was rapidly absorbed with peak serum
136

concentrations achieved in approximately 1 to 1.5 h following administration. Previous reported times to reach
maximum serum concentrations
ranged from 1.5 h (29) to 6 h (30) in
dogs and 1.5 h (22) to 9-12 h (31) in
humans.
The serum PB concentration
remained relatively constant for
approximately 10 h after the rapid
absorption phase. A similar plateau
has been observed in dogs (17,19) and
humans (22,32) after oral PB. It
suggests that input of the drug to
serum from the gastrointestinal tract
(GIT) is being balanced by losses due
to distribution within the body and
elimination. The plateau may also
indicate a relatively constant rate of
GIT uptake for the 10 h period.
Factors such as tablet disintegration,
dissolution and dispersal may influence uptake from the digestive tract. It
is unlikely that tablet disintegration
delayed absorption, since studies in
our laboratory showed this product to
disintegrate rapidly (approximately
1-2 min). Harvey (27) suggested that
the rate-limiting step in PB absorption
may be dissolution and/ or dispersal
within the GIT.
A one-compartment model adequately described the elimination
phase following administration of an
oral dose of PB (Fig. 2). A small
distribution component was evident in
the data but there were insufficient
data points to adequately analyze this
section of the curve. This did not
appear to seriously interfere with
selection of the model since there was
an excellent fit of the data to the
terminal part of the curve predicted by
the one-compartment model.
The decline in serum PB concentrations following oral administration
was slow. This is longer than reported
for oral PB in adult horses (19.0 4.4
h) (20) and dogs (44-62 h) (30), but
similar to humans (81.6 25 h) (33).
The elimination half-life following a
single oral dose of PB was not
significantly different from the IV
experiment. With long-term anticonvulsant therapy, a prolonged elimination half-life is an advantage since less
frequent drug administration is
required to maintain relatively constant tissue levels (16).
Both V'd and Cl(B) values determined following oral administration

were lower than for the IV study. Since

both parameters include AUC in their
calculation, the differences appear to
reflect the consistently larger AUC for
oral PB. In addition, the bioavailability (F) determined by comparing AUC
oral and AUC IV (16) exceeded 1.00.
The F value was corrected for
differences in the molecular weight
(MW) of the drug formulations used
in the study. The MW of PB sodium
(254.22) administered IV is larger than
the MW of PB acid (232.32) given
orally (18). To compare the IV and
oral studies, the IV serum levels were
multiplied by a factor of 1.095
(254.22/ 232.32) (22,33). Further
correction for intraindividual variability in the overall elimination rate
between the IV and oral studies (16)
yielded a final F value of 1.20 0.120.
Bioavailability data for oral PB
have been reported in other species
including dogs (19), humans (22) and
horses (20). It is of interest that
authors using PB sodium for both oral
and IV studies have reported F values
in excess of 1.0 (19,20,22). For
example, Ravis et al (20) determined F
values as high as 1.24 in the horse.
One possible explanation for the
high F value is the administration of
less drug IV than orally. To ensure
that none of the calculated dose was
lost during IV injection, PB levels were
determined before and after passage
through the syringe and catheter
system. No evidence of PB loss within
the injection system could be demonstrated and the amount of drug was as
indicated on the label.
Since PB excretion is enhanced in
alkaline pH, another possible explanation for the high F value was an
elevated urinary pH (34). No significant difference in urinary pH between
the oral and IV studies was
documented.
Administration of a larger dose
than expected orally could influence
the calculated bioavailability.
Although the manufacturer assured us
that the quantity of drug in the tablets
was as indicated on the label, the exact
amount could have varied since the
United States Pharmacopeia regulations consider a range of 90 to 110% of
the labelled amount of PB acceptable
(35). We were unable to determine
accurately the concentration of drug
in the tablets using our assay proce-

dure due to the compounding materials in the tablets. The reason for the
apparent excess bioavailability for
oral PB remains unknown and
requires further investigation.
A maintenance dose was calculated
using the formula of Ravis et al (17).
Based on a desired midtherapeutic
steady state serum concentration of 25
.tig/ mL (17,36-38) and treatment every
24 h, a PB dose of 4.2 mg/ kg would be
required.
Time to reach a steady-state serum
concentration is normally considered
to be five half-lives (16). Approximately 16 days would be required to
achieve a steady state PB concentration in the cat. In cases where it is
desirable to achieve steady state more
rapidly, a loading dose of PB could be
administered.
The maintenance dose calculated in
this study assumes that the elimination
kinetics for PB do not change after
repeated administrations. Although
PB is a potent inducer of hepatic
microsomal enzyme function (39), a
multiple dose study is required before
the influence of induction on the
elimination kinetics can be evaluated
(40,41).
In summary, the pharmacokinetics
of PB suggest that once daily treatment at the suggested dose should
result in adequate therapeutic serum
concentrations. It is, however, recommended that serum PB concentrations
be monitored with long-term anticonvulsant therapy, since the influence of
repeated treatments on the elimination kinetics is not yet known.

ACKNOWLEDGMENTS
The authors wish to thank Jean
Claxton for her excellent technical
assistance and guidance when performing the kinetic analysis and for
the use of her computer programs.

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Vet 1980; 2: 77-86.
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animals. Vet Rec 1986; 118: 484-486.
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