Pharmacokinetics of gabapentin in cats

Kristine T. Siao, BS; Bruno H. Pypendop, DrMedVet, DrVetSci; Jan E. Ilkiw, BVSc, PhD

Objective—To determine the pharmacokinetics of gabapentin in cats after IV and oral

administration.
Animals—6 healthy female adult domestic shorthair cats.
Procedures—Gabapentin was administered IV (4 mg/kg) or orally (10 mg/kg) in a crossover
randomized design. Blood samples were obtained immediately before gabapentin admin-
istration and at various times up to 960 minutes after IV administration or up to 1,440
minutes after oral administration. Blood samples were immediately transferred to tubes
that contained EDTA and were centrifuged at 4°C. Plasma was harvested and stored at
–20°C until analysis. Plasma concentrations of gabapentin were determined by use of liquid
chromatography–mass spectrometry. Gabapentin concentration-time data were fit to com-
partment models.
Results—A 3-compartment model with elimination from the central compartment best de-
scribed the disposition of gabapentin administered IV to cats, but a 1-compartment model
best described the disposition of gabapentin administered orally to cats. After IV administra-
tion, the mean ± SEM apparent volume of the central compartment, apparent volume of
distribution at steady state, and clearance and the harmonic mean ± jackknife pseudo-SD
for terminal half-life were 90.4 ± 11.3 mL/kg, 650 ± 14 mL/kg, 3 ± 0.2 mL/min/kg, and 170
± 21 minutes, respectively. Mean ± SD systemic availability and harmonic mean ± jackknife
pseudo-SD terminal half-life after oral administration were 88.7 ± 11.1% and 177 ± 25 min-
utes, respectively.
Conclusions and Clinical Relevance—The disposition of gabapentin in cats was characterized
by a small volume of distribution and a low clearance. (Am J Vet Res 2010;71:817–821)

G abapentin, a structural analogue of GABA, has been

used as an adjunctive antiepileptic drug to treat
partial seizures in humans.1,2 Gabapentin has been used
AUC
Cl
Abbreviations
Area under the plasma gabapentin curve
Clearance
to treat all types of neuropathic pain,3 and it also can be Cmax Maximum plasma concentration
used to reduce postoperative pain and the amount of F Bioavailability
postoperative opioids required in humans.4 GABA γ-Aminobutyric acid
Although gabapentin resembles GABA, it does not K01 Absorption rate after oral administration
interact with GABAA or GABAB receptors, nor does it in- K10 Elimination rate
hibit GABA uptake. It is not metabolized into GABA or K12 Rate constant of gabapentin transfer from
a GABA agonist.5 Data suggest that it binds to the α2δ the central to the first peripheral
accessory subunit of voltage-dependent calcium chan- compartment
nel complexes6 and has an inhibitory effect on voltage- K13 Rate constant of gabapentin transfer from
gated calcium channels.7 To date, there has been no the central to the second peripheral
consensus on the mechanism of action of gabapentin. compartment
In cats, there are a limited number of options for K21 Rate constant of gabapentin transfer from the
drugs that provide analgesia without undesirable ad- first peripheral to the central compartment
verse effects. Opioids are controlled substances and K31 Rate constant of gabapentin transfer from
the second peripheral to the central
their use can lead to dysphoria, whereas NSAIDs can
compartment
cause toxic effects in cats.8 Alternative analgesic drugs LC Liquid chromatography
for oral administration are needed. MS Mass spectrometry
m/z Mass-to-charge ratio
tmax Time to reach the maximal plasma
Received June 9, 2009. concentration
Accepted July 16, 2009. Vc Apparent volume of the central
From the Department of Surgical and Radiological Sciences, School compartment
of Veterinary Medicine, University of California-Davis, Davis, CA VdSS Apparent volume of distribution at steady
95616.
state
Supported by the Winn Feline Foundation.
The authors thank Scott Stanley for assistance with the gabapentin Vdarea Apparent volume of distribution calculated
assay. from the area under the plasma gaba-
Address correspondence to Dr. Pypendop (bhpypendop@ucdavis. pentin curve and the elimination rate
edu).

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 Gabapentin has several features that make it attrac-
tive for use as an analgesic in cats. Gabapentin is not a
controlled substance and is widely available as an oral
formulation. Also, gabapentin has few toxic effects in
several species.9 Although gabapentin has been used
increasingly in cats, the authors are not aware of any
published data on the pharmacokinetics of this drug in
this species. Without such data, it is difficult to make
rational dosing recommendations. Therefore, the pur-
pose of the study reported here was to characterize the
pharmacokinetics of gabapentin in cats after IV and
oral administration.
Materials and Methods
Animals—Six healthy adult spayed female domes-
tic shorthair cats were used in the study. Mean ± SD
body weight of the cats was 3.7 ± 0.3 kg. Cats were
allowed ad libitum access to food and water during the
study. The study was approved by the Institutional Ani-
mal Care and Use Committee at the University of Cali-
fornia-Davis.
Instrumentation and drug administration—The
day before an experiment, cats were anesthetized by
administration of isoflurane in oxygen. A 22-gauge,
10-cm cathetera was placed in a jugular vein. A light
bandage was placed over the catheter, and the cats were
allowed to recover from anesthesia.
On the day of an experiment, gabapentinb was ad-
ministered IV as a bolus (4 mg/kg) in a medial saphe-
nous vein or orally (10 mg/kg). Immediately before IV
administration, gabapentin was dissolved in water to
achieve a solution with a concentration of 10 mg/mL.
The solution was filtered through a 0.2-µm filter.c For
oral administration, 100-mg gabapentin capsules were
reformulated to contain a dose of approximately 10
mg of gabapentin/kg so that 1 capsule containing an
individual’s dose was administered to each cat. Blood
samples (1.5 mL) were obtained via the jugular cath-
eter prior to gabapentin administration and 1, 2, 4, 8,
15, 30, 60, 120, 240, 480, and 960 minutes after IV ad-
ministration or 5, 10, 20, 30, 45, 60, 90, 180, 360, 720,
and 1,440 minutes after oral administration. Collected
blood samples were inserted into tubes that contained
EDTA; tubes were immediately placed on ice and then
centrifuged at 3,901 X g for 10 minutes at 4°C. Plasma
was harvested and stored at –20°C until analyzed for
gabapentin concentrations.
After a 2-week washout period, each cat was given
gabapentin via the other route of administration. The
order of treatments for each cat was determined by use
of a randomization procedure (random number list
generated by a computer programd).
Gabapentin analysis—Gabapentin was quantitated
in feline plasma by use of LC-MS analysis of extracted
plasma samples. Calibration standards were prepared.
Stock solutions were made by dissolving 10.0 mg of gab-
apentin standarde in 10.0 mL of acetonitrile.f Working
solutions were prepared by dilution of the gabapentin
stock solution with acetnonitrile to achieve concentra-
tions of 10.0, 1.0, and 0.1 mg/mL. Plasma calibrators
were prepared by dilution of the working gabapentin
818
09-06-0215r.indd 818
solutions with drug-free plasma to achieve concentra-
tions of 0.5, 2.0, 5.0, 10, 25, 50, 100, 500, 1,000, 2,000,
5,000 10,000, 20,000, and 30,000 ng/mL. Calibration
curves and negative control samples were prepared fresh
for each quantitative assay. In addition, quality control
samples (plasma fortified with analytes at concentra-
tions at the midpoint of the standard curve) were rou-
tinely included as an additional evaluation of accuracy.
The concentration of gabapentin in each sample was
determined via the internal standardg method by use of
the peak area ratio and linear regression analysis.
Quantitative analyses were performed on a mass
spectrometerh coupled with an LC system.i Chromato-
graphy involved the use of a 50 X 2.1-mm, 3-mm
columnj and a linear gradient of acetonitrile in waterk
with a constant flow of 0.2% formic acidl at a rate of
0.4 mL/min. The acetonitrile concentration was main-
tained at 2% for 0.3 minutes and then increased up to
98% during a period of 2 minutes.
Prior to analysis, all plasma samples were extracted
by use of solid-phase extraction cartridges (200 mg,
3 mL, octadecyl, endcapped, sorbent type C18 cart-
ridges).m Aliquots of 0.4 mL of plasma were treated with
2.0 mL of phosphate buffer (pH, 7.0) fortified with 4 ng
of internal standard in an extraction procedure devel-
oped to elute gabapentin and baclofen in a single frac-
tion. The injection volume was 30 µL.
Detection and quantification involved full-scan
LC-MS-MS transitions of initial product ions for gaba-
pentin (m/z, 172.1). The response for the major prod-
uct ion for gabapentin (m/z, 154.1) was plotted, and
peaks at the proper retention time were integrated with
a computer program.n The same computer program was
also used to generate calibration curves and quantitate
the analytes in all samples.
The concentration of gabapentin in each sample
(eg, calibrators, quality control samples, and unknown
plasma samples) was determined via an internal stan-
dard method by use of the peak area ratio and linear
regression analysis. The response for gabapentin was
linear and yielded values of R2 ≥ 0.99. The technique
was optimized to provide a limit of detection of 0.5
ng/mL and limit of quantitation of 2.0 ng/mL. Intraday
accuracy was 94% and 98% for 25 and 500 ng/mL, re-
spectively. Interday accuracy was 92% and 96% for 25
and 500 ng/mL, respectively. Intraday precision (per-
centage of relative SD) was 2.7% and 1.8% for 25 and
500 ng/mL, respectively. Interday precision (percentage
of a nominal concentration) was 6.4% and 5.5% for 25
and 500 ng/mL, respectively.
Pharmacokinetic analysis—All pharmacokinetic
analyses were performed with a computer program.o
Nonlinear least squares regression was performed on
plasma gabapentin concentrations after IV or oral ad-
ministration. Data for IV administration were weighted
by the reciprocal of the square of the observed plasma
gabapentin concentration. Models (1-, 2-, and 3-com-
partment models) with elimination from the central
compartment were fit to the data for IV administration.
Data for oral administration were weighted by the recip-
rocal of the square of the predicted plasma gabapentin
concentration. Models (1- and 2-compartment models)
with first-order absorption in, and elimination from, the
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 central compartment and with or without lag time were
fit to the data for oral administration. The appropriate
model was selected by observation of the residuals plot
and by use of the Akaike information criterion.10,11 Values
for F were calculated from the ratio of the AUC after oral
and after IV administration (indexed to their respective
dose) by use of the following equation:
F = ([AUCoral X doseIV]/[AUCIV X doseoral]) X 100
where AUCoral and AUCIV were the AUC after oral
and IV administration, respectively; and doseIV and
doseoral were the dose for IV and oral administration,
respectively.
Parameters estimated by use of the model were Vc,
K10, K12, K21, K31, and K13 for IV administration and Vc/F,
K01, and K10 for oral administration. Other pharmaco-
kinetic parameters were calculated by use of standard
pharmacokinetic equations.12 Parameters for oral ad-
ministration were corrected for F, when appropriate.
Normal distribution of pharmacokinetic param-
eters was verified by use of the Shapiro-Wilk test.
Data were reported as the mean ± SEM (range), and
Figure 1—Mean ± SD plasma concentrations of gabapentin after
IV administration of a bolus of gabapentin (4 mg/kg; A) or oral
administration of gabapentin (10 mg/kg; B) to each of 6 cats. The
graph in panel B represents results for only 5 cats; data for 1 cat
were excluded because the data obtained for this cat did not fit
any model (1-, 2-, or 3-compartment models) well. Notice that the
scales of the x- and y-axes differ between panels.
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half-lives were reported as harmonic mean ± jackknife
pseudo-SD (range),13 unless specified otherwise.
Results
A 3-compartment model best described the de-
crease in the plasma concentration of gabapentin after
IV administration (Figure 1). The mean ± SD Vc, VDss,
and Cl were 90.4 ± 11.3 mL/kg (range, 64.1 to 132.4
mL/kg), 650 ± 14 mL/kg (range, 567 to 700 mL/kg),
and 3.0 ± 0.2 mL/min/kg (range, 2.5 to 3.5 mL/min/
kg), respectively, and the harmonic mean ± jackknife
pseudo-SD terminal half-life was 170 ± 21 minutes
(range, 151 to 198 minutes).
A 1-compartment model best described the de-
crease in the plasma concentration of gabapentin after
oral administration (Figure 1). Data after oral admin-
istration for 1 cat were excluded because the data ob-
tained for this cat did not fit any model well. The actual
mean ± SD oral dose administered was 10.0 ± 0.3 mg/
kg. The mean ± SD F after oral administration was 88.7
± 11.1% (range, 49.6% to 118.3%), and the harmonic
mean ± jackknife pseudo-SD terminal half-life was 177
± 25 minutes (range, 151 to 211 minutes). Mean ± SD
tmax after oral administration predicted by use of the
model was 100 ± 22 minutes (range, 58 to 175 min-
utes). Pharmacokinetic parameters for gabapentin were
summarized (Table 1).
Discussion
In the study reported here, we described the phar-
macokinetics of gabapentin after oral and IV adminis-
tration in cats. This information can be used as a basis
to design pharmacodynamic studies in cats. Once ef-
fective concentrations are determined, the data in this
study can be used to design rational protocols for ad-
ministration of gabapentin to cats.
The pharmacokinetics of gabapentin has been
evaluated in humans, dogs, and rats. In humans, gaba-
pentin has a half-life of 6 to 8 hours, is eliminated un-
changed by renal clearance, and does not bind to plas-
ma proteins.14 In rats, the half-life is 2 to 3 hours, and
there is minor biotransformation. However, pharmaco-
kinetic studies in dogs have revealed that gabapentin
has a half-life of 3 to 4 hours, and it is metabolized to
N-methyl-gabapentin.15
To our knowledge, the pharmacokinetics of gaba-
pentin in cats has not been reported. In the study re-
ported here, a 3-compartment model best described
the disposition of gabapentin when administered IV,
whereas a 1-compartment model best described the
disposition of gabapentin when administered orally.
This difference can be attributable to the addition of
the absorption phase when gabapentin is administered
orally. The increasing concentration of gabapentin
in plasma as a result of absorption may have masked
the distribution of gabapentin to peripheral compart-
ments. Although less likely, inadequate timing for col-
lection of blood samples could have contributed to the
unobserved distribution to other compartments. The
pharmacokinetics of gabapentin after oral or IV admin-
istration was characterized by a larger volume of distri-
bution and a higher Cl, compared with the mean Vdarea
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 Table 1—Mean ± SEM (range) values of pharmacokinetic parameters for gabapentin
after IV administration (4 mg/kg, administered as a bolus) or oral administration (10
mg/kg) in 6 cats.

Parameter IV Oral*
F (%) NA 88.7  11.1 (49.6–118.3)
A (ng/mL) 34,772  3,808 (23,885–48,959) NA
B (ng/mL) 7,904  1,394 (3,251–11,242) NA
C (ng/mL)† 4,866.5 (3,072.4–5,420.4) NA
α (/min) 0.793  0.149 (0.301–1.201) NA
β (/min) 0.088  0.025 (0.011–0.162) NA
γ (/min) 0.0041  0.0002 (0.0035–0.0046) NA

t1/2α (min)‡ 0.875  0.402 (0.577–2.301) NA

t1/2β (min)† 9.141 (4.275–64.241) NA
t1/2γ (min)‡ 169.87  20.54 (151.20–197.95) NA

K01 (/min) NA 0.028  0.007 (0.009–0.047)

K10 (/min) 0.035  0.004 (0.026–0.049) 0.004  0.000 (0.003–0.003)
K12 (/min) 0.393  0.058 (0.206–0.534) NA
K21 (/min) 0.265  0.064 (0.069–0.454) NA

K01 t1/2 (min)‡ NA 25.2  15.6 (14.5–80.3)

K10 t1/2 (min)‡ 19.6  5.5 (14.0–26.8) 177.2  25.2 (151.0–211.0)
K31 (/min) 0.0283  0.0057 (0.0071–0.0456) NA
K13 (/min) 0.1624  0.0486 (0.0079–0.2970) NA

Vc (L/kg) 0.090  0.011 (0.064–0.132) 0.770  0.053 (0.660–0.973)

V/F (L/kg) NA 0.928  0.145 (0.748–1.506)
V2 (L/kg)† 0.126 (0.085–0.395) NA
V3 (L/kg) 0.387  0.058 (0.147–0.539) NA
VdSS (L/kg) 0.650  0.014 (0.597–0.700) NA
Vdarea (L/kg)† 0.710 (0.691–0.877) 0.795 (0.747–1.506)

Cl ([mL/min]/kg) 3.02  0.18 (2.45–3.46) 2.99  0.22 (2.45–3.46)

Cl/F ([mL/min]/kg) NA 3.54  0.38 (2.81–4.95)
tmax (min) NA 100  22 (58–175)
Cmax (ng/mL) 47,388  5,102 (30,208–62,378) 7,982  1,053 (4,638–10,550)

*Represents results for only 5 cats; data for 1 cat were excluded because the data
obtained for this cat did not fit any model (1-, 2-, or 3-compartment models) well. †Value
reported is the median (range) because the data were not normally distributed. ‡Value
reported is the harmonic mean  jackknife pseudo-SD (range).
A, B, and C and α, β, and γ = Coefficients and exponents, respectively, in the following
equation used to predict plasma gabapentin concentration at time t: (A X e–αt) + (B X e–βt) +
(C X e–γt), where e is Euler’s number (2.7183). t1/2α = First distribution half-life. t1/2β = Second
distribution half-life. t1/2γ = Elimination half-life. V2 = Apparent volume of the first peripheral
compartment. V3 = Apparent volume of the second peripheral compartment.

(0.158 L/kg) and mean Cl (2.27 [mL/min]/kg) reported
after IV administration in dogs.16 However, both dogs
and cats have a relatively small volume of distribution,
compared with the mean ± SD for Vdarea (1.44 ± 0.50
L/kg) and Vdss (1.23 ± 0.28 L/kg) reported after IV ad-
ministration in rats.15,16 This is probably attributable to
the relatively low lipid solubility of gabapentin (log10
octanol-to-water ratio = –1.2).17 Gabapentin is exten-
sively distributed in tissues of rats.16 However, this
could differ from the situation in cats. The mean ± SD
Cl after IV administration is also higher in rats (9.5 ±
2.0 [mL/kg]/kg in 1 study15 and 9.27 ± 1.9 [mL/kg]/kg
in 1 study16) than in cats and dogs, which results in a
shorter half-life in rats (1.7 hours), compared with the
half-life in dogs and cats (2.9 and 2.8 hours, respec-
tively). The larger volume of distribution and larger
Cl in cats result in a terminal half-life similar to that
in dogs.15,16 The F in cats (mean ± SD, 88.7 ± 11.1%;
range, 49.6% to 118.3%) is higher, compared with the
value for F in dogs (mean, 80%),16 rats (mean ± SD,
79.0 ± 11%),16 and humans (range, 75% to 81%).15 The
F was extremely good in cats (88.7%), but there was
variation among the cats.
After oral administration, Cmax ranged from 4,638 to
10,550 ng/mL and tmax ranged from 58 to 175 minutes.
The tmax in cats after oral administration was similar to
that reported in a study15 of humans, rats, and dogs.
The high interindividual variability in cats in the study
reported here may have been caused by variation in the
F of gabapentin. Because food was not withheld from
the cats (ie, food was available ad libitum), it is hard to
predict whether cats ate close to the time of oral admin-
istration of gabapentin. Gastrointestinal transit time of
drugs reportedly differs between fed cats and cats from
which food is withheld18; thus, the interval between
feeding and oral administration of gabapentin could
have affected the absorption of gabapentin. Differences
in eating habits among cats may have caused variation
in the pharmacokinetic parameters measured. Another
factor that could have added to the variation is the fact
that administration of the gabapentin capsule was not
followed by oral administration of a dose of water (ie, a
water flush). This may have caused the rate at which a
capsule passed through the esophagus to vary. Consis-
tent administration of a water flush could have poten-
tially minimized the variation of transit time through

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 the esophagus, thereby decreasing the variation in tmax
and Cmax; however, it may be difficult to orally admin-
ister a water flush to a cat, especially immediately after
oral administration of a capsule.
In humans, an analgesic effect for neuropathic pain
was achieved at doses of 1,800 mg of gabapentin/d,19
and serum concentrations of gabapentin > 2 µg/mL
resulted in a reduced frequency of seizures.20 Simula-
tions were run on a computer programo to determine
adequate administration that would yield similar con-
centrations in cats. The pharmacokinetic parameters
reported in another study15 were used to calculate ef-
fective plasma concentrations of oral dosages of 1,800
mg/d (600 mg every 8 hours), which were between 4.3
and 8 µg/mL. The pharmacokinetic parameters report-
ed here were used to simulate time-concentration data
after administration of doses targeted to yield plasma
concentrations similar to the plasma concentrations
reported for humans. In cats, an oral administration
schedule of 8 mg/kg every 6 hours would be expected
to result in plasma concentrations similar to that for an
oral administration of 1,800 mg/d in humans. To reach
and maintain plasma concentrations of 2 µg/mL, cats
should be administered 3 mg of gabapentin/kg PO every
6 hours. Pharmacodynamic studies could be conducted
with these dosing regimens to determine whether gaba-
pentin is an effective analgesic in cats.
Gabapentin distribution in cats is characterized by
a small volume of distribution and low Cl. Pharmacody-
namic studies are needed to determine the correlation
between the kinetics of this drug and clinical effects.
a. Central venous catheterization set, Arrow International, Read-
ing, Pa.
b. Gabapentin, United States Pharmacopeia, Rockville, Md.
c. 25-mm syringe filter, Fisher Scientific, Pittsburgh, Pa.
d. JMP 5, SAS Inc, Cary, NC.
e. Gabapentin analytic reference standard, Sigma, St Louis, Mo.
f. High-performance liquid chromatography–grade acetonitrile,
Burdick and Jackson, Muskegon, Mich.
g. Baclofen analytic reference standard, Sigma, St Louis, Mo.
h. TSQ Quantum Ultra triple quadrupole mass spectrometer,
Thermo Scientific, San Jose, Calif.
i. 1100 Series liquid chromatography system, Agilent Technolo-
gies, Palo Alto, Calif.
j. Discovery C18, Supelco, State College, Pa.
k. High-performance liquid chromatography–grade water, Burdick
and Jackson, Muskegon, Mich.
l. Spectrophotometric-grade formic acid, Aldrich, St Louis, Mo.
m. Clean Screen, United Chemical Technologies Inc, Bristol, Pa.
n. LCQuan software, Thermo Scientific, San Jose, Calif.
o. WinNonLin Pro, version 5.0.1, Pharsight, Cary, NC.
AJVR, Vol 71, No. 7, July 2010 821
09-06-0215r.indd 821
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