Handbook of Clinical Neurology, Vol.

119 (3rd series)

Neurologic Aspects of Systemic Disease Part I
Jose Biller and Jose M. Ferro, Editors
© 2014 Elsevier B.V. All rights reserved

Chapter 27

Use of antiepileptic drugs in hepatic and renal disease

JORGE J. ASCONAPÉ*
Department of Neurology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL, USA

INTRODUCTION Dialysis can further modify these pharmacokinetic

parameters or result in significant removal of the drug.
The occurrence of seizures in the presence of hepatic or
The dialyzability of a drug depends on several factors,
liver disease is not uncommon in clinical practice. Patients
including molecular weight, protein binding, plasma
with epilepsy are not immune to hepatic or renal disease,
concentration, blood flow, hematocrit, and the effi-
and patients with hepatic or renal failure often suffer
ciency of the dialyzer (Israni et al., 2006). Dose supple-
from acute reactive seizures secondary to metabolic or
mentation at the time of dialysis may be required for
electrolyte disturbances or other associated comorbidities.
highly extractable drugs.
Since the liver and kidney are the main organs involved in
Most antiepileptic drugs undergo some degree of
the elimination of most drugs (Table 27.1), their dysfunc-
biotransformation, which occurs almost exclusively in
tion can have important effects on the disposition of the
the microsomal mixed-function oxidase system. Phase I
antiepileptic drugs. A clear understanding of these phar-
reactions, including oxidation, reduction, or hydroxyl-
macokinetic effects is essential when selecting a drug in
ation, transform the lipophilic active drug into a more
patients with liver or renal disease. In the past two
polar, water-soluble metabolite. These metabolites may
decades, with the introduction of newer antiepileptic
undergo a subsequent phase II reaction by combining with
drugs, many with a better pharmacokinetic profile than
endogenous substrates, such as glucuronic acid, to form a
the classic drugs, the number of options available has
more polar compound. Liver disease can delay the elimi-
greatly expanded, facilitating the management of these
nation rate of the drug from plasma, leading to a prolon-
patients. The classic antiepileptic drugs, such as phenyt-
gation of the half-life and drug accumulation (Ahmed and
oin, carbamazepine, or valproate, are mostly eliminated
Siddiqui, 2006). Drug metabolism is influenced by hepatic
via hepatic metabolism, therefore, their use is problematic
blood flow, protein binding, degree of drug uptake by the
in patients with liver failure. With most of the newer anti-
hepatocyte, functional capacity of the hepatocyte, and
epileptic drugs, the kidneys play a much more important
patency of the hepatobiliary system. Because of the large
role in their elimination, offering a better alternative to
hepatic reserve capacity, liver disease must be extensive
patients with liver disease.
before drug metabolism is impaired.
Renal disease can prolong the elimination of the par-
ent drug or an active metabolite and lead to accumula-
tion and clinical toxicity (Asconapé and Penry, 1982). INDIVIDUAL ANTIEPILEPTIC DRUGS
Lower doses and longer interdose intervals may be nec-
Phenytoin
essary in these cases. Renal disease can also affect the
protein binding, distribution and metabolism of a drug. Phenytoin (5,5-diphenylhydantoin) is a weak organic acid
The protein binding of anionic acidic drugs, such as phe- with a pKa of 8.31. It is completely but irregularly
nytoin and valproate, can be reduced significantly by absorbed after oral administration, with peak serum
renal failure causing difficulties in the interpretation levels reached 4–8 hours following a single oral dose.
of total serum concentrations commonly used in clinical Phenytoin is 90% protein bound, almost exclusively to
practice. Measuring the free fraction concentrations is the albumin, with a 10% free fraction responsible for
more accurate in these cases. the pharmacologic action. The elimination of phenytoin

*Correspondence to: Jorge J. Asconapé, M.D., Department of Neurology, Maguire Center, Suite 2700, Loyola University Chicago,
2160 South First Avenue, Maywood, Illinois 60153, USA. Tel: þ1-708-216-3407, Fax: þ1-708-216-8028, E-mail: jasconape@lumc.edu
418 J.J. ASCONAPÉ
Table 27.1
Elimination of antiepileptic drugs

Hepatic metabolism Renal elimination

(proportion excreted
Drug CYP 450 Isoenzyme UDPGT Other pathways unchanged by the kidney)

Carbamazepine 85% Major: CYP 3A4 15% Negligible <1%

Minor: CYP 1A2/2C8
Diazepam 80% CYP 2C19, CYP 3A4 Negligible Negligible <5%
Eslicarbazepine – 41% Negligible 52%
Ethosuximide 65% Major: CYP 3A4 Negligible Negligible 20–25%
Minor: CYP 2B/2C/2E1
Ezogabine/ None – Extensive Acetylation 36%
retigabine
Felbamate <20% CYP 3A4/2E1 10% 25% esterase 45–55%
Fosphenytoin – – Negligible Metabolized to phenytoin <5%
by phosphatases (blood,
liver, kidney)
Gabapentin None – None None >95%
Lacosamide 50% CYP 2C19 None None 40%
Lamotrigine 1A4 Negligible 70–80% Negligible 10%
Levetiracetam Negligible – None 24% hydrolysis 66%
(extrahepatic)
Lorazepam Negligible 90% Negligible <1%
Midazolam 85% CYP 3A4 Negligible Negligible <1%
Oxcarbazepine* 4% 49% Cytosol arylketone 27%
reductase (parent drug)
Phenobarbital 20–35% CYP 2C9/19 None Negligible 20–25%
Phenytoin 90% Major: CYP 2C9 Negligible Negligible <5%
Minor: CYP 2C19
Pregabalin Negligible – Negligible Negligible >95%
Primidone 40–60% ? Some Negligible 40–60%
Propofol Negligible CYP 1A9 50% Sulfation <1%
Rufinamide None – 11% 70% carboxylesterase- <2%
mediated hydrolysis
Tiagabine 90% CYP 3A4 Negligible Negligible <2%
Topiramate 20–40% Unknown Unknown 60–70%
Valproate <20% CYP 1A3, 2B7 30–50% 40% b-oxidation <3%
(mitochondrial hepatic
metabolism)
Vigabatrin Negligible – None Negligible 80–95%
Zonisamide 50% CYP 3A4 None 15% N-acetylation 35%
(hepatic)

*Refers to the monohydroxy derivative (MHD).

CYP, cytochrome P450; UDPGT, uridinine diphosphate-glucuronosyltransferase.

is almost exclusively by hepatic biotransformation,
with < 5% of a given dose eliminated unchanged in
the urine (Butler, 1957). Phenytoin is metabolized by
the cytochrome P450 system, with the CYP2C9 being
the primary isoenzyme, and CYP2C19 playing a more
important role when phenytoin serum concentration
exceeds 18 mg/mL. The main metabolic pathway of phe-
nytoin is parahydroxylation, resulting in the formation
of 5-(p-hydroxyphenyl)-5-phenylhydantoin (pHPPH),
an inactive metabolite (Bochner et al., 1973). Approxi-
mately 96% of plasma pHPPH is conjugated to glucuro-
nides, with 60–80% of a single dose of PHT excreted as
pHPPH glucuronide. Phenytoin undergoes glomerular
filtration and subsequent tubular reabsorption; pHPPH,
a more polar metabolite, is handled almost exclusively by
glomerular filtration (Borga et al., 1979). One of the
major limitations with the clinical use of phenytoin is
its capacity of saturating the metabolic pathways at
 USE OF ANTIEPILEPTIC DRUGS IN HEPATIC AND RENAL DISEASE
serum concentration within the therapeutic range of 10–
20 mg/mL. The elimination of phenytoin follows a dose-
dependent, nonlinear kinetics (Michaelis–Menten)
model, which can result in a disproportionate increase
in the serum concentration with relatively small incre-
ments in the dose.
Plasma of patients with chronic renal failure has a
decreased binding capacity for phenytoin (Odar-
Cederl€ of et al., 1970; Reidenberg et al., 1971; Hooper
et al., 1974; Reidenberg and Drayer, 1978; Vanholder
et al., 1988). The percentage of unbound fraction can
be as high as 30%, and the degree of impairment of bind-
ing capacity correlates with the level of blood urea nitro-
gen, serum creatinine, creatinine clearance, and the
degree of physical disability (Reidenberg et al., 1971;
Olsen et al., 1975). In a study of patients with acute renal A single daily dose of phenytoin, therefore, should be
failure from different etiologies, the free fraction of
phenytoin was found to range from 14% to 45%; how-
ever, no clear correlation with the above-mentioned
markers of renal failure was found (Tiula et al., 1987).
In this study, the serum albumin concentration was the
best predictor of the free phenytoin concentrations
(Tiula et al., 1987). The mechanism of the decreased
binding capacity in uremia is not entirely clear, with
possible explanations including: accumulation of com-
petitive or noncompetitive inhibitors in the serum, an
alteration in the structure or conformation of the albu-
min molecule, and hypoalbuminemia. Hippuric acid, cer-
tain organic acids, and peptides include ligands that have
been shown to displace phenytoin from the albumin mol-
ecule in renal failure (Depner and Gulyassy, 1980;
Kinniburgh and Boyd, 1981; Gulyassy et al., 1983).
Hypoalbuminemic patients have been shown to have a
greater unbound fraction of phenytoin and an increased
risk of clinical toxicity (Boston Collaborative Drug
Surveillance Program, 1973); a significant correlation
between albumin levels and the degree of impairment
of the binding capacity has been demonstrated in uremia
(Hooper et al., 1974; Reidenberg and Drayer, 1978) and in
the nephrotic syndrome with normal renal function
(Gugler et al., 1975; Gugler and Azarnoff, 1976). How-
ever, decreased plasma protein binding of PHT is seen
in uremic patients with normal albumin levels, indicating
that hypoalbuminemia is probably only a contributing
factor.
The decreased phenytoin binding capacity results in
an increase in the apparent volume of distribution (Vd)
of the drug, with lower total serum concentrations for
a given dose (Odar-Cederl€ of and Borga, 1974; Van
Peer et al., 1981). The unbound fraction concentration,
however, remains essentially unchanged, and the ratio
of free to total drug is increased. Therefore, caution
should be used when interpreting total serum phenytoin
concentration in uremic patients, since, for a free
419
fraction between 1 and 2 mg/mL, the usual therapeutic
range of 10–20 mg/mL will be reduced to about
5–10 mg/mL in patients with end-stage renal disease.
Equations used to normalize total phenytoin concentra-
tions in the presence of renal failure or hypoalbumine-
mia have been found to be inaccurate in a significant
proportion of patients, resulting in either over- or under-
prediction of the normalized phenytoin concentrations
(Mauro et al., 1989). The use of free phenytoin levels
in this setting is highly recommended. Salivary
levels have also been proven to adequate for monitoring
purposes (McAuliffe et al., 1977).
The half-life of phenytoin is decreased to approxi-
mately 8 hours in patients with chronic renal failure
(Letter et al., 1971; Odar-Cederl€of and Borga, 1974).
discouraged in uremic patients. The elimination of phe-
nytoin is essentially liver-dependent, with < 5% of the
drug eliminated unchanged in the urine. Thus, signifi-
cant accumulation of phenytoin even in the presence
of end-stage renal disease does not occur, and dose
adjustments are not necessary. The main metabolite of
phenytoin, pHPPH glucuronide, undergoes renal excre-
tion and significantly accumulates in renal failure,
whereas the unconjugated pHPPH does not accumulate
(Letter et al., 1971; Borga et al., 1979). However, pHPPH
is an inactive metabolite, and its accumulation appears to
be of no clinical consequence.
Given its high protein binding and poor water solubil-
ity, phenytoin is poorly dialyzable, and in most cases
supplemental doses after dialysis are not necessary.
An early study indicated that only 2–4% of an intrave-
nous dose was recovered in the dialysate of seven uremic
patients, with the dialyzer extracting about 4.5% of the
phenytoin presented to it (Martin et al., 1977). However,
with the use of newer high-efficiency dialyzers, signifi-
cant drops in phenytoin serum concentrations, resulting
in breakthrough seizures, have been reported (Frenchie
and Bastani, 1998). Hemodialysis can affect the protein
binding of phenytoin, but reports have been conflicting.
A decrease in the binding capacity of phenytoin follow-
ing hemodialysis has been observed, probably due to the
displacement of phenytoin from the albumin molecule
by elevated levels of nonesterified fatty acids resulting
from the use of heparin (Dromgoole, 1973; Adler
et al., 1975). However, an increase in the binding capacity
of phenytoin during dialysis has also been reported
(Steele et al., 1979).
Plasma from patients with liver failure has a reduced
binding capacity for phenytoin (Reidenberg and
Affrime, 1973; Hooper et al., 1974; Olsen et al., 1975).
Although the exact mechanism remains unclear, the
degree of binding decrease has a good correlation with
albumin concentration in plasma (Lunde et al., 1970;
420 J.J. ASCONAPÉ
Rane et al., 1971; Hooper et al., 1974; Blaschke et al.,
1975) and also with levels of total plasma bilirubin
(Rane et al., 1971). The correlation was even higher when
both variables were considered together (Lunde et al.,
1970; Rane et al., 1971). The degree of impairment of
the phenytoin-binding capacity, however, is not a severe
as that observed in renal disease, and is usually of no
clinical significance. Adjustments in the therapeutic
range of the total phenytoin serum concentration are
usually not needed as suggested by studies in alcoholic
cirrhosis (Affrime and Reidenberg, 1975) and acute viral
hepatitis (Blaschke et al., 1975). In hyperbilirubinemic
neonates, however, the reduction in phenytoin binding
may be substantial. In this situation, if the dose of phe-
nytoin is estimated on the basis of bodyweight, a free
fraction within the toxic range can be achieved (Rane
et al., 1971).
The effects of liver failure on the elimination of phe-
nytoin have not been adequately studied. Kutt et al.
reported four patients with liver disease receiving phe-
nytoin and phenobarbital who developed clinical toxicity
as hepatic impairment increased (Kutt et al., 1964).
Accumulation of the parent drugs was observed, as well
as reduced excretion of the corresponding metabolites in
the urine. Blaschke et al. found no changes in the half-
life or plasma clearance of phenytoin in patients with
acute viral hepatitis (Blaschke et al., 1975).
In the presence of renal failure, quantitative adjust-
ments in the dose of phenytoin are usually not necessary.
Total phenytoin serum concentrations need to be inter-
preted with caution given the increase in the free to total
phenytoin concentration ratio in severe renal failure.
Free phenytoin levels are highly recommended for mon-
itoring purposes. Removal of phenytoin during dialysis
is negligible and supplemental dosing after dialysis is
usually not necessary.
In the presence of severe hepatic disease the clearance
of phenytoin can be reduced resulting in clinical intoxi-
cation. This situation may be aggravated by the nonlinear
kinetics of phenytoin. Since no simple markers of liver
function exist, phenytoin should be used with caution
in liver disease. Frequent serum level determinations
are recommended.
Valproic acid
Valproic acid (2-propyl-pentanoic acid; dipropyl-acetic
acid; 2-propyl-valeric acid) is a simple, eight-carbon,
branched-chain carboxylic acid with a pKa of 4.9. Well
absorbed after oral administration, peak levels are
observed within 0.5–4 hours. Of the total plasma concen-
tration, 90% is protein bound, with a resulting small vol-
ume of distribution. The protein binding of valproic acid
is nonlinear, progressively decreasing at higher plasma
concentrations. Elimination half-life is between 10 and
16 hours in monotherapy, but is reduced to 6–8 hours with
the concomitant use of enzyme-inducing drugs.
Hepatic metabolism is the main route of elimination, with
only 1–3% of a given dose excreted unchanged in the
urine. Metabolic pathways include glucuronidation,
b-oxidation, and !-oxidation. Some of the metabolites
of valproic acid are biologically active. Valproic acid
has no enzyme-inducing properties, but inhibits the
metabolism of lamotrigine, phenobarbital, and the 10-11-
carbamazepine epoxide. Total plasma concentration
between 50 and 100 mg/mL or free plasma concentrations
of 5–10 mg/mL are considered optimal in clinical practice.
The effects of renal disease on the pharmacokinetics
of valproic acid are very similar to the ones described for
phenytoin, reflecting the fact that both drugs are weak
organic acids with very high (90%) protein binding under
usual clinical conditions. The plasma protein binding is
decreased in patients with uremia. The degree of impair-
ment was found to correlate well with serum creatinine,
blood urea nitrogen, uric acid concentrations, and
creatinine clearance, and was independent of the albu-
min and total protein concentrations in plasma. The pres-
ence of hypoalbuminemia, acting as a contributing
factor, further impairs the plasma binding capacity,
and may be an important factor in patients with the
nephrotic syndrome. Protein binding of valproic acid
was found to be further reduced during hemodialysis
(Bruni et al., 1980). As is the case with phenytoin, the
decrease in the protein binding of valproic acid results
in an increased apparent volume of distribution, with
lower steady-state total plasma concentrations for a
given dose, while the free levels remain unchanged.
Accumulation of valproic acid is unlikely in the presence
of renal failure since its elimination is almost exclusively
by hepatic biotransformation (Kandrotas et al., 1990).
However, the possibility of accumulation of active
metabolites is a potential concern that has not been prop-
erly studied. A slight reduction (about 27%) in the
unbound clearance of valproic acid has been observed
in patients with severe renal failure (creatinine clearan-
ce < 10 mL/min) (Kandrotas et al., 1990). Approximately
20% of a dose of valproic acid is extracted by
conventional, low-efficiency hemodialysis, resulting in
slight drops in the valproic acid serum levels. Plasma
levels, however, recover a few hours after dialysis, with
no significant differences in the half-life of valproic acid
between dialysis and nondialysis days (Kandrotas et al.,
1990; Dasgupta et al., 1996). Dose supplementation
after hemodialysis is generally not necessary. With the
use of newer, high-flux dialyzers, however, the extrac-
tion is significantly increased, and dose supplementation
may be required in some cases (Kane et al., 2000;
Kielstein et al., 2003).
 USE OF ANTIEPILEPTIC DRUGS IN HEPATIC AND RENAL DISEASE
The disposition of valproic acid was studied in
patients with alcoholic cirrhosis and acute viral hepatitis
(Klotz et al., 1978). Plasma protein binding of valproic
acid was reduced in patients with cirrhosis (70  11.3%)
and acute hepatitis (78  14.1%) compared to controls
(88  5.2%). The apparent volume of distribution was
increased and lower peak plasma concentrations were
observed in both groups compared to controls. Plasma
elimination half-life was prolonged in patients with cir-
rhosis (18.9  5.1 h) and acute hepatitis (17.0  3.7 h) ver-
sus controls (12.2  3.7 h). The total plasma clearance of
valproic acid, however, was not impaired, likely the
result of increased penetration of valproic acid into
the cells as a result of the decreased protein-binding
capacity. When plasma clearance for free valproic acid
was calculated, it was found to be significantly reduced
only in patients with cirrhosis, indicating the possibility
of impaired biotransformation. Finally, these authors
found no abnormalities in the pattern of excretion of
valproate metabolites in the urine. Patients in this study
were suspected to have mild liver failure based on labo-
ratory parameters. Other authors have found a signifi-
cant increase in the plasma half-life and a reduction in
the clearance of total drug in a group of patients in
the acute stage of viral hepatitis (Gugler and von
Unruh, 1980).
Phenobarbital
Phenobarbital (5-ethyl-5-phenylbarbituric acid) is a weak
acid with a molecular weight of 232.23 and low water sol-
ubility. It is well absorbed after oral administration, and
45–60% of the drug is bound to plasma proteins. Metab-
olism of phenobarbital is mostly by hydroxylation
and subsequent glucuronidation (Tang et al., 1977).
Main metabolites include parahydroxyphenobarbital
and N-hydroxyphenobarbital, both biologically inactive.
Between 9% and 33% of phenobarbital is excreted
unchanged in the urine, with the renal clearance affected
by urine pH and flow. Elimination half-life ranges from
53 to 140 hours.
The half-life of phenobarbital has been reported to be
unchanged in the presence of renal insufficiency
(Reidenberg and Affrime, 1973). Some drug accumula-
tion, however, is to be expected in the presence of severe
renal failure. Hemodialysis removes 20–50% of the drug
during a 4 hour period, depending on the type of dialyzer
and blood flow rate. Low-efficiency, low-blood flow
dialyzers show a clearance of about 20% (Zawada
et al., 1983), whereas high-efficiency, high-blood flow
dialysis increases the clearance to about 50% (Palmer,
2000). Peritoneal dialysis has been shown to clear about
35–40% of the daily dose of phenobarbital over a 24 hour
period (Marquardt et al., 1992; Porto et al., 1997). There
421
are no clear recommendations on the supplemental dos-
ing of phenobarbital following hemo- or peritoneal dial-
ysis. Pre- and postdialysis phenobarbital serum level
determinations can help in individualizing the dosing
requirements.
The disposition of phenobarbital has not been ade-
quately studied in patients with hepatic disease. Since
a significant proportion of phenobarbital is eliminated
by direct renal excretion, the drug has a relatively low
risk of accumulation in liver disease. In a single-dose
study, the half-life of phenobarbital was significantly
prolonged in patients with liver cirrhosis (130  15 h)
when compared to a control group (86  3 h) (Alvin
et al., 1975). In the same study, in a group of patients with
acute viral hepatitis, the prolongation of the half-life
observed did not reach statistical significance but a large
intersubject variability was found. Drug accumulation
was reported in two patients on chronic phenobarbital
therapy with chronic cirrhosis (Kutt et al., 1964). Since
biliary excretion of phenobarbital is insignificant in
humans, dose adjustment is not necessary in patients
with cholestasis (Alvin et al., 1975).
Primidone
Primidone (2-deoxyphenobarbital) is well absorbed after
oral administration, with about 25% of the drug bound
to plasma proteins. It is metabolized in the liver to pheny-
lethylmalonamide (PEMA) and phenobarbital, both bio-
logically active. Half-life of primidone is 3–12 hours,
that of PEMA 29–36 hours. Approximately 15–40% of
primidone is excreted unchanged in the urine. Renal insuf-
ficiency can lead to accumulation of primidone, and
dose adjustments may be necessary, but no clear guide-
lines are available. The use of primidone in renal failure
is further complicated by the fact that the active metabo-
lites, PEMA and phenobarbital, may accumulate dispro-
portionally to the primidone. In the case reported by
Heipertz et al., serum levels of PEMA and primidone were
proportionally higher than those of phenobarbital, and
were thought to be responsible for the signs of clinical
intoxication (Heipertz et al., 1979). In the case reported
by Stern, very high levels of PEMA correlated with clinical
signs of toxicity whereas phenobarbital levels were only
slightly elevated and primidone levels were within the
therapeutic range (Stern, 1977). Serum levels of all three
compounds may be necessary to properly assess the pos-
sibility of primidone intoxication in uremic patients.
Hemodialysis removes 20–50% of a primidone dose.
A 30% dose supplementation has been recommended
prior to hemodialysis (Lee et al., 1982; Streete et al., 1990).
There are no studies of the effects of liver disease on
the pharmacokinetics of primidone.
422 J.J. ASCONAPÉ
Carbamazepine, oxcarbazepine, hepatic failure. Close monitoring of carbamazepine
and eslicarbazepine serum concentration is recommended in this situation.
Carbamazepine, oxcarbazepine, and eslicarbazepine
OXCARBAZEPINE
acetate belong to the dibenzazepine family and are
closely related structurally. In terms of their elimination, Oxcarbazepine (10,11-dihydro-10-oxo-5H-dibenz(b,f )
however, these drugs have important differences. Car- azepine-5-carboxamide) is a keto-analogue of carbamaz-
bamazepine is eliminated almost exclusively by hepatic epine. Oxcarbazepine, a prodrug, undergoes rapid pre-
metabolism whereas oxcarbazepine and eslicarbazepine systemic 10-keto reduction by the cytosol arylketone
are prodrugs whose main active metabolite is eliminated reductase to the 10-monohydroxy derivative (MHD),
mostly by renal excretion. the pharmacologically active compound. MHD is pri-
marily converted to a glucuronide conjugate, with a
small amount further hydroxylated to a dihydroxy deriv-
CARBAMAZEPINE ative (DHD), an inactive metabolite. The two major reac-
tions controlling the disposition of oxcarbazepine and
Carbamazepine (5-H-dibenz[b,f ]azepine-5-carboxamide)
MHD (reduction and glucuronidation) are nonoxidative.
has a molecular weight of 236.3 and very poor water sol-
As a result, oxcarbazepine has a much lower propensity
ubility. Its bioavailability is approximately 80% after oral
to induce P450 oxidative enzymes than carbamazepine,
administration, with peak plasma levels reached in 4–12
and a more favorable drug–drug interaction potential.
hours. About 70–80% of the drug in plasma is protein
Furthermore, the reduction and glucuronidation of
bound, mostly to globulins (Hooper et al., 1975). Elimina-
drugs are not affected as much by hepatic impairment
tion of carbamazepine is almost exclusively by hepatic
as oxidative metabolism. Approximately 38% of MHD
biotransformation via the CYP3A4, with < 1% of the
is bound to plasma proteins. The half-life of MHD is
drug eliminated by direct renal excretion. Epoxidation
8–10 hours (Lloyd et al., 1994).
and hydroxylation are the main metabolic pathways.
In the study by Rouan et al. (1994), there was a linear
The 10-11-carbamazepine epoxide, an active metabolite,
correlation between the creatinine clearance and the
undergoes further hydroxylation with < 2% eliminated
clearance of the MHD and its conjugated metabolites.
as such in the urine. Carbamazepine is a potent inducer
In subjects with severe renal insufficiency (creatinine
of the CYP450 system and is capable of inducing its
clearance < 10 mL/min), the elimination half-life of the
own metabolism as well as the metabolism of other com-
MHD was prolonged to approximately 19 hours, with a
monly used drugs such as oral contraceptives, warfarin,
corresponding 2–2.5 times increase in the mean area
digoxin, ciclosporin, and tacrolimus.
under the curve in the plasma concentration-time curves
Renal disease does not affect the protein binding of
of oxcarbazepine and the MHD compared to healthy con-
carbamazepine (Hooper et al., 1975). Since the drug and
trols (Rouan et al., 1994). The authors concluded that, in
its active metabolite, the 10-11-carbamazepine epoxide,
patients with mild renal failure (creatinine clearan-
are eliminated almost exclusively by biotransformation,
ce > 30 mL/min), no dose adjustments are necessary. In
no significant accumulation is observed even in the pres-
patients with moderate renal impairment (creatinine clear-
ence of severe renal failure, and dose adjustments are
ance 10–30 mL/min), a 50% reduction in the target dose
typically not necessary. Carbamazepine has relatively
of oxcarbazepine is recommended. In patients with end-
low extractability during dialysis and routine dose sup-
stage renal disease (creatinine clearance < 10 mL/min),
plementation is usually not recommended (Lee et al.,
no specific dosage recommendations were given, but an
1980). Hemodialysis, however, has been shown to be
even more conservative dosing is warranted. There are
effective in the management of carbamazepine intoxica-
no data on the disposition of MHD during dialysis.
tion, with 22–50% reductions in the serum concentra-
The pharmacokinetics of oxcarbazepine and MHD
tions of the drug reported, so caution is recommended
are not affected by mild or moderate hepatic dysfunc-
(Schuerer et al., 2000; Kielstein et al., 2002; Tapolyai
tion (Child–Pugh Hepatic Impairment Classification
et al., 2002; Chetty et al., 2003).
types A and B, respectively), and dose adjustments are
In the presence of mild liver insufficiency, the protein
usually not necessary (Asconapé and D’Souza, 2004).
binding of carbamazepine was found to be significantly
Patients with severe hepatic failure (Child–Pugh C) have
decreased when compared to normal controls (Hooper
not been studied adequately.
et al., 1975). The decrease, however, was slight, and
did not correlate with any laboratory parameters. The
ESLICARBAZEPINE ACETATE
disposition of carbamazepine has not been adequately
studied in subjects with liver disease, but significant Eslicarbazepine acetate, (S)-(-)-10-acetoxy-10,11-dihy-
accumulation is to be expected in the presence of severe dro-5H-dibenzazepine-5-carboxamide, differs from
 USE OF ANTIEPILEPTIC DRUGS IN HEPATIC AND RENAL DISEASE
oxcarbazepine in that it is metabolized almost
exclusively to the (S)-enantiomer (designated as S-licar-
bazepine) with less than a 5% chiral conversion to the
(R)-enantiomer, whereas oxcarbazepine is converted to
both (S)- and (R)- enantiomers in about a 4–5:1 proportion
(Hainzl et al., 2001). Eslicarbazepine acetate is an oral
prodrug that is rapidly and extensively metabolized
by the liver via a hydrolytic first-pass metabolism into
S-licarbazepine, the biologically active drug. Eslicarbaze-
pine acetate is well absorbed after oral administration
with a bioavailability about 16% higher than that observed
after an equivalent dose of oxcarbazepine (Almeida and
Soares-da-Silva, 2003; Almeida et al., 2005). Peak plasma
concentrations (tmax) are observed in 1–4 hours. Plasma
protein binding is low (<40%). Eslicarbazepine acetate
has a half-life of 13–20 hours, and displays linear kinetics
at doses of 400–1200 mg/day (Almeida and Soares-
da-Silva, 2007). It is eliminated predominantly by renal
excretion, with 91% of the drug recovered in urine
following an oral dose (Almeida and Soares-da-Silva,
2007). Eslicarbazepine acetate is rapidly converted by
hydrolysis to eslicarbazepine. In healthy volunteers, of
the dose recovered in the urine, 52% corresponded to esli-
carbazepine and 41% to eslicarbazepine-glucuronide
(Maia et al., 2008). Eslicarbazepine has a clearance rate
of 20–30 mL/min, with 20% of the dose recovered in
the urine after 12 hours and 40% within 24 hours
(Almeida and Soares-da-Silva, 2007).
In subjects with mild renal impairment eslicarbaze-
pine demonstrated slightly slower elimination rates com-
pared to normal volunteers (10.2 mL/min versus 17.
3 mL/min, respectively) (Maia et al., 2008). As expected,
patients with moderate or severe renal impairment
showed much lower clearance rates (3.7 mL/min and
1.5 mL/min, respectively) (Maia et al., 2008). Dose
adjustments are generally required in the presence of
moderate or severe renal impairment (creatinine clearan-
ce < 50 mL/min). There is no information on the effects
of hemodialysis on the serum concentrations of eslicar-
bazepine, but significant extraction is to be expected and
dose supplementation may be necessary.
The clearance of eslicarbazepine was not signifi-
cantly affected in the presence of mild or moderate
hepatic failure, and dose adjustments are usually not
necessary in this setting (Almeida et al., 2008). The phar-
macokinetics of eslicarbazepine has not been studied in
patients with severe hepatic impairment.
Lamotrigine
Lamotrigine (3,5-diamino-6-(2,3-dicholorophenyl)-1,2,4-
triazine) is a phenyyltriazine with a molecular weight
of 256.09 and poor solubility in water (Dickins and
Chen, 2002). Lamotrigine is well absorbed after oral
423
administration, has an apparent volume of distribution
after oral administration of 1.14, and is about 55% pro-
tein bound. The elimination half-life is 24–35 hours.
However, when used concomitantly with enzyme-
inducing drugs, the half-life is reduced to approximately
14 hours, and, in the presence of valproate, increased to
about 70 hours. Lamotrigine is metabolized into several
inactive compounds, of which the aromatic N-2 glucuro-
nide is the most important. In healthy volunteers, 71% of
the orally administered lamotrigine was recovered as N-2
glucuronide, and 10% as unchanged lamotrigine
(Dickins and Chen, 2002).
Lamotrigine has not been adequately studied in
patients with renal disease. In a small study, the renal
clearance of lamotrigine was found to be decreased in
patients with chronic renal failure compared to healthy
controls. This difference was not clinically relevant since
the renal clearance of lamotrigine has a minor role in the
overall elimination of the drug (Wootton et al., 1997). In
this study, the mean half-life of lamotrigine was 36 hours,
prolonged compared to 28 hours in the healthy volunteers,
probably reflecting a larger volume of distribution in the
patients (Dickins and Chen, 2002). In another study, fol-
lowing the administration of a single 100 mg dose of
lamotrigine in patients with renal failure, the mean lamo-
trigine clearance was reduced at 27.9 mL/min and the
half-life prolonged at 50.7 hours in patients with renal fail-
ure not undergoing dialysis compared to the correspond-
ing values of healthy controls at 38.5 mL/min and 25.7
hours, respectively (Fillastre et al., 1993). In dialyzed
patients, mean half-life was 59.6 hours off dialysis and
15.5 hours during dialysis (Fillastre et al., 1993). On aver-
age, 17% of the lamotrigine body pool was removed for
every 4 hour dialysis session (Fillastre et al., 1993). In view
of these findings, daily dosing of lamotrigine may need to
be reduced in patients with moderate to severe renal fail-
ure. Posthemodialysis supplementation is probably not
necessary in most patients. Clearance with peritoneal dial-
ysis has not been studied.
The pharmacokinetics of lamotrigine has not been
well studied in patients with liver failure. In healthy sub-
jects with unconjugated hyperbilirubinemia (Gilbert syn-
drome), characterized by a deficiency of the enzyme
bilirubin uridine diphosphate glucuronyl transferase
(UGT), which is involved in the metabolism of lamotri-
gine, the clearance of lamotrigine was 32% lower and
its half-life 37% longer than in healthy controls
(Posner et al., 1989). These differences, however, were
considered unlikely to be of clinical significance.
Levetiracetam
Levetiracetam, (S-a-ethyl-2-oxo-1-pyrrolidine acet-
amide), a racemically pure ethyl analog of piracetam,
424 J.J. ASCONAPÉ
is structurally unrelated to other antiepileptic drugs
(Patsalos, 2004). It is rapidly and almost completely
absorbed (>95%) after oral administration with a Tmax
of 1.3 hours. It is not protein bound (<10%), has a vol-
ume of distribution of 0.5–0.7 L/kg, and a half-life of
6–8 hours (Patsalos, 2004). Levetiracetam is mostly elim-
inated through the kidneys. Approximately 95% of the
administered dose was recovered in the urine in healthy
volunteers. The total body clearance is approximately
0.96 mL/min/kg, and the renal clearance 0.6 mL/min/
kg in adults, 0.8 mL/min/kg in children, and 0.5 mL/
min/kg in the elderly (Patsalos, 2004). Levetiracetam
undergoes glomerular filtration and approximately
66% of the dose is excreted unchanged in the urine.
The remainder is metabolized, through enzymatic hydro-
lysis of the acetamide group (<25% of the administered
dose), to an inactive carboxylic acid metabolite. Other
minor inactive metabolites, accounting for < 3% of
the administered dose, have been identified as well
(Radtke, 2001). The metabolism of levetiracetam is inde-
pendent of the cytochrome P450 system.
The elimination of levetiracetam is significantly
delayed in the presence of renal failure, with the clear-
ance of the drug being directly proportional to the creat-
inine clearance (French, 2001). The half-life of the drug
ranges from approximately 10 hours in the presence of
mild renal failure to 24 hours in severe renal failure
(French, 2001). Therefore, dose adjustments are usually
necessary depending on the severity of the renal failure
(Table 27.2). Levetiracetam is efficiently removed by
hemodialysis, with approximately 50% of the drug pool
removed by 4 hours of dialysis. A supplemental dose of
250–500 mg per 4 hours of dialysis is recommended by
the manufacturer.
Liver failure does not affect the elimination of levetir-
acetam significantly. A single-dose (1000 mg) study in
male subjects with varying degrees of hepatic failure has
been conducted (French, 2001). In patients with mild or
moderate hepatic failure (Child–Pugh class A and B
respectively), no significant changes in the pharmacokinet-
ics of the drug were found. In patients with severe hepatic
failure (Child–Pugh class C), clearance was reduced by
46% and the plasma concentrations were increased com-
pared to healthy controls. However, these patients also
had renal failure, which could account for the pharmaco-
kinetic changes observed. In general, dose adjustments are
not necessary in patients with hepatic disease.
Topiramate
Topiramate (2,3:4,5-bis-O-(1-methylethylidene)-b-D-
fructopyranose sulfamate), is a sulfamate-substituted
derivative of D-fructose. It is minimally bound to serum
proteins (15%) and has a half-life of approximately 21
hours. Topiramate is not extensively metabolized. In
healthy volunteers, about 20% of the administered
dose is metabolized; however, about 50% of the drug
is metabolized with the concomitant use of enzyme-
inducing antiepileptic drugs (Britzi et al., 2005).
Serum concentrations of the drug were 40–50% lower
in the presence of enzyme inducers. No active
metabolites have been identified in humans. The drug
is eliminated predominantly by the kidney, with
50–80% of the drug recovered unchanged in the urine.
Oral plasma clearance (CL/F) is approximately
20–30 mL/min.
Clearance of topiramate was reduced by 42% in mod-
erate renal failure (creatinine clearance 30–69 mL/min/
1.73 m2) and by 54% in severe renal failure (creatinine
clearance < 30 mL/min/1.73 m2) compared to normal
renal function subjects (creatinine clearance > 70 mL/
min/1.73 m2). In subjects with renal failure (creatinine
clearance < 70 mL/min/1.73 m2), a 50% reduction of
the usual adult dose is recommended by the manufac-
turer. Topiramate is cleared by hemodialysis at a rate
that is 4–6 times greater than in individuals with normal
renal function.
The effects of hepatic disease on the disposition of
topiramate have not been adequately studied, but signif-
icant accumulation is not to be expected. A 30% increase
in the drug concentration has been reported in moderate
to severe hepatic failure, but the mechanism is unclear
(Ahmed and Siddiqui, 2006).
Lacosamide
Lacosamide, (R)-2-acetamido-N-benzyl-3-methoxypro-
prionamide, is a functionalized amino acid with a molec-
ular weight of 250.30. It is a white to light yellow
crystalline powder that is soluble in water and acetoni-
trile, and slightly soluble in ethanol.
Lacosamide is well absorbed after oral administration
with a bioavailabilty of approximately 100% (Hovinga,
2003). Food does not affect the rate or extent of the
absorption (Cawello et al., 2004). The volume of distri-
bution of lacosamide is 0.6 L/kg and the binding to
plasma proteins is < 15%. Lacosamide is primarily elim-
inated from the systemic circulation by renal excretion
and biotransformation. After oral or intravenous admin-
istration, 95% of the lacosamide is recovered in the urine
and < 0.5% in the feces. The major compounds found in
the urine include: unchanged lacosamide (approximately
40%), O-desmethyl metabolite (approximately 30%),
and a structurally unknown polar fraction (approxi-
mately 20%). The metabolites have no pharmacologic
activity. Metabolism of lacosamide is through the
CYP2C19. The half-life of lacosamide is approximately
13 hours.
 USE OF ANTIEPILEPTIC DRUGS IN HEPATIC AND RENAL DISEASE 425
Table 27.2
Dose adjustments for antiepileptic drugs in adult patients with renal failure

Total daily dose according to GFR

Drug 60–89 mL/min 30–59 mL/min 15–29 mL/min <15 mL/min

Carbamazepine 400–2400 mg No adjustment necessary No adjustment necessary No adjustment necessary

Eslicarbazepine 800–1200 mg Reduce dose by 50% Insufficient data, Insufficient data, use with
use with caution caution
Ethosuximide 500–1500 mg No adjustment Adjustment may be Adjustment may be
necessary necessary necessary
Ezogabine/ 600–1200 mg 300–600 mg (50% 300–600 mg 300–600 mg
retigabine reduction)
Felbamate 1200–3600 mg Reduce dose by 50% Insufficient data, Insufficient data, use
use with caution with caution
Gabapentin 900–3600 mg/ 400–1400 mg/day (BID) 200–700 mg/day (QD) 100–300 mg/day (QD)
day (BID or
TID)
Lacosamide 200–400 mg No adjustment necessary Maximum dose of Maximum dose of
300 mg/day for GFR 300 mg/day for GFR
<30 mL/min <30 mL/min
Lamotrigine 200–400 mg Insufficient data, use Insufficient data, use Insufficient data, use
with caution with caution with caution
Levetiracetam 500–1000 mg 250–750 mg BID 250–500 mg BID 250–500 mg BID
BID
Oxcarbazepine 300–600 mg 300–600 mg BID Reduce dose by 50% Insufficient data, use
BID with caution
Phenobarbital 60–240 mg Insufficient data, use Insufficient data, use Insufficient data, use with
with caution with caution caution. BID dosing
Phenytoin 200–600 mg No adjustment necessary No adjustment necessary No adjustment necessary
Pregabalin 150–600 mg/day 75–300 mg/day 25–150 mg/day (QD 25–75 mg/day (QD)
(BID or TID) (BID or TID) or BID)
Primidone 750–2000 mg Insufficient data, use Insufficient data, use Insufficient data, use
with caution with caution with caution
Rufinamide 800–3200 mg No adjustment necessary No adjustment necessary No adjustment necessary
Tiagabine 32–56 mg No adjustment necessary No adjustment necessary No adjustment necessary
Topiramate 100–200 mg 50–100 mg BID for 50–100 mg BID 50–100 mg BID
BID GFR <70 mL/min
Valproate 1000–4000 mg No adjustment necessary No adjustment necessary No adjustment necessary
Vigabatrin 1000–3000 mg 25% dose reduction for 50% dose reduction for 75% dose reduction for
GFR >50 to 80 mL/min GFR >30 to 50 mL/min GFR >10 to <30 mL/min
Zonisamide 200–400 mg 200–400 mg Insufficient data, use Insufficient data, use
with caution with caution

GFR, glomerular filtration rate; BID, twice daily; QD, once daily; QOD, once every other day.

The presence of renal disease may affect the elimina-
tion of lacosamide. The area under the curve was
increased by 25% in mild (creatinine clearance 30–
50 mL/min) and 60% in severe (creatinine clearan-
ce  30 mL/min) renal insufficiency when compared to
subjects with normal renal function (creatinine clearan-
ce > 80 mL/min). There were no changes observed in the
Cmax. Dose adjustments are usually not necessary in
the presence of mild and moderate renal insufficiency.
A 75% reduction in the total daily maintenance dose is
usually recommended in the presence of severe renal
failure. Four hours of hemodialysis reduces the area
under the curve of lacosamide by about 50%. Therefore,
a 25–50% dose supplementation is recommended
following dialysis.
In the presence of mild liver insufficiency (Child–
Pugh A) no dose adjustments are usually necessary. In
moderate hepatic failure (Child–Pugh B) a 50–60%
increase in the area under the curve was observed
compared to normal controls. A 75% reduction in the
426 J.J. ASCONAPÉ
usual maintenance dose has been recommended in
these patients. The elimination of lacosamide has not
been studied in patients with severe hepatic failure
(Child–Pugh C).
Tiagabine
Tiagabine ((-)-(R)-1-[4,4-bis(3methyl-2-thienyl)-3-
butenyl]-3-piperidinecarboxylic acid hydrochloride) is a
selective GABA reuptake inhibitor with modest efficacy
for partial seizures. Tiagabine has an absolute oral bioa-
vailabilty of 90% and a Tmax of about 1 hour (Adkins and
Noble, 1998). Its volume of distribution is 1 L/kg and
more than 95% of the drug is bound to plasma proteins
(Adkins and Noble, 1998). Tiagabine is extensively
metabolized by the liver (CYP3A4), with 63% of an oral
dose recovered in the feces and 25% in the urine. Only
1% of the drug is eliminated unchanged in the urine.
The plasma clearance is 12.8 L/h, but increases to
21.4 L/h when used in conjunction with enzyme-inducing
drugs. The elimination half-life is 5–8 hours, (2–3 hours
with enzymatic induction).
Impaired renal function and hemodialysis do not affect
the pharmacokinetics of tiagabine significantly and dose
adjustments are not necessary (Cato et al., 1998). In the
presence of hepatic disease, the clearance of tiagabine is
reduced proportionally to the severity of the liver failure
and significant accumulation of the drug may occur
(Lau et al., 1997). In subjects with normal hepatic function,
mild and moderate impairment, the elimination half-life
of tiagabine was 7, 12 and 16 hours, respectively (Lau
et al., 1997). The free tiagabine concentrations and the free
fraction were increased in the subjects with hepatic impair-
ment. No studies have been conducted in subjects with
severe hepatic failure. Tiagabine should be used cautiously
in subjects with hepatic failure.
Gabapentin and pregabalin
Gabapentin and pregabalin belong to a category of func-
tionalized amino acids designed to mimic the chemical
structure of g-aminobutyric acid (GABA), but lacking
any direct GABAergic effect.
Gabapentin (1-(aminomethyl)cyclohexane acetic acid)
is highly soluble in water and has a molecular weight of
171.34. It has saturable absorption after oral administra-
tion, with a progressive decrease in bioavailability as the
dose increases (McLean, 1994). It has almost no protein
binding and its volume of distribution standardized for
weight is 0.65–1.4 L/kg. Gabapentin undergoes no
hepatic metabolism. The absorbed drug is eliminated
entirely by the kidney unchanged. Its elimination rate
constant, plasma clearance and renal clearance are line-
arly related to the creatinine clearance (McLean, 1994).
The elimination half-life of gabapentin is 6–7 hours
and the clearance 100–300 mL/min.
Renal failure significantly alters the elimination of
gabapentin and adjustments in the maintenance dosage
are usually necessary (Table 27.2) (Blum et al., 1994).
After a single 400 mg dose of gabapentin in anuric sub-
jects, the mean gabapentin half-life was 132 hours in
between hemodialysis periods, increasing during hemo-
dialysis to a mean half-life of about 4 hours (Wong et al.,
1995). Due to its high water solubility, low molecular
weight and negligible protein binding, gabapentin is
effectively extracted by hemodialysis (Wong et al.,
1995). Plasma levels of gabapentin were reduced by
40% during the first 2 hours of hemodialysis compared
to predialysis levels (Wong et al., 1995). Approximately
50% of the body pool of gabapentin is expected to be
extracted during a 4 hour session of hemodialysis
(Wong et al., 1995). Therefore, a postdialysis dose sup-
plementation is usually necessary to maintain steady-
state plasma concentrations (Table 27.3).
Given its pharmacokinetic properties, the disposition
of gabapentin is unlikely to be affected by liver disease.
The pharmacokinetics of gabapentin, however, has not
been systematically studied in patients with liver failure.
Pregabalin (S-3-(aminomethyl)-5-methylhexanoic
acid) has a molecular weight of 159.23 and is readily sol-
uble in water. It is well absorbed (>90%) after oral
administration (Ben-Menachem, 2004). Pregabalin
undergoes negligible metabolism in humans and it does
not bind to plasma proteins. The elimination half-life of
pregabalin is about 6 hours in healthy subjects. Pregaba-
lin is eliminated from the systemic circulation by direct
renal excretion as unchanged drug, with a renal clear-
ance of 67.0–80.9 mL/min in healthy volunteers.
Pregabalin clearance is nearly proportional to the cre-
atinine clearance, with both the area under the curve and
the elimination half-life increasing with decreasing renal
function (Randinitis et al., 2003). Similarly to gabapen-
tin, pregabalin is effectively extracted by hemodialysis.
The plasma concentrations of pregabalin fall approxi-
mately 50% following 4 hours of hemodialysis. Dose
adjustments in the maintenance dose and postdialysis
dose supplementation are, therefore, necessary in the
presence of renal failure (Table 27.3).
Liver disease is not expected to affect the disposition
of pregabalin, and dose adjustments are not necessary.
Vigabatrin
Vigabatrin (4-amino-5-hexenoic acid; g-vinyl GABA) is
an irreversible, specific inhibitor of the GABA transam-
inase. It is readily soluble in water and the molecular
weight is 129.16. Vigabatrin is completely absorbed fol-
lowing oral administration. It does not bind to plasma
 USE OF ANTIEPILEPTIC DRUGS IN HEPATIC AND RENAL DISEASE 427
Table 27.3
Antiepileptic drugs and hemodialysis

Molecular Water Plasma protein Volume of Dose supplementation

Drug weight solubility binding distribution (L/kg) (per 4 hours of hemodialysis)

Carbamazepine 236.3 Very low 70–80% 0.8–1.2 Not necessary

Eslicarbazepine Low 38% (MHD) 2.7 Not studied (probably necessary)
Ethosuximide 141.17 High None 0.65 Necessary: 50% of total daily dose
Ezogabine/retigabine 303.3 Low 80% 2–3 Not studied
Felbamate 238.24 Very low 20–25% 0.75 Not studied (probably not necessary)
Gabapentin 171.34 High None 0.65–1.4 Necessary: 100–200% of total daily dose
Lacosamide 250.3 High <15% 0.6 Necessary: 50% of total daily dose
Lamotrigine 256.09 Low 55% 0.9–1.3 Usually not necessary
Levetiracetam 170.21 High <10% 0.5–0.7 Necessary: 50% of total daily dose
Oxcarbazepine 252.3 Low 38% (MHD) 0.3–0.8 Not studied (probably necessary)
Phenobarbital 232.23 Low 45–60% 0.4–0.7 Probably necessary, but not well
established. Pre- and postdialysis levels
recommended for dosing
Phenytoin 252.26 Low 90% 0.5–0.8 Usually not necessary. However,
70–80% in significant extraction has been reported
ESRD with use of high-efficiency dialyzers
Pregabalin 159.23 High None 0.5 Necessary: 100–200% of total daily dose
Primidone 218.25 Low 25% 0.6–1.0 Necessary: 30% supplemental dose prior
to dialysis
Rufinamide 238.2 Very low 34% 0.8–1.2 Not necessary
Tiagabine 412.0 Low 96% 1.0 Not necessary
Topiramate 339.4 Low 15% 0.6–1.0 Necessary: 50% of total daily dose
Valproate 144.2 Very low 90% 0.1–0.4 Usually not necessary. However,
70–80% in significant extraction has been reported
ESRD with use of high-efficiency dialyzers
Vigabatrin 129.16 High None 0.8 Not studied
Zonisamide 212.23 Low 40–60% 1.09–1.77 May be necessary: 25–50% of total
daily dose

MHD, monohydroxy derivative; ESRD, end-stage renal disease.

proteins and is widely distributed in the body (volume of
distribution: 0.8–1.1 L/kg). Vigabatrin is not significantly
metabolized and its elimination is primarily through
renal excretion. The half-life is approximately 5–8 hours,
and the total clearance 1.7–1.9 mL/min/kg (Grant and
Heel, 1991). About 80% of the oral dose is eliminated
in the urine as unchanged drug.
In the presence of renal disease, vigabatrin accumu-
lates proportionally to the decrease in the creatinine clear-
ance (Haegele et al., 1988). In subjects with mild renal
failure (CLcr > 50–80 mL/min), the mean area under
the curve was increased by 30% and the half-life by
55%. In moderate renal failure (CLcr > 30–50 mL/min),
the mean area under the curve and the half-life increased
twofold. In severe renal failure (CLcr > 10– 30 mL/min),
the area under the curve increased 4.5-fold and the
half-life 3.5-fold. As a result, the maintenance dose of
vigabatrin should be reduced by 25%, 50%, or 75% in
the presence of mild, moderate, or severe renal failure,
respectively. The effects of dialysis on the clearance of
vigabatrin have not been studied adequately, but, given
its chemical and pharmacokinetic characteristics, it is
likely that the drug will be significantly extracted. How-
ever, considering that the biologic half-life of vigabatrin,
determined by irreversible enzymatic inhibition, is in the
order of several days, fluctuation of serum concentra-
tions during hemodialysis are probably not as clinically
relevant as with other antiepileptic drugs.
The elimination of vigabatrin in the presence of liver
failure has not been studied, but is not likely to be
affected.
Zonisamide
Zonisamide (1,2-benzisoxazole-3-methanesulfonamide)
has a molecular weight of 212.23 and a pH-dependent
water solubility, with low solubility at acidic or neutral
pH, and increased solubility as the pH increases beyond
428 J.J. ASCONAPÉ
8. Zonisamide is absorbed rapidly and completely after
oral administration (Leppik, 2004). The elimination
half-life is long, about 50–60 hours. The drug distributes
evenly in the body, with a volume of distribution between
1.09 and 1.77 L/kg. Zonisamide is 40–60% bound to
plasma proteins, and has an even higher affinity to bind
to erythrocytes. Zonisamide is extensively metabolized
in humans, with the main pathways including glucuro-
nide conjugation, acetylation, and hydroxylation fol-
lowed by oxidation. After a single dose in humans,
approximately 30% of the drug is recovered unchanged
in the urine, 20% as N-acetyl-zonisamide, and 50% as the
glucuronide of the open-ring metabolite (Buchanan
et al., 1996).
The effects of renal failure on the disposition of zoni-
samide have not been adequately studied. Significant
accumulation of the drug is not to be expected in the
presence of mild to moderate renal failure since only
30% of the drug is eliminated directly by the kidney.
Data from the manufacturer indicates that, following
a single 300 mg dose of zonisamide, a 35% increase in
the area under the curve was observed in subjects with
severe renal failure (CLcr < 20 mL/min). In a small
study, a 50% reduction in the plasma concentration of
zonisamide was observed following 4–5 hours of hemo-
dialysis (Ijiri et al., 2004). Levels of zonisamide remained
low 5–6 hours after dialysis, suggesting that there was no
redistribution of the drug. A postdialysis supplemental
dose is not routinely recommended, but may be neces-
sary in some cases.
The pharmacokinetics of zonisamide has not been
studied in subjects with liver disease. Caution is recom-
mended when prescribing zonisamide in the presence of
moderate to severe hepatic failure.
Felbamate
Felbamate (2-phenyl-1,3-propanediol dicarbamate) has a
molecular weight of 238.24 and very low water
solubility. It is well absorbed (90%) after oral administra-
tion (Palmer and McTavisk, 1993). Approximately 20–
25% of the drug is bound to serum proteins. Of the
absorbed drug, 40–50% is eliminated by direct renal
excretion and the rest undergoes biotransformation,
resulting in mostly inactive or weakly active
metabolites (Shumaker et al., 1990). Mean elimination
half-life was 16–22 hours in healthy volunteers
(Shumaker et al., 1990).
Clearance of felbamate is decreased in the presence
of renal failure and the drug is likely to accumulate in
patients with moderate to severe renal failure (Glue
et al., 1997). The dosing of felbamate in the presence
of renal failure has not been adequately studied to pro-
vide specific recommendations.
The pharmacokinetics of felbamate has not been
studied in subjects with liver failure. Since the use of
the drug has been associated with fulminant liver failure,
it is better avoided in patients with hepatic disease.
Ethosuximide
Ethosuximide (2-ethyl-2-methylsuccinimide) is a water-
soluble weak acid with a molecular weight of 141.17. It
is well absorbed after oral intake (Buchanan et al.,
1973). Ethosuximide is not bound to plasma proteins,
and it is distributed through body water with an apparent
volume of distribution of 0.65 L/kg. Ethosuximide is
eliminated primarily by metabolism, with only about
20% of an administered dose recovered unchanged in
the urine (Buchanan et al., 1973). The elimination half-
life is 40–60 hours, and is generally higher in children
than in adults.
Decreased renal function is not likely to affect the
elimination of ethosuximide significantly and dose
adjustments are probably not needed. Ethosuximide is
removed efficiently by hemodialysis and peritoneal dial-
ysis (Marbury et al., 1981; Marquardt et al., 1992). The
elimination half-life of ethosuximide was reduced to
3–4 hours during hemodialysis, and approximately
40–50% of the total daily dose of ethosuximide was
removed during a 4 hour session of hemodialysis using
a low-efficiency dialyzer (Marbury et al., 1981). A single
case report in a child demonstrated that 50% of the total
daily dose of ethosuximide was removed by peritoneal
dialysis (Marquardt et al., 1992). Patients on ethosuxi-
mide will probably need dose supplementation at the
time of dialysis, but this had not been systematically
investigated.
Because ethosuximide is eliminated predominantly
by metabolism, hepatic disease is expected to impair
its elimination. The pharmacokinetics of ethosuximide,
however, has not been studied in subjects with liver
failure.
Rufinamide
Rufinamide (1-((2,6-difluorophenyl)methyl)-1H-1,2,3-
triazole-4 carboxamide) is a triazole derivative with a
molecular weight of 238.2 and very poor water solubility.
Rufinamide is well absorbed after oral administration up
to doses of 1600 mg, with a nonlinear decrease in bio-
availability observed at higher doses (Perucca et al.,
2008). A small proportion (34%) of the drug is bound
to plasma proteins, mostly albumin. Elimination half-life
is 6–10 hours, with an apparent volume of distribution of
50 L at a dose of 3200 mg/day. Rufinamide is exten-
sively metabolized via hydrolysis by carboxylesterases
to a pharmacologically inactive carboxylic acid deriva-
tive. The metabolism of rufinamide does not involve
 USE OF ANTIEPILEPTIC DRUGS IN HEPATIC AND RENAL DISEASE 429
the cytochrome P450. Less than 2% of a given dose is limited information on the effects of hemodialysis on
eliminated unchanged in the urine. The pharmacokinet- the disposition of ezogabine/retigabine.
ics of rufinamide is not affected by impaired renal func- The effects of varying degrees of liver impairment on
tion and the drug is not significantly extracted by the pharmacokinetics of ezogabine/retigabine were stud-
hemodialysis (Perucca et al., 2008). A regimen of three ied following a single 100 mg dose. Mild liver failure
hemodialyses a week carried out 3 hours after dosing (Child–Pugh score 5–6) had no significant effect on
of rufinamide was predicted to reduce the average area the elimination of ezogabine/retigabine. In subjects with
under the curve over 1 week by 12% compared to subjects moderate (Child–Pugh score 7–9) and severe (Child–
not undergoing dialysis (Perucca et al., 2008). Therefore, Pugh score > 9) hepatic impairment there was a 50%
dose supplementation in patients on hemodialysis is gen- and 100% increase in the area under the curve, respec-
erally not required. tively. There was an approximately 30% increase in the
The effects of hepatic failure on the pharmacokinet- exposure of the N-acetyl metabolite in subjects with
ics of rufinamide have not been studied. The drug should moderate to severe hepatic impairment. Dose reductions
be used with caution in patients with mild or moderate are recommended in moderate to severe hepatic impair-
liver disease and probably avoided in the presence of ment. Initial dose should not exceed 150 mg/day in these
severe hepatic impairment. groups. Maximal doses recommended are 750 mg/day in
moderate and 600 mg/day in severe liver failure.

Ezogabine/retigabine
Ezogabine/retigabine (N-(2-amino-4-(4-fluorobenzyla-
mino)-phenyl) carbamic acid ethyl ester) was recently
approved for the adjunctive treatment of partial epilepsy.
Known worldwide as retigabine (INN), it is called ezoga-
bine (USAN) in the US. Its mechanism of action is not
fully understood, but it appears to exert its main anticon-
vulsant effect by enhancing potassium currents (Kv7.2 to
7.5) through activation of the voltage-gated potassium
channels (KCNQ2/3 and KCNQ3/5) (Plosker and Scott,
2006). It has a molecular weight of 303.3 and low water
solubility. It is rapidly absorbed after oral administration.
Ezogabine/retigabine is approximately 80% bound to
plasma proteins and has a volume of distribution of
2–3 L/kg. Ezogabine/retigabine undergoes extensive
phase II metabolism via glucuronidation and acetylation.
Its monoacetylated metabolite, N-acetyl ezogabine/retiga-
bine, is biologically active, but less potent than the parent
compound (Blackburn-Munro et al., 2005). The elimina-
tion of ezogabine/retigabine is predominantly renal, with
84% of an administered dose recovered in the urine
(Hermann et al., 2003). The renal clearance following
intravenous administration is 0.4–0.6 L/h/kg. About
36% of the drug is recovered unchanged in the urine,
and 18% as the N-acetyl metabolite. The elimination
half-life is 7–11 hours.
Data provided by the manufacturer indicate that, fol-
lowing a single dose of 100 mg of ezogabine/retigabine,
the area under the curve was increased by about 30% in
patients with mild renal insufficiency (creatinine
clearance  50 to  80 mL/min) and increased by about
100% with moderate renal insufficiency (creatinine
clearance  30 to  50 mL/min). A reduction of 50% in
the total daily dose has been recommended for patients
with a creatinine clearance  50 mL/min. There is very
CONCLUSIONS
Based on their route of elimination, antiepileptic drugs can
be divided into three main groups. Drugs that are elimi-
nated unchanged by the kidneys or undergo minimal
metabolism, drugs that are removed almost exclusively
by hepatic metabolism, and drugs that are eliminated by
a combination of renal and nonrenal routes. Drugs in
the first group include gabapentin, pregabalin, vigabatrin,
and topiramate when used as monotherapy or associated
with nonenzyme-inducing drugs. These drugs will require
major dose adjustments in patients with severe renal insuf-
ficiency and may be better avoided in these cases. Drugs
eliminated predominantly by biotransformation include
phenytoin, valproate, carbamazepine, tiagabine, and
rufinamide. These drugs are at significant risk of
accumulation with advanced hepatic disease. Drugs in
the intermediate group include levetiracetam, lacosamide,
zonisamide, primidone, phenobarbital, ezogabine/retiga-
bine, oxcarbazepine, eslicarbazepine, ethosuximide, and
felbamate. These drugs can be used cautiously in patients
with either renal or liver failure. Lamotrigine, oxcarbaze-
pine, and eslicarbazepine mostly undergo extensive phase
II metabolism. Since the reactions involving phase II
metabolism are very ubiquitous in extrahepatic tissues,
the elimination of these drugs is not significantly affected
by liver disease.
Antiepileptic drugs that are at high risk of being
extracted by hemodialysis include ethosuximide,
gabapentin, lacosamide, levetiracetam, pregabalin, and
topiramate. Dose supplementation is usually necessary
in these cases. Pre- and postdialysis serum concentrations
can be helpful in estimating the need for supplementation.
The use of antiepileptic drugs in the presence of
hepatic or renal disease is complex and requires great
430 J.J. ASCONAPÉ
familiarity with the pharmacokinetics of these agents
(Lacerda et al., 2006). Closer follow-up of the patients
and more frequent monitoring of serum concentrations
are required to optimize clinical outcomes.
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