Food and Chemical Toxicology 142 (2020) 111393

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Food and Chemical Toxicology

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Review

Phenytoin – An anti-seizure drug: Overview of its chemistry, pharmacology T

and toxicology
Jiri Patockaa,b, Qinghua Wuc,d, Eugenie Nepovimovac, Kamil Kucab,c,∗
a
Faculty of Health and Social Studies, Department of Radiology and Toxicology, University of South Bohemia Ceske Budejovice, Ceske Budejovice, Czech Republic
b
Biomedical Research Centre, University Hospital, Hradec Kralove, Czech Republic
c
Department of Chemistry, Faculty of Science, University of Hradec Kralove, Hradec Kralove, Czech Republic
d
College of Life Science, Yangtze University, Jingzhou, 434025, China

ARTICLE INFO ABSTRACT

Keywords: Phenytoin is a long-standing, anti-seizure drug widely used in clinical practice. It has also been evaluated in the
Phenytoin context of many other illnesses in addition to its original epilepsy indication. The narrow therapeutic index of
Pharmacokinetics phenytoin and its ubiquitous daily use pose a high risk of poisoning. This review article focuses on the chemistry,
Toxicity pharmacokinetics, and toxicology of phenytoin, with a special focus on its mutagenicity, carcinogenicity, and
Side effect
teratogenicity. The side effects on human health associated with phenytoin use are thoroughly described. In
DRESS syndrome
Cerebellar atrophy
particular, DRESS syndrome and cerebellar atrophy are addressed. This review will help in further under-
standing the benefits phenytoin use in the treatment of epilepsy.

1. Introduction of status epilepticus, especially where no further improvement is ob-

Phenytoin is an anti-seizure drug that has been under clinical eva-
luation for around eight decades. It is primarily used for the treatment
of tonic-clonic and partial seizures (Abou-Khalil, 2016). Phenytoin has
a highly selective inhibitory effect on the motor area of the cerebral
cortex. For its mode of action, phenytoin binds to the inactivated state
of the Na+ channel to prolong the neuronal refractory period
(Hesselink, 2017). Moreover, it is generally believed that phenytoin
exerts its antiepileptic effect by stabilising the function of brain cell
membranes and increasing the levels of the inhibitory neuro-
transmitters serotonin (5-HT) and γ-aminobutyric acid (GABA) in the
brain (Hesselink, 2017; Keppel Hesselink and Kopsky, 2017a,b).
Through these mechanisms, phenytoin prevents the spread of abnormal
discharge and has anti-epileptic effects. The anti-neuralgia activity of
phenytoin may also be related to these same mechanisms; a reduction
in synaptic transmission or a reduction in transient stimuli that cause
neuronal discharge (Hall et al., 2020). In cardiac tissue, phenytoin in-
hibits the ectopic rhythm of the atrium and ventricle, and accelerates
the conduction of the atrioventricular node to reduce myocardial au-
tonomy, producing an antiarrhythmic effect (Zhang et al., 2018).
Phenytoin can be administered by oral delivery or parenteral de-
livery. The intravenous version of this drug is usually made available as
a sodium salt, and this can be adapted to a propylene glycol-alcohol-
water solution for parenteral administration of phenytoin for treatment
served with benzodiazepines (Prasad et al., 2014). Occasionally, neu-
ropathic pain or heart arrhythmias are also treated in this fashion
(Somberg, 1985; Kopsky et al., 2017). In addition, neurological, psy-
chiatric, and non-CNS indications of phenytoin have been identified,
such as wound healing, and several of these indications have been in-
vestigated in subsequent pilot studies (Şimşek et al., 2014). Wound
healing is one of the indications most thoroughly investigated (Keppel
Hesselink, 2018; Barratt et al., 1997).
However, phenytoin treatment is associated with several side ef-
fects, and toxicity plays a key role in these issues (Imam et al., 2014).
An excessive dose of phenytoin inhibits the central nervous system,
causes cerebellar dysfunction, dyskinesia, and induces peripheral neu-
ropathy. In addition, phenytoin can cause gingival hyperplasia, induce
pseudolymphomas and malignant lymphomas, and cause allergic re-
actions (Hesselink, 2017; Farook et al., 2019). As mentioned above,
intravenous injections of phenytoin slow the conduction rate between
myocardial fibres and eliminate ectopic rhythms, producing a similar
effect to quinidine (Mathews et al., 2019). In addition, phenytoin can
cause cerebellar syndrome, which manifests itself as ataxia, nystagmus,
hand tremor, and diplopia. These manifestations of cerebellar syn-
drome are dependent on phenytoin dose and blood concentration;
tremor occurs at an average plasma concentration of 20 μg/mL, and
ataxia occurs at 30 μg/mL. A coma can occurred at average plasma
concentrations of 40 μg/mL or more (Zhang et al., 2018). In the long-

∗
Corresponding author. Biomedical Research Centre, University Hospital, Hradec Kralove, Czech Republic.
E-mail addresses: kamil.kuca@uhk.cz, kamil.kuca@fnhk.cz (K. Kuca).

https://doi.org/10.1016/j.fct.2020.111393
Received 1 January 2020; Received in revised form 16 April 2020; Accepted 24 April 2020
Available online 04 May 2020
0278-6915/ © 2020 Published by Elsevier Ltd.
J. Patocka, et al.
term, sudden seizures may become worse during phenytoin treatment,
although seizures can become more worse following withdrawal of this
medicine.
Phenytoin is more and more widely used in clinical practice, in-
cluding for wound healing, migraine, dizziness, hiccups, myocardial
infarction, and burns (Keppel Hesselink and Kopsky, 2017a; b).
Therefore, the development and utilisation of this drug has attracted
increasing attention. However, the adverse reactions associated with
phenytoin treatment should not be ignored; known symptoms include
gastrointestinal irritation, gum hyperplasia, allergic reactions, and
mental health issues (Sadeghi et al., 2018). To prevent such serious
adverse consequences, it is necessary that phenytoin is used reasonably
in clinical practice. This review article focuses on the chemistry, me-
chanism of action, pharmacokinetics, toxicology of phenytoin, and its
side effects on human health.
2. History
The German chemist Heinrich Biltz synthesised phenytoin (diphe-
nylhydantoin) for the very first time in 1908. He later sold his work to
Parke-Davis (Keppel Hesselink and Kopsky, 2017a,b). The additional
usefulness of phenytoin was revealed in 1938 by Tracy Putnam and H.
Houston Merritt, when they discovered that it could be used to control
seizures, while avoiding the sedation that was typical to phenobarbital
(Merritt and Putnam, 1984). Phenytoin has been examined and eval-
uated in the context of many illnesses subsequent to its original epilepsy
indication. For several disorders, phenytoin is still undergoing some
form of innovation, including for bipolar disorder and wound healing,
amongst others (Keppel Hesselink, 2018). Using meta-analysis, it has
also been revealed that phenytoin may be used to manage different
types of ulcers (Thangaraju et al., 2015). The use of phenytoin as a
neuroprotector, in the context of multiple sclerosis, has also been ex-
plored in clinical trials (Raftopoulos et al., 2016).
3. Chemistry
Phenytoin (Fig. 1) is a hydantoin derivative (5,5-difenylhydantoine,
5,5′-diphenylimidazolidine-2,4-dione; C15H12N2O2; M.W. 252.27; CAS
Registry Number 57-41-0). It is a fine white or almost white crystalline
powder with the following characteristics: m.p. 295–298 °C, (O'Neil,
2001); pKa = 8.33, (Sangster, 1994); log P (octanol water) = 2.47,
(Hansch et al., 1995); slightly soluble in water (32 mg/L), (Yalkowsky
and He, 2003). Moreover, phenytoin is soluble in alkali hydroxides,
alcohol, acetone (O'Neil, 2001) and acetic acid (Lide and Milne, 1994).
Phenytoin is sensitive to light (Sunshine, 1969) and solutions are yel-
lowed in light (Thompson and Micromedex, 2007). Finally, phenytoin
is odourless (or almost odourless) and tasteless (IARC, 1972).
There are two methods through which phenytoin can be synthe-
sised. Phenytoin synthesis can be achieved by adding base-catalysed
urea to benzyl to produce benzilic acid, from which phenytoin is pro-
duced following a rearrangement. This process is called Biltz synthesis
of phenytoin (Safari et al., 2009). In addition, phenytoin can be
Fig. 1. Chemical structure of phenytoin.
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Food and Chemical Toxicology 142 (2020) 111393
produced by oxidation of benzoin with nitric acid to produce the
benzyl, after which the procedure is the same as for Biltz synthesis. In
this process, almonds may be used as a source of benzaldehyde
(Ashnagar et al., 2009). Water-soluble phenytoin derivatives have also
been synthesised (Bosch et al., 1999). It should be noted that during
decomposition caused by heat, phenytoin typically produces several
toxic fumes, including nitrogen oxide, carbon monoxide and carbon
dioxide (Lewis, 2004).
4. Mechanism of action
The mechanism of action of phenytoin in neuropharmacology has
been investigated for more than 80 years (Hesselink, 2017). Phenytoin
is a voltage-gated, sodium channel blocker (Hains et al., 2004). It exerts
its effect by stabilising the inactive state of the Na+ channel and
prolonging the neuronal refractory period (Hesselink, 2017; Keppel
Hesselink and Kopsky, 2017a; b). Through this mode of action, phe-
nytoin regulates the bioelectrical activities of various systems in hu-
mans. Importantly, phenytoin inhibits or eliminates abnormal electrical
activity in nerve and muscle cells without affecting the production and
conduction of normal bioelectricity. The electrophysiological basis of
this effect involves the regulation of the transmembrane movement and
intracellular distribution of Na+, K+, and Ca2+ (Keppel Hesselink,
2017; Martin et al., 2014). Phenytoin has an especially significant
blocking effect on the Na+ channels of neurons with high-frequency
abnormal discharge, where it inhibits these repeated high-frequency
discharges; in contrast, phenytoin has no significant effect on normal
low-frequency discharges (Martin et al., 2014). In addition, phenytoin
inhibits the rapidly inactivating (T-type) Ca2+ channels of neurons and
inhibits Ca2+ influx (Keppel Hesselink and Kopsky, 2017a). Through
this mechanism, phenytoin affects the transmission of Ca2+-dependent
multiple neurotransmitters at the synapse, and the post-synaptic re-
sponses.
Phenytoin also regulates hormone secretion of endocrine glands
cells and stimulates metabolism in the liver drug enzyme system.
Moreover, phenytoin increases high density lipoprotein concentration,
and stimulates granulation and capillary formation in healing tissues
(Taing et al., 2017; Hesselink, 2017). The stability of phenytoin effects
on cell membrane bioelectric activity is manifested in its ability to
correct excessive cell excitement caused by various activities: phenytoin
can correct the excessive excitability of squid giant axonal cells caused
by high-frequency electrical stimulation or low Ca2+ and Mg2+; phe-
nytoin can increase resting potential in a high-potassium depolarisation
state, and reduce the frequency of endplate electrical sobbing, thereby
affecting the motor nerve endplate potential (Suwalsky et al., 2006). In
a recent study, phenytoin was shown to inhibit Ca2+ in CD38 pathways
and cause oxidative stress, inflammation, and depression (Sadeghi
et al., 2018).
Phenytoin regulates a series of neurotransmitters including acet-
ylcholine, serotonin, norepinephrine, dopamine, GABA, and endorphins
(Chou et al., 2014; Granger et al., 1995). At high concentrations, phe-
nytoin can inhibit GABA uptake at nerve endings, indirectly enhancing
the role of GABA by inducing GABA receptor proliferation; the end
result is an increase in Cl− influx and hyperpolarisation, and sub-
sequent inhibition of the incidence and spread of abnormal high-fre-
quency discharge (Chou et al., 2014; Zhang et al., 2019). While phe-
nytoin also reduces the concentration of acetylcholine in the brain,
small doses of phenytoin promote the release of acetylcholine from the
intestinal parasympathetic nerve terminals and ganglia, thereby sti-
mulating contraction of the Gastro-intestinal tract (Zhang et al., 2019).
In cardiac tissue, phenytoin shortens cardiac action potentials and
prolongs the refractory period (Razmaraii et al., 2016). In the central
nervous system, phenytoin targets neurons with high-frequency ac-
tivity, though most of its actions are exerted on the motor cortex (Chao
and Alzheimer, 1995). Thus, any spread from a seizure's focal point is
prevented and activity in the brain that is known to cause the tonic-
J. Patocka, et al.
clonic seizure's tonic phase is diminished (Osorio and Reed, 1989).
5. Pharmacokinetics
5.1. Absorption, distribution, metabolism, and excretion (ADME)
Phenytoin is well absorbed following oral administration (Urashima
et al., 2019). Its absorption takes place predominantly in the duo-
denum. The rate of dissolution of phenytoin in the intestines informs its
level of absorption. Peak plasma concentrations are typically reached
during a four to 8-h period. The distribution of the drug is widespread
throughout the body (distribution volume 0.8 L/kg). Phenytoin easily
crosses the blood – brain barrier and it is extensively bound (~90%) to
plasma albumin (Treiman and Woodbury, 1995). Phenytoin also easily
crosses the placenta (Mirkin, 1971). Indeed, similar plasma con-
centrations of phenytoin have been measured in maternal and umbilical
cord (Nau et al., 1982). However, levels are typically low in breast milk
obtained from mothers with epilepsy (Mirkin, 1971).
Phenytoin is metabolised by cytochrome P450 enzyme to 5-(p-hy-
droxyphenyl)-5-phenylhydantoin (4′-HPPH). Further metabolisation to
a catechol is possible, and this can extemporaneously oxidise to qui-
none and semiquinone species (Cuttle et al., 2000; Ozkaynakci et al.,
2015). Phenytoin metabolism has been widely studied in vitro with
respect to human subjects (Yasumori et al., 1999; Komatsu et al., 2000)
and in vivo (Maguire, 1988; Szabo et al., 1990). Four oxidative meta-
bolites are reported, 4′-HPPH, 3′-HPPH, 3′,4′-diHPPH, and 3′,4′-dihy-
drodiol (Maguire, 1988; Szabo et al., 1990). Research suggests that
phenytoin is oxidised to 4′-HPPH by CYP2C9 in humans, and to a minor
extent by CYP2C19 (Bajpai et al., 1996). However, the role played by
the P450s in the development of other metabolites requires further
investigation. Recent reports suggest that the contribution of CYP3A4,
CYP2C9, and CYP2C19 to liver microsomal 3′,4′-diHPPH formation
from primary hydroxylated metabolites differs according to the in-
dividual person (Komatsu et al., 2000; Lakehal et al., 2002). CYP2C9
variants are observed to play a role in the metabolism of phenytoin in
the Chinese population (Chen et al., 2016). Furthermore, according to
recent studies, phenytoin has much higher CYP3A4-inducing potency.
Therefore, CYP3A4-metabolised drugs may generally be required
during concurrent treatment with phenytoin (Hole et al., 2018).
Research has also been conducted to study phenytoin metabolism in
animal subjects (Chow et al., 1980; Billings, 1983; Doecke et al., 1990).
It should be noted that rates of 4′-HPPH formation in rat liver micro-
somes were 10 times higher than in humans (Munns et al., 1997). The
reasons for this difference in P450 metabolism are still unclear. Phe-
nytoin has been shown to induce several forms of P450 (Fleishaker
et al., 1995; Ghosal et al., 1996; Yamazaki et al., 1996). However, it is
unknown whether administrating phenytoin can lead to auto-induced
metabolism in humans and rats (Edeki and Brase, 1995; Chetty et al.,
1998).
Phenytoin displays non-linear elimination pharmacokinetics
(Browne and LeDuc, 1995). A result of this non-linearity is that the
elimination half-life differs with plasma concentration. A saturation of
metabolite-inducing enzymes is the reason for the non-linearity in the
elimination of phenytoin (Browne and LeDuc, 1995). As shown in
Fig. 2, the main primary metabolites are 5(3′-hydroxyphenyl)-5-phe-
nylhydantoin (3′-HPPH), 5(4′-hydroxyphenyl)-5-phenylhydantoin (4′-
HPPH), 5(3′,4′-dihydroxyphenyl)-5-phenylhydantoin (3′,4′-diHPPH),
and 5(3′,4′-dihydroxy-1′,5′-cyclohexydiene-1-yl)-5-phenylhydantoin
(3′,4′-dihydrodiol). In addition, arene-oxide is a highly reactive and
extremely unstable hypothetical metabolite which has never been iso-
lated. Arene oxide may be responsible for the carcinogenic effects of
phenytoin. The main secondary metabolites are glucuronide con-
jugates of phenytoin and its hydroxylated derivatives (Scriba et al.,
1995).
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Food and Chemical Toxicology 142 (2020) 111393
5.2. Side effects of phenytoin
Common side effects of phenytoin include a large number of non-
specific symptoms (Hwang and Tsai, 2004). These include drowsiness
(Salinsky et al., 1996), fatigue (Siniscalchi et al., 2013), loss of control
of bodily movements and loss of balance or coordination (Iivanainen
and Savolinen, 1983), irritability (Stephens and Shaffer, 1970), rest-
lessness (Drake, 1988), and several involuntary functions (Ahmad et al.,
1975; Gunduz et al., 2013) including involuntary eye movements
(Bittencourt et al., 1980; Matsue et al., 1981).
Phenytoin can cause cutaneous adverse reactions, from maculo-
papular exanthema to SCAR (severe cutaneous adverse reaction), in-
cluding drug reactions with eosinophilia, and systemic symptoms, in-
cluding Stevens-Johnson syndrome and toxic epidermal necrolysis. The
pharmacogenomic basis of these severe cutaneous adverse side effects
can be linked to genetic factors (Chung et al., 2014).
Typically, the reactions include poor coordination, an increase in
the growth of hair, stomach aches, loss of appetite, nausea, and gingival
enlargement (Arya et al., 2012; Chacko and Abraham, 2014; Onaolapo
et al., 2018). Potentially more serious side effects include liver pro-
blems (Lee et al., 1976; Curry et al., 2018), bone marrow suppression
(Sugimoto et al., 1982) and toxic epidermal necrolysis (Wu et al.,
2018). Hepatotoxicity related to phenytoin is a serious idiosyncratic
side effect that is observed in a small percentage of those undergoing
treatment. It is accompanied by a host of symptoms ranging from a
fever to arthralgias (Smythe and Umstead, 1989). In some patients,
phenytoin can cause liver necrosis (Lee et al., 1976).
Many other syndromes have been attributed to phenytoin use. These
include: paradoxical seizure (Chua et al., 1999); drug withdrawal sei-
zure (Nolan et al., 2013a,b); iplopia, blurred vision, and colour dis-
turbances (López et al., 1999); encephalopathy (Mehndiratta, 2016);
ventricular fibrillation (Merlo González et al., 2002); atrioventricular
conduction disorder (Magadle et al., 1999); enlarged lymph nodes
(Schwinghammer and Howrie, 1983); purple spots on the skin (Oelze
and Pillow, 2013); and maculopapular exanthema leading to severe
cutaneous adverse side effects. These are supplemental to the common
side effects described earlier, such as systematic and eosinophilia
symptoms, toxic epidermal necrolysis, Stevens-Johnson syndrome
(Chung et al., 2014), coarsening of facial features (Sasaki et al., 1999),
periarteritis nodosa (Haas, 1967), megaloblastic (folate-deficiency)
anaemia (Scott and Weir, 1980), low blood calcium levels (hypo-
calcaemia) (Nseir et al., 2013), and immunoglobulin abnormalities
(Yabuki and Nakaya, 1976).
In addition, adverse effects related with phenytoin use can include
various psychiatric disorders or behavioural symptoms, specifically
those associated with vitamin B12 or a folic acid deficiency (Reynolds,
1967; Matsuura, 1999; Gatzonis et al., 2003). A rare case of toxicity was
recently reported that presented itself as psychosis resulting from vi-
tamin deficiency (Borasi et al., 2015). However, it is necessary to re-
cognise that psychological and behavioural side effects occur more
frequently in patients taking antiepileptics other than phenytoin (Chen
et al., 2017).
5.3. DRESS syndrome
Allergic reactions to phenytoin present themselves as a rash. They
can sometimes, if rarely, take up more severe forms, e.g. anaphylaxis or
DRESS (drug reaction with eosinophilia and systemic symptoms)
(Kumkamthornkul et al., 2018). A side effect linked to DRESS syndrome
is the drug-induced hypersensitivity syndrome (amongst other names).
This side effect is a known SCAR (severe cutaneous adverse reaction)
and can prove to be life-threatening (Sullivan and Shear, 2001). Drug-
induced hypersensitivity syndrome is associated with phenytoin in most
cases and was originally referred to as phenytoin hypersensitivity
syndrome (De et al., 2018). Although this syndrome was subsequently
discovered to occur with several different drugs, phenytoin remains a
J. Patocka, et al.
Fig. 2. Proposed pathways of phenytoin metabolism.
frequent cause of this allergic reaction (Brizendine and Naik, 2013;
Deka et al., 2013; Hall and Fromm, 2013; Velasco and McDermott,
2014; Yampayon et al., 2017). DRESS typically has a two to six-week
latency period. While it is known that the pathophysiology of DRESS
involves the activation of lymphocytes and reactivation of viruses, its
pathophysiology is not completely understood (Yampayon et al., 2017).
DRESS is normally associated with a morbilliform cutaneous eruption,
and this is accompanied by lymphadenopathy, and a rise in tempera-
ture. The severity of DRESS is linked to systemic involvement, and it
can result in multiple organ-failure (Ghannam et al., 2017).
5.4. Cerebellar atrophy
The adverse side effects of phenytoin can be chronic and/or acute.
As the amount of phenytoin rises, there is a disproportionate rise in the
plasma drug concentration, despite the increments in dosage itself
being small, and this increase in plasma drug concentration is accom-
panied by a change from subtherapeutic to toxic levels (McNamara,
1996). These plasma drug concentration changes are highly linked to
4
Food and Chemical Toxicology 142 (2020) 111393
CNS dysfunction, viz. ataxia, drowsiness, and nystagmus (Browne,
1997). However, these reactions can be reversed when the dosage is
reduced. A chronic overdose has been found to be responsible for cer-
ebellar atrophy in adult patients being administered phenytoin
(Kokenge et al., 1965; Selhorst et al., 1972; Ghatak et al., 1976; Mc Lain
et al., 1980; Baier et al., 1984; Ney et al., 1994; Ahuja et al., 2000; Tan
et al., 2001; De Marcos et al., 2003; Lee et al., 2003; Chow and Szeto,
2007; Kumar et al., 2013). Evidence has been reported that CYP2C9
polymorphisms are associated with an increase in the frequency of
cerebellar atrophy following the use of phenytoin (Silvado et al., 2018).
6. Toxicology
The therapeutic range for phenytoin is narrow and a total serum
concentration greater than 80 μM is, for many patients, linked to
clinically relevant toxicity (Praveen-kumar and Desai, 2014). Phenytoin
is typically excreted by the kidneys after it has been metabolised by
hepatic enzymes. However, a toxic accumulation of phenytoin can
present itself in the context of people with renal failure (Chua et al.,
J. Patocka, et al. Food and Chemical Toxicology 142 (2020) 111393

Table 1
Published toxicity data for phenytoin.
Species Test Typea Route Reported Dose Source

mouse LD50 intravenous 92 mg/kg Stille and Brunckow (1954)

mouse LD50 intraperitoneal 100 mg/kg TOXNET
mouse LD50 subcutaneous 110 mg/kg Stille and Brunckow (1954)
mouse LD50 Oral 150 mg/kg TOXNET
mouse LD50 unreported 800 mg/kg (800 mg/kg) TOXNET
rat LD50 intravenous 101 mg/kg TOXNET
rat LD50 intraperitoneal 352 mg/kg Kemp et al. (1971)
rat LD50 oral 1635 mg/kg Graziani et al. (1983)
rat LD50 subcutaneous > 1500 mg/kg Masuda et al. (1980)
rabbit LD50 intravenous 56.4 mg/kg Graziani et al. (1983)
rabbit LD50 oral > 3000 mg/kg TOXNET
dog LD50 intravenous 90 mg/kg Usdin and Efron (1972)
child LDLo oral 100 mg/kg Theil et al. (1961)
child TDLo intravenous 15 mg/kg Howrie and Crumrine (1985)
child TDLo intravenous 15 mg/kg Krishnamoorthy et al. (1983)
child TDLo oral 3 mg/kg Wilson et al. (1976)
child TDLo oral 11 mg/kg Zinsmeister and Marks. (1976)
child LDLo oral 140 mg/kg Bajoghli (1961)
child TDLo unreported 18 mg/kg Zinsmeister and Marks (1976)
man TDLo oral 31 mg/kg TOXNET
man TDLo oral 1300 mg/kg Gams et al. (1968)
women TDLo oral 106 mg/kg TOXNET
women TDLo oral 200 mg/kg Weichbrodt and Elliott, 1987.
women TDLo oral 540 mg/kg Mahatma et al. (1989)

a
LD50 = Median Lethal Dose, LDLo = Lethal Dose Low, TDLo = Toxic Dose Low, NOAEL = No-Observed-Adverse-Effect Level.

2000). Haemodialysis does not remove phenytoin because it is 90%
albumin bound (Martin et al., 1977). While this form of toxicity is not
typically fatal, it can lead to neurological symptoms ranging from a
coma (Craig, 2005), to nystagmus (Praveen-kumar and Desai, 2014), to
ataxia (Shanmugarajah et al., 2018). On rare occasions, intravenous
applications may face complications stemming from Purple Glove
Syndrome (PGS) (Garbovsky et al., 2015). PGS is a serious side effect
that can lead to amputation (Jaain et al., 2015; Okogbaa et al., 2015).
Toxicity relating to phenytoin can be a product of dose misuse, dose
adjustment, an interaction with other drugs, or a patient's changing
physiology (Kang et al., 2013; Srinivasan et al., 2015). The first
symptoms of phenytoin intoxication are nausea, dysfunctions related to
the central nervous system (such as ataxia or nystagmus), a depressed
state, and coma (Craig, 2005). Problems such as hypotension or ar-
rhythmia are not typically linked to the use of this drug. However, in
cases of parenteral administration, these problems may present them-
selves. Phenytoin is considered a moderately toxic substance (Imam
et al., 2014). On its own, the likelihood that phenytoin intoxication will
result in patient death is considered to be very low. The published acute
toxicity data for phenytoin in different organisms are summarised in
Table 1. Data on mutagenicity, carcinogenicity, and teratogenicity are
provided in separate subchapters.
The mutagenicity of phenytoin and the mutagenicity of its major
metabolite, 5-(4-hydroxyphenyl)-5-phenylhydantoin (HPPH), have
been tested in vitro on different Salmonella typhimurium strains (TA1535,
TA100, TA1537, TA1538, TA98) using an Ames test (Sezzano et al.,
1982; Léonard et al., 1984; Riedel and Obe, 1984). From the results of
these studies, it was concluded that phenytoin does not have mutagenic
properties.
The experimental approach used in earlier mutagenicity tests
(Montes de Oca-Luna et al., 1984; Barcellona et al., 1987) is likely to be
responsible for generating reactive arene-oxide (Daly et al., 1972), an
extremely unstable metabolite that has never been isolated (Brown and
LeDuc, 1995). Therefore, phenytoin was found not to be directly gen-
otoxic in the context of a set of shorter-term assays using cytogenetics
(Kindig et al., 1992).
Experiments in laboratory animals have not provided any evidence
of phenytoin carcinogenicity (Jang et al., 1987; Maeda et al., 1988;
Chhabra et al., 1993); although in one case the results are inconsistent
(NTP, 1993). Hepatocellular neoplasia in phenytoin-treated rodents
have little to no relevance for humans. At present, in the context of
epilepsy patients, no link has been found between cancer of the liver
and phenytoin (Dethloff et al., 1996; Singh et al., 2005; Friedman et al.,
2009).
There are some indications that phenytoin is linked to a larger risk
of congenital malformations (Danielsson et al., 2005; Eroğlu et al.,
2008). The risk of congenital malformations is linked to phenytoin's
antiepileptic activity. A good number of studies have revealed that this
is the main risk factor for a rise in the incidence of congenital mal-
formations. The risks associated with teratogenicity are multifactorial
and include factors such as a patient's genetic predisposition (Canger
et al., 1999).
Typically, therapy against phenytoin toxicity would involve sup-
portive care. Therapy is focussed on the vital functions of the patient's
body, alongside managing vomit and nausea. In addition, supportive
care is essential to prevent injuries that can otherwise result from ataxia
or confusion. There is no antidote to phenytoin toxicity, and little
evidence to suggest that enhanced elimination or gastrointestinal de-
contamination can speed up recovery (Zhang et al., 2019).
7. Conclusions
Phenytoin is a long-standing antiepileptic drug which exerts its ef-
fects by reducing the influx of Na+ and Ca2+ into nerve cells and
promoting the release of GABA; thus phenytoin effectively inhibits the
abnormal discharge of neurons, prevents the transmission of abnormal
impulses, and reduces the symptoms of withdrawal. In the brain, opioid
μ and δ receptors mediate epilepsy-like reactions, and endogenous
opioid peptides and opioid receptors are involved in the pathophy-
siology of primary epilepsy. A correlation may exist between the pa-
thogenesis of addictive diseases and epilepsy. Therefore, antiepileptic
drugs may be used to treat addictive diseases. Phenytoin treatment can
control withdrawal symptoms in heroin addicts and can effectively
reduce the use of alternatives, such as methadone, in the treatment of
opioid addicts without affecting their efficacy. Moreover, phenytoin
effectively improves symptoms of anxiety, craving, and protracted
withdrawal.
Phenytoin-induced toxicity can occur following an increase in the

5
J. Patocka, et al.
daily dose, a change in formulation or brand, or a change in the fre-
quency of administration. In recent years, there have been many reports
of adverse reactions caused by therapeutic doses of phenytoin.
However, there is no specific antidote to phenytoin toxicity. Therefore,
individualised administration is of great significance for the safe and
effective use of phenytoin. With the widespread application of new
molecular biology techniques, current research on individualised phe-
nytoin medication has gradually evolved from traditional drug therapy
monitoring to pharmacogenomics. From population pharmacokinetics,
nonlinear mixed effect modelling (NONMEM) has led to the develop-
ment of a useful tool for designing gene-oriented and individualised
drug regimens.
In summary, phenytoin has a wide range of biological activities and
pharmacological indications. In addition to being used clinically to
treat epilepsy, phenytoin is also used to treat a variety of diseases, in-
cluding migraine, dizziness, hiccups, myocardial infarction, burns, and
in promoting wound healing. Although phenytoin has been used in
epilepsy treatment for many years and has been somewhat superseded
by newer anti-epileptic medicines, there is good reason to believe that
phenytoin will find new life as a drug for the individualised treatment
of epilepsy, addiction, migraine, and other diseases.
Declaration of competing interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influ-
ence the work reported in this paper.
Acknowledgement
This work was supported by the Excelence project UHK.
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