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

toxicology

Jiri Patocka, Qinghua Wu, Eugenie Nepovimova, Kamil Kuca

PII: S0278-6915(20)30281-7
DOI: https://doi.org/10.1016/j.fct.2020.111393
Reference: FCT 111393

To appear in: Food and Chemical Toxicology

Received Date: 1 January 2020

Revised Date: 16 April 2020
Accepted Date: 24 April 2020

Please cite this article as: Patocka, J., Wu, Q., Nepovimova, E., Kuca, K., Phenytoin – An anti-seizure
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Phenytoin – an Anti-Seizure Drug: Overview of its Chemistry,

Pharmacology and Toxicology

Jiri Patocka,1,2 Qinghua Wu,3,4 Eugenie Nepovimova,3 and Kamil Kuca2,3*

1. Faculty of Health and Social Studies, Department of Radiology and Toxicology, University

of South Bohemia Ceske Budejovice, Ceske Budejovice, Czech Republic.

2. Biomedical Research Centre, University Hospital, Hradec Kralove, Czech Republic.

3. Department of Chemistry, Faculty of Science, University of Hradec Kralove, Hradec

Kralove, Czech Republic.

4
College of Life Science, Yangtze University, Jingzhou 434025 China

Corresponding author: Prof. Kamil Kuca

kamil.kuca@uhk.cz

+420 603 289 166

ORCID: 0000-0001-9664-1109

Acknowledgement

This work was supported be Czech Science Foundation project: 17-19968-S.

Phenytoin – an Anti-Seizure Drug: Overview of its Chemistry,

Pharmacology and Toxicology

Abstract

Phenytoin is a long-standing, anti-seizure drug widely used in clinical practice. It has also

been evaluated in the context of many other illnesses in addition to its original epilepsy

indication. The narrow therapeutic index of phenytoin and its ubiquitous daily use pose a high

risk of poisoning. This review article focuses on the chemistry, pharmacokinetics, and

toxicology of phenytoin, with a special focus on its mutagenicity, carcinogenicity, and

teratogenicity. The side effects on human health associated with phenytoin use are thoroughly

described. In particular, DRESS syndrome and cerebellar atrophy are addressed. This review

will help in further understanding the benefits phenytoin use in the treatment of epilepsy.

Keywords: phenytoin; pharmacokinetics; toxicity; side effect; DRESS syndrome; cerebellar

atrophy.
INTRODUCTION

Phenytoin is an anti-seizure drug that has been under clinical evaluation 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 (Keppel 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 neurotransmitters serotonin

(5-HT) and γ-aminobutyric acid (GABA) in the brain (Keppel 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 inhibits the ectopic rhythm of the atrium and ventricle, and accelerates the

conduction of the atrioventricular node to reduce myocardial autonomy, producing an

antiarrhythmic effect (Zhang et al. 2018).

Phenytoin can be administered by oral delivery or parenteral delivery. 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 of status epilepticus, especially where no further improvement is observed with

benzodiazepines (Prasad et al., 2014). Occasionally, neuropathic pain or heart arrhythmias are

also treated in this fashion (Somberg, 1985; Kopsky et al., 2017). In addition, neurological,

psychiatric, and non-CNS indications of phenytoin have been identified, such as wound
healing, and several of these indications have been investigated 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 effects, 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

neuropathy. In addition, phenytoin can cause gingival hyperplasia, induce pseudolymphomas

and malignant lymphomas, and cause allergic reactions (Keppel 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 syndrome 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-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, including 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, mechanism of action, pharmacokinetics, toxicology

of phenytoin, and its side effects on human health.

HISTORY

The German chemist Heinrich Biltz synthesised phenytoin (diphenylhydantoin) for the

very first time in 1908. He later sold his work to Parke-Davis (Keppel Hesselink and Kopsky,

2017). 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 evaluated 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 explored in clinical trials

(Raftopoulos et al., 2016).

CHEMISTRY

Phenytoin (Figure 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 yellowed 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 synthesised. Phenytoin synthesis

can be achieved by adding base-catalysed urea to benzyl to produce benzilic acid, from which

phenytoin is produced following a rearrangement. This process is called Biltz synthesis of

phenytoin (Safari et al., 2009). In addition, phenytoin can be 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).

MECHANISM OF ACTION

The mechanism of action of phenytoin in neuropharmacology has been investigated for

more than 80 years (Keppel 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 (Keppel Hesselink, 2017; Keppel
Hesselink and Kopsky, 2017a,b). Through this mode of action, phenytoin regulates the

bioelectrical activities of various systems in humans. 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 responses.

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; Keppel 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+; phenytoin

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 acetylcholine, serotonin,

norepinephrine, dopamine, GABA, and endorphins (Chou et al. 2014; Granger et al. 1995).

At high concentrations, phenytoin 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 subsequent inhibition of the incidence and

spread of abnormal high-frequency discharge (Chou et al. 2014; Zhang et al. 2019). While

phenytoin 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 stimulating 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 activity, 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-clonic seizure’s tonic

phase is diminished (Osorio and Reed, 1989).

PHARMACOKINETICS

Absorption, distribution, metabolism, and excretion (ADME)

Phenytoin is well absorbed following oral administration (Urashima et al. 2019). Its

absorption takes place predominantly in the duodenum. The rate of dissolution of phenytoin

in the intestines informs its level of absorption. Peak plasma concentrations are typically

reached during a four to eight-hour 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

concentrations 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-hydroxyphenyl)-5-

phenylhydantoin (4'-HPPH). Further metabolisation to a catechol is possible, and this can

extemporaneously oxidise to quinone 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 metabolites are reported, 4′-HPPH, 3′-HPPH, 3′,4′-

diHPPH, and 3′,4′-dihydrodiol (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 individual 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 microsomes were 10 times higher than in humans (Munns et al.,

1997). The reasons for this difference in P450 metabolism are still unclear. Phenytoin 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 & 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 & LeDuc, 1995). As shown in Figure 2, the main primary

metabolites are 5(3'-hydroxyphenyl)-5-phenylhydantoin (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 isolated. Arene oxide may be responsible for the carcinogenic effects of

phenytoin. The main secondary metabolites are glucuronide conjugates of phenytoin and its

hydroxylated derivatives (Scriba et al. 1995).

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),

restlessness (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 maculopapular exanthema to

SCAR (severe cutaneous adverse reaction), including drug reactions with eosinophilia, and

systemic symptoms, including 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

problems (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 seizure (Nolan et al., 2013a,b); iplopia, blurred

vision, and colour disturbances (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 (hypocalcaemia) (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 vitamin

deficiency (Borasi et al., 2015). However, it is necessary to recognise that psychological and

behavioural side effects occur more frequently in patients taking antiepileptics other than

phenytoin (Chen et al., 2017).

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 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 temperature. The

severity of DRESS is linked to systemic involvement, and it can result in multiple organ-

failure (Ghannam et al., 2017).

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

accompanied by a change from subtherapeutic to toxic levels (McNamara, 1996). These

plasma drug concentration changes are highly linked to 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 cerebellar

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).

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., 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 arrhythmia are not typically linked to the use of this

drug. However, in cases of parenteral administration, these problems may present themselves.

Phenytoin is considered a moderately toxic substance (Imam et al., 1990). 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 genotoxic 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., 19988; 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

malformations. 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 supportive 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 decontamination can speed up recovery (Zhang

et al. 2019).

CONCLUSIONS

Phenytoin is a long-standing antiepileptic drug which exerts its effects 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 pathophysiology of primary epilepsy. A correlation may exist between the

pathogenesis 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 daily dose, a change in

formulation or brand, or a change in the frequency 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 phenytoin medication has gradually evolved from traditional drug therapy

monitoring to pharmacogenomics. From population pharmacokinetics, nonlinear mixed effect

modelling (NONMEM) has led to the development 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, including 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.

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 Table 1. Published Toxicity Data for Phenytoin

Species Test Type * 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 800mg/kg TOXNET
(800mg/kg)
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

* LD50 = Median Lethal Dose, LDLo = Lethal Dose Low, TDLo = Toxic Dose Low, NOAEL

= No-Observed-Adverse-Effect Level
Figure 1. Chemical structure of phenytoin
Figure 2. Proposed pathways of phenytoin metabolism.
HIGHLIGHTS

• phenytoin chemistry, pharmacokinetics and toxicology is reviewed

• special accent on mutagenicity, carcinogenicity and teratogenicity of phenytoin is

made

• side effects of phenytoin on human health are thoroughly described

• special attention on DRESS syndrome and cerebellar atrophy is paid

Declaration of interests

☒ The authors declare that they have no known competing financial interests or personal relationships
that could have appeared to influence the work reported in this paper.

☒The authors declare the following financial interests/personal relationships which may be considered
as potential competing interests:

Qinghua Wu
Declaration of interests

☒ The authors declare that they have no known competing financial interests or personal relationships
that could have appeared to influence the work reported in this paper.

☒The authors declare the following financial interests/personal relationships which may be considered
as potential competing interests:

Eugenie Nepovimova
Declaration of interests

☒ The authors declare that they have no known competing financial interests or personal relationships
that could have appeared to influence the work reported in this paper.

☒The authors declare the following financial interests/personal relationships which may be considered
as potential competing interests:

Jiri Patocka
Declaration of interests

☒ The authors declare that they have no known competing financial interests or personal relationships
that could have appeared to influence the work reported in this paper.

☒The authors declare the following financial interests/personal relationships which may be considered
as potential competing interests:

Kamil Kuca