Interaction between Cytochrome P450 Isozymes and Antiseizure Medications: A Literature Review

Urfianty^1,2*, Aidah Juliaty¹, Idham Jaya Ganda¹, Jumraini Tammase³,

Irfan Idris², Irawan Mangunatmadja⁴, Muhammad Yunus Amran³, Yanti Leman⁵

¹Department of Pediatrics, Faculty of Medicine,

Hasanuddin University, Makassar, 90245, South Sulawesi, Indonesia.

²Doctoral Program, Graduate School of Medicine,

Hasanuddin University, Makassar, 90245, South Sulawesi, Indonesia.

³Department of Neurology, Faculty of Medicine,

Hasanuddin University, Makassar, 90245, South Sulawesi, Indonesia.

⁴Departement of Pediatrics, Faculty of Medicine,

University of Indonesia, Jakarta Pusat, 10430, Jakarta, Indonesia.

⁵Department of Pharmacology, Faculty of Medicine,

Hasanuddin University, Makassar, 90245, South Sulawesi, Indonesia.

*Corresponding Author E-mail: urfiantysaid@yahoo.com

ABSTRACT:

Antiseizure medications (ASMs) are frequently utilized either as ongoing supplementary treatment or as the primary therapy for epilepsy. Different ASMs either inhibit of induce isoenzymes of CYP450 system, potentially altering the pharmacokinetic characteristics of various medications, including in polytherapy of ASMs. This study investigate the interaction between CYP450 and ASMs, with emphasis on pharmacokinetic interactions. This literature study included publications from the last 5 years (2018-2023) that are relevant to the topic and important publications retrieved and reviewed from the PubMed, ResearchGate, and Google Scholar databases by using a combination of main keywords "antiseizure medications", "cytochrome P450", "pharmacokinetics", "metabolism" and other relevant keywords. It was found that due to the role of CYP450 enzymes in metabolizing most therapeutic drugs, individuals using ASMs that induce these enzymes may metabolize a diverse array of concurrently administered medications more rapidly, potentially leading to an increase in dosage requirements. Phenytoin, primidone, phenobarbital and carbamazepine enhance the function of various cytochrome P450 (CYP) enzymes, such as CYP2C9, CYP1A2, CYP3A4 and CYP2C19. On the other hand, inhibition of these enzymes could elevate the plasma level of drugs that are metabolized via those enzymes. Valproic acid and oxcarbazepine are the examples of CYP450 inhibitors. The majority of significant interactions involving ASMs in clinical contexts arise from either the stimulation or suppression of CYP450 drug-metabolizing enzymes. These interactions can lead to alterations in the pharmacokinetic characteristics of various medications. Typically, adjustments to the dosage of the affected AED are necessary. Additional research and investigations are necessary regarding possible interaction between CYP450 and newer ASMs to determine the possible outcome due to these interactions.

KEYWORDS: Antiseizure medications, Cytochrome P450, Pharmacokinetics, Metabolism.

INTRODUCTION:

Epilepsy is a chronic neurological condition impacting 65 million individuals globally, spanning all age groups. Its occurrence is most prevalent among young children below the age of 2 and adults aged 65 and above.^1,2 Around 50% to 60% of children who experience seizure eventually outgrow them and do not have seizures in adulthood. This condition stands as the foremost neurological contributor to a reduction in overall quality of life.^2–4 Correct intervention can only commence once epilepsy is accurately diagnosed, primarily through clinical evaluations. Diagnostic investigations, primarily based on electroencephalography and neuroimaging, particularly magnetic resonance imaging, provide essential support in this process.^5–9

Population-based research on drug usage reported that 19% to 24% of individuals with epilepsy treated with polytherapy involving ASMs. Recent investigations into both children and adult populations with treatment-resistant epilepsy show that 64% of children receive polytherapy with two or more ASMs, while adults (35%) contend with CNS-related comorbidities, posing a significant risk of interactions.^10,11 As age increases, the use of polytherapy and the likelihood of interactions with other medications also rise. Among those experiencing new-onset epilepsy, the elderly constitute the largest demographic, facing a notable risk of interactions with commonly prescribed drugs.^12–14

The P450 enzyme system in the liver metabolizes the majority of ASMs.¹⁵ Cytochrome P450 (CYP450) enzymes derive their name from their association with cellular membranes (cyto) and their possession of a heme-containing- pigment (P and chrome) that absorbs light at 450 nm upon exposure to carbon monoxide.¹⁶ The CYP2C9,CYP1A2, CYP2D6, CYP2C19, CYP3A5 and CYP3A4 enzymes that handle about 90% of drug metabolism, although out of more than 50 enzymes of CYP450.^17–20Various ASMs can either induce or inhibit specific isoenzymes within this system, potentially leading to alterations in the pharmacokinetic characteristics of various medications., including in polytherapy of ASMs.¹¹

This study focused on clinically significant interactions between ASMs, particularly their combined effects on CYP450 enzymes, with emphasis on pharmacokinetic interactions. This study is expected to be the basis for future studies for advanced drug interactions in newer ASMs which have not been described in previous reviews.

METHODS:

This study is a literature review study. The search strategy used a combination of the keywords "antiseizure medications", "cytochrome P450", "pharmacokinetics", "metabolism", and other relevant keywords. Publications from last 5 years (2018-2023) that are relevant to the topic plus important publications to include are then retrieved from the PubMed, ResearchGate, and Google Scholar databases.

Pathogenesis of Epilepsy:

Epilepsies represent a diverse and intricate array of conditions primarily distinguished by recurring, spontaneous, and unpredictable seizures. Seizures and epilepsy result from disruption inhibitory and excitatory signals in nervous system. Several mechanisms that control neuron electrical function, many different ways to perturb this balance, and therefore many different causes of both epilepsy and seizures. There are 6 categories for etiology of epilepsy: structural, genetic, immune, infectious, metabolic, and unknown.^13,15 The mechanisms can result in epilepsy (Figure 1).^21,22

Classification of Epilepsy:

An operational classification of seizure introduced by The International League Against Epilepsy (ILAE). (Figure 2).⁶

Figure 2. Classifcation of Epilepsy ILAE 2017⁶

Three cathegory of seizures such as generalized, focal and unknown onset. Focal epilepsies encompass both unifocal and multifocal disorders, and also seizures that affect unilateral hemisphere. Various seizure types can be observed, such as focal impaired awareness seizures, focal aware seizures, focal non-motor seizures, focal motor seizures and focal to bilateral tonic-clonic seizures. ^2,5,6

ASMs:

ASMs are medications that reduce the seizures’ frequency or intensity in individuals with epilepsy. The term "anticonvulsant drug," although formerly used interchangeably with AED, is now less precise because not all seizures involving convulsive movements. No decisive evidence to implied that ASMs "cure" epilepsy or modify its course significantly. Nevertheless, many patients who have achieved complete seizure control for two or more years can safely discontinue ASMs. The main purpose of the treatment is to optimize seizure management while minimizing any negative drug effects, ultimately enhancing the patient's quality of life.^5,8,23,24

A seizure occurs when a hyperexcitable network of neurons exhibits abnormal electrical activity, disrupting the balance between excitation and inhibition. Successful seizure management typically involves enhancing inhibitory mechanisms or counteracting excitatory processes. Given that the typical resting state of a neuronal membrane is characterized by a negative intracellular potential, inhibitory mechanisms work to further polarize the neuron negatively, resulting in hyperpolarization of the membrane. Conversely, excitatory processes work to depolarize the cell by reducing the negativity or increasing the positivity of the intracellular potential. Inhibition is often facilitated by potassion influx or chloride efflux currents at ionic level, while excitation involves calcium or sodium influx currents. Medications can directly target specific ion channels or indirectly impact neurotransmitter or receptor synthesis, metabolism, or function, thus regulating channel activity. Gamma amino butyric acid (GABA) is the main neurotransmitter which inhibits in the CNS. The main important excitatory neurotransmitter is glutamate, involved in several receptor subtypes.^5,8,10

ASMs can be categorized based on their primary mode of action, although many exhibit multiple actions, while some have mechanisms of action that remain unclear (Figure 3).²⁵

Figure 3. Mechanisms of action of ASMs²⁵

The primary categories include calcium current inhibitors, sodium channel blockers, enhancers of gamma-aminobutyric acid (GABA), blockers of glutamate, inhibitors of carbonic anhydrase, hormones, and medications with mechanisms of action that are not fully understood. Drugs of choice in ASMs were revealed in Table 1.

Table 1. Drugs of choice in ASMs^{5,10,11,26–28}

Drug	Indication	Pharmacokinetics	Laboratory/ Clinical Monitoring	Mechanism of Action
First-Generation ASMs
Carbamazepine	Complex partial seizures, generalized tonic-clonic seizures, mixed seizure patterns or other partial or generalized seizures. Not given for Absence seizures.	Half-life: Start from 25–65 hrs, decrease at 12–17 hrs on repeated doses Bioavailability: 89% Plasma Protein Binding: 70–80% Peak concentrations in plasma of carbamazepine epoxide are achieved in two hours or less for suspension, whereas enteric-coated tablets are slower on average 5–7 hours	CBC, LFT	Inhibit sodium channels that depend on voltage during high-frequency firing
Phenobabital	Generalized and partial seizures.	Half-life: Adults: 53–118 hrs (mean 79 hrs) Children and newborns (<48 hrs old): 60–180 hrs (mean 110 hrs) Bioavailability: 70–90% Plasma Protein Binding:20–45% Plasma concentration peaked at 2 hours post oral administration	Sedation, CBC, LFT, serum levels	At high firing frequencies, they inhibit voltage-dependent sodium channels.
Phenytoin	Prescribed for managing generalized tonic-clonic, complex partial seizures, as well as for preventing and treating seizures during or after neurosurgery.	Half-life: Oral: 7–42 hrs (average 22 hrs) Infatabs: 7–29 hrs (average 14 hrs) Bioavailability: 100% Plasma Protein Binding: 90–95% Peak plasma concentration for the extended-release capsule occurs between 4 to 12 hours, while for the chewable tablet and suspension, it ranges from 2 to 3 hours	CBC, LFT, Serum Levels	At high firing frequencies, they inhibit voltage-dependent sodium channels.
Valproate	Indicated for simple and complex absence seizures. It recommended for use as both monotherapy and adjunctive therapy. It is also used as an adjunctive treatment for patients with multiple seizure types, including absence seizures	Half-life: Newborns (1^st week of life): 30–60 hours Newborns <10 days: 10–67 hours Children > 2 months: 7–13 hours 2–14 years: 3.5–20 hours Adults: 8–17 hours Bioavailability: Approximately 100% (oral and IV are equivalent) Plasma Protein Binding: 80–90%	CBC, LFT	May increase GABA transmission in certain circuits and inhibit voltage-dependent sodium channels
Ethosuximide	Prescribed for managing absence seizures.	Half-life: Children: 30 hrs Adults: 50–60 hrs Bioavailability: 100% Plasma Protein Binding: <10% Plasma concentrations peaked in 1 to 4 hours for capsules, whereas syrup is faster.	CBC, LFT	Block low threshold, “transient\|” (T-type) calcium channel in neurons of thalamic.
Second-Generation ASMs
Felbamate	Indicated for partial seizures, with or without generalization in adults. It also used to treat partial and generalized seizures associated with Lennox-Gastaut syndrome in children	Half-life: 20–30 hrs Bioavailability: 90% Plasma Protein Binding: 22–25% Peak plasma concentrations achieved in about 3 hours.	CBC, LFT	It could inhibit sodium channels that depend on voltage during high-frequency firing and adjust the NMDA receptor by interacting with the strychnine-insensitive glycine receptor.
Gabapentin	Prescribed as an additional therapy. It can be given to adults. It used to manage partial seizures with or without secondary generalization.	Half-life: 5–7 hrs Bioavailability: 60% Plasma Protein Binding: < 3% Peak concentrations in plasma in 2-3 hours.	Weight	May modulate amino acid transport into brain and interfere with GABA re-uptake
Lamotrigine	Prescribed as supplementary treatment for adults experiencing partial seizures and generalized seizures associated with Lennox-Gastaut Syndrome.	Half-life: Ages 10 mnthso-5.3 years: 7.7–44.9 hrs Ages 5–11 years: 7.0–65.8 hrs Adults: 14.4–70.3 hrs Depends if patient is on an Behaviour-inducing or inhibiting anticonvulsant Bioavailability: 98% Plasma Protein Binding:** 55% Peak plasma concentration achieved within 2 to 3 hours.	Rash, CBC, LFT	It inhibits sodium channels that depend on voltage during high-frequency firing and disrupts the abnormal release of glutamate.
Oxcarbazepine	Indicated for complex partial seizures and generalized tonic-clonic seizures. It also can be used for mixed seizure patterns or other partial or generalized seizures. Not indicated for Absence seizures.	Half-life: 3 to 13 hrs Bioavailability: 96% Plasma Protein Binding: 33% Peak plasma concentration within 4 hours	BMP, hyponatremia	It inhibits sodium channels that depend on voltage during high-frequency firing and affects potassium channels.
Topiramate	Prescribed as an additional treatment for both pediatric and adults aged 2–16 years. It used to pediatric with partial onset seizures or primary generalized tonic-clonic seizures.	Half-life: 21 hrs Bioavailability: 80% Plasma Protein Binding: 13–17% Peak concentration in plasma between 2 to 4 hours	Weight, renal stones, cognition, ocular pressure	It inhibits sodium channels that rely on voltage during high-frequency firing, enhances the frequency at which GABA opens chloride channels (at a different site than benzodiazepines), and opposes glutamate's effects on the AMPA/kainate receptor subtype.
Zonisamide		Half-life: 50 – 70 hrs Bioavailability: 82 –88% Plasma Protein Binding: 40–60%	None	It inhibits T-type calcium channels and voltage-dependent sodium channels.
Third Generation ASMs
Vigabatrin	Infantile spasms* Partial seizures* * not FDA approved	Half-life: 50 – 70 hrs Bioavailability: 82 –88% Plasma Protein Binding: 40–60%	Visual fields	Irreversibly inhibits GABA-transaminase
Others: clobazam, lacosamide, perampenel, rufinamide, levetiracetam, etc.

Table 2. Significant CYP450 enzymes and their ASMs inhibitors, inducers, and substrates¹¹

Drugs	Elimination main route	Main enzyme system involved	Degradation of CYP	Induction of CYP	Inhibition of CYP
Older generation ASMs
Carbamazepine	Oxidation	CYP3A4	Yes, 3A4, and epoxide hydrolase (metabolite)	Yes, CYP3A4, 2C9, 1A2	No
Ethosuximide	Oxidation	CYP3A4	Yes, CYP3A4	No	No
Phenobarbital	Oxidation + N-glucosidation (75% of the drug) and excretion via the renals (25%)	CYP2C19 and CYP2C9	Yes, 2C19, 2E1, CYP2C9	Yes, CYP3A4, 2C9, 1A2	No
Phenytoin	Oxidation	CYP2C9 and CYP2C19	Yes, CYP2C9, 2C19	Yes, CYP3A4, 2C9, 1A2	Yes, CYP2C9
Valproic acid	Oxidation (>50% of drug) and glucuronide conjugation (30–40%)	Oxidation of mitochondrial, CYPs and glucuronyl transferases	Yes, 2A6, 2B6 2C9, 2C19 and oxidation of mitochondrials	No	Yes,CYP3A4?, CYP2C9 and epoxide hydrolase
Newer generation ASMs
Felbamate	Oxidation (>50% of drug) and excretion via the renals (>30%)	Inducible isoforms of CYP	Yes, CYP 3A4, 2E1	CYP3A4	CYP2C19
Gabapentin	Excretion via the renals	None	No	No	No
Lamotrigine	Glucuronide conjugation	Type 1A4 Glucuronyl transferase	No	No	No
Levetiracetam	Excretion via the renals (75% of drug) and hydrolysis (25%)	Hydrolase	No	No	No
Oxcarbazepine	>50% of drug eliminate from lucuronide conjugation <30% of drug renal excretion.	Glucuronyl transferases	No	Yes, CYP3A4	Yes, CYP2C19
Pregabalin	Excretion via the renals	None	No	No	No
Tiagabine	Oxidation	CYP3A4	Yes, CYP3A4	No	No
Topiramate	Oxidation (20–60%) and excretion via the renals (40–80%)	Inducible CYP isoforms	Yes,but the spesific isoenzymes not identified	Yes, CYP3A4 (At dose >200 mg/day)	Yes, CYP2C19

CONCLUSION:

ASMs are medications designed to reduce the occurrence and/or intensity of seizures in individuals suffering from epilepsy. Most significant interactions with ASMs in a clinical setting are caused by the activation or suppression of enzymes that metabolize drugs. The majority of ASMs undergo metabolism in the liver through processes such as hydroxylation or conjugation, with the P450 enzyme system in the liver is in charge for the metabolism of most of these ASMs.

CONFLICT OF INTEREST:

All the authors confirm that there are no conflicts of interest related to this study.

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Received on 26.02.2024 Revised on 09.07.2024

Accepted on 17.10.2024 Published on 27.03.2025

Available online from March 27, 2025

Research J. Pharmacy and Technology. 2025;18(3):1089-1095.

DOI: 10.52711/0974-360X.2025.00156

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