Association Between ABCB1 Gene Polymorphisms and DrugResistant Epilepsy: an Integrative Review

Melo, Maria Madalena Corrêa; Rodrigues, João Paulo Vilela; Silva, Luana Sueli; Santos, Lincoln Marques Cavalcante; Varallo, Fabiana Rossi; Moraes, Natália Valadares de; Pereira, Leonardo Régis Leira

doi:10.1590/s2175-97902026e25063

Abstract

ABCB1 gene polymorphisms have been associated with drug-resistant epilepsy (DRE). This integrative review evaluates the impact of key ABCB1 single nucleotide polymorphisms (SNPs)- C3435T (rs1045642), G2677T/A (rs2032582), and C1236T (rs1128503)-on the pharmacokinetics and therapeutic response to antiseizure medications (ASMs), including carbamazepine (CBZ), lamotrigine (LTG), and topiramate (TPM). Evidence suggests that these polymorphisms significantly affect CBZ and LTG efficacy by altering drug pharmacokinetics and increasing systemic exposure. In contrast, no consistent association has been observed between these variants and TPM response. These findings support the integration of pharmacogenetic information into clinical decisionmaking to optimize ASM therapy and reduce the risk of drug resistance in epilepsy management.

Keywords:
Drug-resistant epilepsy; Genetic polymorphism; Pharmacogenetics.

INTRODUCTION

Epilepsy is a chronic neurological disorder characterized by a predisposition to recurrent, unprovoked seizures (Chen et al., 2023). Approximately 50 million people worldwide are affected by epilepsy, with a prevalence ranging from 4 to 10 cases per 1,000 individuals (Fiest et al., 2017). These statistics make epilepsy one of the most prevalent neurological conditions globally (Fiest et al., 2017; Sander, 2003).

Most patients respond well to antiseizure medications (ASMs). However, about one-third develop drug-resistant epilepsy (DRE) (Moshé et al., 2015). The International League Against Epilepsy (ILAE) defines drug resistance as the failure to control seizures despite the use of two appropriately chosen, tolerated, and adequately used ASMs, either as monotherapy or in combination (Kwan et al., 2010). The mechanisms underlying drug resistance are not fully understood but are believed to involve various genetic factors, including gene polymorphisms encoding drug-metabolizing enzymes and transporters (Kidd et al., 2001).

Among drug transporters, the clinical relevance of P-glycoprotein (P-gp) in epilepsy arises from its high expression at the blood-brain barrier (BBB), where it can reduce the brain penetration of ASMs, potentially contributing to drug resistance (Amin, 2013; Sterjev et al., 2012). P-gp belongs to the ATP-binding cassette superfamily and is broadly expressed in several human tissues, including the intestinal epithelium, liver, kidney, placenta, and the endothelial cells of BBB (Ahmed Juvale et al., 2022). In epithelial cells, such as those in the intestines and kidney tubules, P-gp is primarily located on the apical (luminal) membrane, where it pumps xenobiotics back into the lumen (Amin, 2013). In endothelial cells of the BBB, P-gp is expressed on the luminal (apical) side of the capillary endothelium, restricting drug entry into the brain (Chaves et al., 2024). This polarized expression is crucial for its function as a protective barrier against potentially harmful substances (Ahmed Juvale et al., 2022).

Given its strategic localization, P-gp significantly influences the pharmacokinetics of many drugs, including ASMs, by limiting their absorption, distribution, and access to the central nervous system (CNS) (Shahid et al., 2024; Seo et al., 2006). P-gp is encoded by the ABCB1 gene, also known as the multidrug resistance 1 (MDR1) gene, and gene polymorphisms in this gene have been extensively investigated due to their potential role in ASM resistance. Variations in the ABCB1 gene, such as the C3435T (rs1045642), G2677T/A (rs2032582), and C1236T (rs1128503) polymorphisms, can affect the expression and/or function of P-gp (Uhr et al., 2008). For instance, the 3435T allele has been associated with reduced P-gp expression in the intestines, potentially increasing systemic drug exposure (Santos et al., 2024). Although the impact of these polymorphisms on P-gp activity at the BBB remains less consistent, reduced P-gp activity could lead to increased drug penetration into the brain. Consequently, such genetic differences may influence CNS drug concentrations and play a role in individual variability in treatment response (O'Brien et al., 2012; Löscher, Potschka, 2005).

The rationale for focusing this review on ABCB1 polymorphisms lies in the hypothesis that active efflux mediated by P-gp is a key mechanism of DRE, especially for ASMs that are known or suspected substrates of this transporter. Studies suggest that altered P-gp activity can influence the pharmacokinetics of carbamazepine (CBZ), lamotrigine (LTG), and topiramate (TPM), potentially leading to treatment failure in some patients (Puranik et al., 2013; Lovrić et al., 2012; Zhao et al., 2022). For instance, CBZ is a known substrate of P-gp, and certain ABCB1 polymorphisms have been correlated with reduced therapeutic response (Fan et al., 2021). Although LTG and TPM are not as well established as P-gp substrates as CBZ, evidence suggests that their membrane permeability is limited, and P-gp may play a role in modulating their brain bioavailability (Gidal, 2014). Understanding these genetic variations is crucial for optimizing epilepsy management, particularly for patients who do not respond to conventional pharmacological therapies (Shahid et al., 2024).

In this context, this integrative review aims to assess the available evidence on the relationship between ABCB1 gene polymorphisms and drug resistance to CBZ, LTG, and TPM. The goal is to contribute to a more individualized and effective therapeutic approach for treating DRE.

MATERIAL AND METHODS

An integrative approach was adopted to identify evidence regarding the association between ABCB1 gene polymorphisms and DRE to CBZ, LTG, and TPM. The review protocol was registered in the Open Science Framework (OSF), and the methodology followed the PRISMA guidelines for systematic reviews (Page et al., 2021). The methodological quality was assessed using the Joanna Briggs Institute (JBI) tool, ensuring the validity and reliability of the analyzed evidence (Barker et al., 2023; Moola et al., 2020).

Eligibility Criteria

Studies were selected based on pre-established criteria. Eligible articles had to be published in English, Portuguese, or Spanish, be primary studies without temporal limitations, and address the association between ABCB1 gene polymorphisms and pharmacokinetic alterations or DRE to CBZ, LTG, and/ or TPM. Case reports, literature reviews, in vivo studies not involving humans, in vitro studies, commentaries, letters, and articles with incomplete or duplicate data were excluded.

Search Strategy

To conduct this review, the following research question was formulated: What is the evidence regarding the association between ABCB1 gene polymorphisms and pharmacokinetic alterations and drug resistance to CBZ, LTG, and TPM in patients with epilepsy? Based on this question, a search was conducted in the PUBMED, EMBASE, SCOPUS, and LILACS databases, using descriptors related to epilepsy ("Epilepsy", "DrugResistant Epilepsy", "Seizure Disorder"), the ASMs of interest ("Carbamazepine", "Lamotrigine", "Topiramate"), and genetic polymorphisms ("Gene Polymorphism", "ABCB1 protein, human"). The search strategy was last executed in November 2024.

Study Selection, Data Collection, and Data Analysis

The study selection and data collection process were conducted by the first and second authors. Search results from the databases were exported to the Rayyan platform, where duplicate articles were removed. Initial screening involved evaluating titles and abstracts to identify studies that met the inclusion criteria. Full-text articles were reviewed to confirm eligibility and ensure their relevance to the objectives of the review.

Data Extraction and Management

Data extraction was performed independently by the first, second, third, and fourth authors. The information collected focused on the study aim, study design, sample size, population characteristics, investigated drugs, main outcomes, and the ABCB1 gene polymorphisms analyzed. The data were organized and managed using Excel software (Microsoft Corp., Redmond, WA, USA) to facilitate the analysis and synthesis of the findings.

RESULTS

Study Selection

The database search resulted in 4,351 articles. After screening and exclusions, 28 studies were included. Details of the process are presented in the flow Figure 1.

FIGURE 1
PRISMA flow diagram of the study selection process.

Study Characteristics

The studies included in this review were primarily cohort studies (20), along with 7 case-control studies and one randomized controlled trial (RCT). A total of 8,912 patients were included, all diagnosed with epilepsy, representing a range of ages and both male and female participants. The studies were conducted in various countries, with the majority from China. In some studies, the location was not clearly specified (Table I).

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TABLE I
Studies included in the review

Study Quality

The methodological rigor of the included studies was assessed using the JBI checklists, developed for different study designs, and is presented in Table II. These tools evaluate aspects such as clear inclusion criteria, validity of measurements, control of confounding factors, adequacy of sample size, and rigor in data analysis. Each item is assessed as "yes," "no," "unclear," or "not applicable." Based on the number of criteria met, studies are classified as having strong, moderate, or weak methodological rigor, ensuring a systematic and standardized evaluation of methodological quality.

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TABLE II
Methodological Rigor of the Included Studies

This review included three different study designs. Most cohort studies had moderate methodological rigor (15), while a smaller number were classified as weak (7) or strong (2), indicating variability in quality. In the case-control studies, there was a balanced distribution between moderate (3) and weak (3) prevalence, with one study classified as strong. The only RCT included was rated as strong, reflecting the robustness of this design.

Impact of ABCB1 Gene Polymorphisms on PK and Drug Response

The studies included in this review investigated the relationship between ABCB1 gene polymorphisms and changes in the PK and drug resistance of CBZ, LTG, and/or TPM. These studies examined how genetic variations can influence plasma levels of ASMs as well as treatment response in patients with epilepsy (Table III).

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TABLE III
Impact of ABCB1 Gene Polymorphisms on PK and DRE in the Studies Included

Among the key findings, the impact of the C3435T (rs1045642) polymorphism on resistance to CBZ stands out, with the presence of the TT genotype consistently associated with increased resistance in multiple studies (Seo et al., 2006; Lovrić et al., 2012; Subenthiran et al., 2013a,b; Budikayanti et al., 2023; Rashid et al., 2024). This SNP is associated with a change in P-gp activity, where the presence of the T allele may reduce P-gp activity, affecting drug excretion and plasma concentration. The T allele is common in various populations, with frequencies typically ranging from 30-50%, depending on ethnicity. While there are no universally accepted dosage recommendations, dosage adjustments may be required based on plasma drug levels due to the altered pharmacokinetics (Sterjev et al., 2012; Saiz-Rodríguez et al., 2018).

Additionally, the G2677T/A (rs2032582) polymorphism was found to be relevant, with the T allele linked to resistance to CBZ in monotherapy, as observed in several studies (Seo et al., 2006; Lovrić et al., 2012; Rashid et al., 2024). The SNP G2677T/A (rs2032582) is associated with reduced P-gp activity, similar to C3435T (rs1045642), leading to decreased excretion of certain drugs. The TT or TA genotype may be linked to resistance to CBZ in monotherapy, resulting in reduced therapeutic effects. Dose adjustments may be necessary, especially in CBZ monotherapy, due to altered pharmacokinetics (Subenthiran et al., 2013a,b).

The SNP rs1128503 (C>T) is associated with increased clearance of CBZ, suggesting that individuals with this variant may metabolize the drug more efficiently, potentially leading to lower plasma concentrations (Puranik et al., 2013; Hung et al., 2012). In contrast, the C3435T (rs1045642, TT genotype) is associated with lower adjusted CBZ concentrations, likely due to reduced P-gp activity, which decreases drug excretion. Therefore, individuals with the TT genotype may experience higher plasma concentrations of CBZ, potentially requiring dose adjustments to avoid toxicity. These findings highlight how different genetic variants can impact drug clearance and concentrations, emphasizing the need for personalized dosing strategies (Seo et al., 2006; Lovrić et al., 2012; Subenthiran et al., 2013a,b; Budikayanti et al., 2023; Rashid et al., 2024).

Regarding LTG, the C1236T (rs1128503) and C3435T (rs1045642) polymorphisms also showed implications (Lovrić et al., 2012). Individuals with the 1236CC genotype exhibited significantly higher LTG concentrations, while the C3435T (rs1045642) genotype was associated with drug resistance (Lovrić et al., 2012; Subenthiran et al., 2013a,b). Furthermore, patients with the GG genotype in rs1128503 demonstrated lower LTG clearance, indicating reduced metabolism and potential for higher plasma concentrations (Wang et al., 2021; Zhou et al., 2015). The C1236T (rs1128503) can influence P-gp function, with the T allele associated with higher protein activity, potentially reducing drug concentrations in the blood. The CC genotype is linked to higher LTG concentrations, which may imply greater efficacy, while the TT genotype could be associated with drug resistance. Dose adjustments may be necessary for LTG, particularly for patients with the CC genotype (Hsin et al., 2020).

For TPM, although less studied, no significant associations were observed between the polymorphisms analyzed in the ABCB1 gene and its PK or drug resistance. These results suggest that for TPM, other biological factors or genes may be more relevant than ABCB1 gene polymorphisms in treatment response (Lovrić et al., 2012; Elmagid et al., 2021; Riva et al., 2023; Petrenaite et al., 2022).

Overall, among the 28 studies analyzed, CBZ was the most studied drug, especially regarding the polymorphisms C3435T (rs1045642), G2677T/A (rs2032582), and C1236T (rs1128503), which emerged as the most investigated SNPs in the context of drug resistance. Despite some investigations not finding statistically significant associations between polymorphisms and clinical outcomes, the positive analysis suggests that these relevant findings have the potential to improve the understanding of pharmacogenetics in epilepsy treatment, guiding more personalized therapeutic approaches.

The studies included in this review encompassed a wide diversity of populations and age ranges, focusing on investigating the impact of ABCB1 gene polymorphisms on PK and therapeutic response to ASMs.

In terms of age distribution, most of the research involved young and middle-aged adults (18-59 years), although some studies analyzed children (2-16 years) and elderly individuals (up to 86 years). These differences reflect the demographic characteristics specific to each population and suggest that genetic factors may have differentiated impacts depending on age. ABCB1 gene polymorphisms showed significant influence on drug resistance and changes in PK of CBZ and LTG, particularly in Asian, European, and African American populations. In contrast, TPM did not show relevant associations, indicating the need to explore other genetic or biological factors.

In summary, the review also highlighted geographic and demographic disparities in the available studies. The predominance of Asian and European populations contrasts with the scarcity of data from regions such as South America and Africa, emphasizing the need for future investigations to address these gaps and expand the global applicability of the findings.

DISCUSSION

This article investigated the relationship between ABCB1 gene polymorphisms and changes in PK and DRE to CBZ, LTG, and TPM. Drug resistance remains a significant challenge, and polymorphisms in the ABCB1 gene have been implicated in modulating responses to pharmacological treatments. Resistance to drugs may be explained by alterations in P-gp expression, which influences drug absorption and elimination, thereby reducing plasma concentrations and, consequently, its effectiveness (Callaghan, Luk, Bebawy, 2014).

Globally, ABCB1 polymorphisms exhibit significant interethnic variability, influencing patterns of drug response and adverse drug reactions (ADR) (Lovrić et al., 2012; Kidd et al., 2001; Meng et al., 2011; Haerian et al., 2011a,b; Olafuyi et al., 2021). Studies have demonstrated notable differences in allele and genotype frequencies across European, African, and Asian populations. For example, in European and American white populations, the frequency of individuals homozygous for the C and T alleles at the C3435T (rs1045642) polymorphism is approximately 25% for each genotype. In contrast, the TT genotype is rare in African populations, with frequencies ranging from 0% to 6% (Schwab et al., 2003; Ameyaw et al., 2001; Schaeffeler et al., 2001). Among Asians, the frequency of the T allele ranges from 52% to 62% (Balram et al., 2003).

In South America, and particularly in Brazil, the study of ABCB1 polymorphisms is especially relevant due to the region’s high genetic diversity, shaped by a complex history of Indigenous, European, and African admixture (Suarez-Kurtz et al., 2012). This unique genetic landscape significantly impacts pharmacogenetic variability (Suarez-Kurtz, 2010; Naslavsky et al., 2022). In Brazil, allele and genotype distributions of the C3435T (rs1045642) polymorphism vary substantially according to ancestry. The T allele frequency was 47% in white individuals, 43% in those of mixed ancestry, 25% in Black individuals, and 38% in Asians (Kim et al., 2020; Santos et al., 2011; Estrela et al., 2008). Furthermore, the distribution of C3435T (rs1045642) genotypes also differs among ethnic groups: Amerindian individuals presented 51.4% CC, 10.4% CT, and 15.8% TT genotypes; those of Caucasian descent had 43.2% CC, 16.9% CT, and 18.0% TT; individuals of mixed ancestry (Mulatto) showed 35.9% CC, 16.5% CT, and 21.3% TT; and African descent individuals had 32.8% CC, 20.2% CT, and 26.3% TT (Kim et al., 2020; Santos et al., 2011; Estrela et al., 2008). These findings highlight the need for population-specific pharmacogenetic studies to develop more effective and personalized therapeutic strategies, especially DRE, where P-gp mediated drug efflux plays a critical role in treatment outcomes.

CBZ, for example, is a first-line drug for monotherapy or adjunctive therapy in focal seizures, with or without secondary generalization (Brasil, 2022). Resistance to this drug affects a significant proportion of patients. Our results highlighted that the C3435T (rs1045642) polymorphism has been consistently associated with CBZ resistance, with the TT genotype being frequently found in patients resistant to the drug (Seo et al., 2006; Lovrić et al., 2012; Haerian et al., 2011b; Subenthiran et al., 2013a; Budikayanti et al., 2023; Sterjev et al., 2012; Rashid et al., 2024). These findings corroborate previous studies that identified a higher frequency of the T allele in CBZ-resistant patients (Kimchi-Sarfaty et al., 2007; Chouchi et al., 2017). Studies conducted in Asian and African American populations also reported an association between this polymorphism and higher resistance, reflecting significant interethnic variability in therapeutic response to the drug (Meng et al., 2011; Wang et al., 2015; Zhu et al., 2014; Puranik et al., 2013).

Evidence also suggests that the G2677T/A (rs2032582) polymorphism is associated with the development of drug resistance to CBZ (Seo et al., 2006; Lovrić et al., 2012; Rashid et al., 2024). In this case, the T allele is associated with therapeutic failure, especially in monotherapy with CBZ, as observed in studies involving Asian patients (Meng et al., 2011; Haerian et al., 2011a). According to Subenthiran et al. (2013b), the G2677T (rs2032582) polymorphism impacts the response to pharmacological therapy in patients with complex focal seizures, indicating that the T allele may serve as a useful marker to predict the response to CBZ.

Another important polymorphism in the context of CBZ is C1236T (rs1128503), which is also associated with differences in plasma concentrations and drug resistance (Seo et al., 2006; Lovrić et al., 2012; Rashid et al., 2024). Patients with the CC genotype exhibit higher plasma concentrations of CBZ, suggesting slower metabolism of the drug (Seo et al., 2006; Lovrić et al., 2012; Puranik et al., 2013; Zhu et al., 2014). These findings align with other results identifying higher CBZ concentrations in patients with the CC genotype for the C1236T (rs1128503) polymorphism in the ABCB1 gene (Lovrić et al., 2012).

LTG is a widely prescribed drug for monotherapy in focal seizures, with or without secondary generalization, in patients over 12 years old who are intolerant to or resistant to first-line ASMs (Brasil, 2022). A reallife European study included in this review showed that C1236T (rs1128503) and C3435T (rs1045642) polymorphisms in the ABCB1 gene influence LTG concentrations in blood (Lovrić et al., 2012). The CC genotype for the C1236T (rs1128503) polymorphism is associated with higher LTG concentrations, indicating a slower rate of drug metabolism (Sun et al., 2016). This plasma concentration alteration is consistent with the results of another study in our review suggesting dose adjustment for LTG based on genetic profiles (OrtegaVázquez et al., 2020).

Regarding the C3435T (rs1045642) polymorphism, there is evidence of a more complex association with drug resistance. The TT genotype would be related to a reduced response to the drug (Lovrić et al., 2012). Additionally, another study showed that the genotypes (CC, CT, and TT) are significantly more common in patients with DRE (Emich-Widera et al., 2014). The presence of the T allele may reduce LTG effectiveness by inducing P-gp, which acts as an efflux pump at the blood-brain barrier (Emich-Widera et al., 2014). Therefore, in patients with this polymorphism, drug resistance would be related to reduced penetration of LTG into the CNS (Callaghan, Luk, Bebawy, 2014; Panebianco et al., 2023).

Our findings also suggested that the rs1128503 (C>T) polymorphism is associated with lower LTG clearance, indicating that this polymorphism may be an important marker for adjusting LTG dosage in patients predisposed to higher drug concentrations (Chen et al., 2018; Petrenaite et al., 2022; Wang et al., 2021; Ortega-Vázquez et al., 2020; Zhou et al., 2015). One study showed that adjusting LTG dose based on ABCB1 polymorphisms could improve therapeutic efficacy, reducing the risk of ADR and optimizing seizure control (Chen et al., 2018). More robust studies examining the association between ABCB1 gene polymorphisms and LTG response and resistance are needed, as genes most frequently studied in relation to LTG response and resistance are those encoding cytochrome P450 enzymes (CYP450) and Glucuronosyltransferase (UGT) (Saruwatari et al., 2010; Jiang, Fu, Shen, 2024).

Regarding TPM, an effective therapeutic option for various types of epileptic seizures, we found no significant association with ABCB1 gene polymorphisms such as C3435T (rs1045642) and G2677T (rs2032582), and treatment response (Lovrić et al., 2012; Elmagid et al., 2021; Riva et al., 2023; Petrenaite et al., 2022). The literature suggests that TPM metabolism is not significantly altered by ABCB1 gene polymorphisms. This suggests that other genetic or biological factors may have a more substantial impact on TPM PK and therapeutic response (Fariba, Saadabadi, 2024) In contrast to CBZ and LTG, studies indicate that TPM drug resistance may be influenced by different variables, such as interactions with other transport and metabolism mechanisms that do not directly involve P-gp (Yeung et al., 2000).

Pharmacogenetic testing is becoming increasingly crucial in the context of personalized medicine, offering the potential to optimize drug therapy by tailoring treatments to individual genetic profiles. In this regard, clinical guidelines, such as those provided by the Clinical Pharmacogenetics Implementation Consortium (CPIC), play a pivotal role in ensuring that pharmacogenetic information is integrated into clinical practice in a practical and clinically relevant manner. These guidelines are essential for ensuring that pharmacogenetic testing is implemented in a clinically relevant and practical manner (Abdullah-Koolmees et al., 2021).

For epilepsy treatment, CPIC guidelines offers evidence-based guidelines to help clinicians interpret genetic testing to optimize drug therapy. These guidelines are particularly essential for drugs with well-established pharmacogenetic associations, such as carbamazepine where genetic variants, such as HLA-B*15:02 and HLA-A*31:01, are known to significantly influence the risk of severe adverse reactions (Phillips et al., 2018; Leckband et al., 2013). By following CPIC guidelines, clinicians can make informed decisions based on genetic testing results, which may help avoid serious adverse events and optimize therapeutic outcomes.

Despite the potential benefits of pharmacogenetic testing, its clinical implementation remains underutilized. One of the key challenges to its broader adoption is the need for more robust, large-scale studies assessing the clinical utility of pharmacogenetic testing across diverse populations. Furthermore, the integration of these testing strategies into routine clinical practice for epilepsy treatment is crucial. This integration could involve developing clear protocols for genetic testing in clinical settings and ensuring that healthcare providers are adequately trained to interpret and act on pharmacogenetic results (Hippman, Nislow, 2019).

In conclusion, adherence to CPIC guidelines is vital to the successful implementation of pharmacogenetics in epilepsy treatment, as these guidelines help clinicians navigate the complexities of genetic testing and provide personalized, safer, and more effective treatment options for patients.

In summary, the implementation of pharmacogenetic testing in clinical practice may help guide more accurate drug and dose selection, minimizing the risk of resistance and ADRs. Furthermore, integrating these findings into therapeutic management can enhance treatment adherence, reduce seizures, and improve patients' quality of life. These advancements also hold promise for the development of clinical guidelines that include genetic profiling as a criterion for ASMs prescription.

Limitations in the Included Studies

The main limitations of the included studies were the small sample size and the lack of stringent control in biological sample collection. The exclusion of comorbidities also limited the diversity of the data. While the inclusion of only patients on monotherapy is a strength, as it avoids bias from drug interactions, it is important to note that larger and multicenter studies are needed to further assess the findings across different populations. A meta-analysis could be considered to account for the effect of sample size on this assessment.

Strengths of the Review

This review provides an analysis of the relationship between ABCB1 gene polymorphisms and drug resistance to CBZ, LTG, and TPM. The quality of this article is reflected in the integration of clinical studies with different designs, such as cohort, casecontrol, and RCT, offering a comprehensive and robust understanding of the impact of polymorphisms on PK and therapeutic response.

Moreover, the analysis of genetic variations across different populations enabled the examination of data from Asian, European, and African American populations, addressing ethnic diversity and its implications for epilepsy treatment. Another notable aspect is the synthesis of results, with a clear explanation of the associations between the most investigated polymorphisms and treatment resistance. This enhances the understanding and application of the findings in the clinical context.

CONCLUSION

The analysis demonstrated that polymorphisms such as C3435T (rs1045642), G2677T (rs2032582), and C1236T (rs1128503) impact the PK and drug resistance to CBZ and LTG. This review highlights the essential role of pharmacogenetics in personalizing the treatment of patients with DRE, emphasizing the importance of considering genetic variability across populations. The results suggest that implementing therapeutic strategies tailored to genetic profiles has the potential to predict drug resistance and improve the effectiveness of pharmacological therapy, thereby enhancing the quality of life for individuals diagnosed with epilepsy, particularly those with difficult to control seizures.

DATA AVAILABILITY STATEMENT

Use of data not disclosed.

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Edited by

Associate Editor:
Silvya Stuchi Maria-Engler

Publication Dates

Publication in this collection
14 Aug 2026
Date of issue
2026

History

Received
26 Jan 2025
Accepted
03 June 2025

This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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References	Research Design	Outcome of Critical Appraisal (JBI)
Chen et al., 2018	Cohort study	Moderate
Riva et al., 2023	Cohort study	Weak
Seo et al., 2006	Cohort study	Strong
Lovrić et al., 2012	Cohort study	Moderate
Buathet et al., 2013	Cohort study	Weak
Puranik et al., 2013	Cohort study	Moderate
Ozgon et al., 2007	Cohort study	Weak
Hung et al., 2012	Cohort study	Moderate
Subenthiran et al., 2013a	Case Control study	Weak
Petrenaite et al., 2022	Cohort study	Moderate
Meng et al., 2011	Cohort study	Moderate
Wang et al., 2015	Cohort study	Moderate
Zhu et al., 2014	Cohort study	Weak
Wang et al., 2021	Cohort study	Weak
Grover et al., 2010	Case Control study	Weak
Vazquez et al., 2020	Cohort study	Moderate
Domjanović et al., 2018	Cohort study	Strong
Simon et al., 2007	Cohort study	Moderate
Haerian et al., 2011a	Case Control study	Moderate
Subenthiran et al., 2013b	Case Control study	Strong
Budikayanti et al., 2023	Case Control study	Weak
Glauser et al., 2017	Randomized Controlled Trial	Strong
Milosheska et al., 2016	Cohort study	Moderate
Zhou et al., 2015	Cohort study	Moderate
Elmagid et al., 2021	Case Control study	Weak
Sterjev et al., 2012	Cohort study	Moderate
Haerian et al., 2011b	Case Control study	Moderate
Rashid et al., 2024	Cohort study	Moderate

References	Aim of Research	Drugs Studied	Polymorphisms of the ABCB1 Gene Studied	Study Populations	Main Findings
Chen et al., 2018	To model lamotrigine pharmacokinetics in Chinese children with epilepsy, focusing on genetic, demographic, and clinical factors.	LTG	ABCB1 (rs3213619, rs3842, rs1128503, rs1045642, rs2032582)	Chinese, aged 2-16 years	That analysis did not reveal any association between ABCB1 haplotypes and LTG pharmacokinetics.
Riva et al., 2023	To explore the potential clinical utility and influence on therapeutic strategies of pharmacogenomic testing in a small cohort of patients with epilepsy.	CBZ, ZNS, CLB, VPA, RUF, LCM, PB, TPM, LEV, LTG, STP, CLZ, NZP, PGB, ETS, OXC, PER, ACZ.	ABCB1 (3435)	Italian, aged 2-60 years	No statistical association was found between ABCB1 polymorphisms and the drugs studied in this article.
Seo et al., 2006	To investigate the effect of ABCB1 polymorphisms on ASMs responsiveness and carbamazepine pharmacokinetics in epileptic patients prescribed CBZ therapy.	CBZ, PHT, PB, VPA, ZNS, BDZ.	ABCB1 (T-129C, C1236T, G2677T/A and C3435T).	Japanese, aged 1.8-51.3 years	Japanese patients with drug-resistant epilepsy had higher frequencies of certain ABCB1 gene variants. The CCGG-CC diplotype was linked to better ASM responsiveness, but no ABCB1 polymorphisms affected CBZ C/D ratios.
Lovrić et al., 2012	To evaluate the impact of ABCB1 genetic variants C1236T, G2677T/A, and C3435T on lamotrigine blood level.	LTG, VPA, PB, PHT, CBZ, OXC, TPM.	ABCB1 (C1236T, G2677T/A, C3435T).	Croatian, aged 38 ± 14 years	Carriers of the 1236CC genotype had significantly higher lamotrigine concentrations and dose-corrected values compared to CT and TT carriers (P = 0.021 and P = 0.017, respectively). These associations remained significant after correcting for multiple testing.
Buathet et al., 2013	To assess whether a candidate genetic variant in ABCB1 genes is associated with the response to LTG in Thai patients with epilepsy.	LTG	ABCB1 c.3435C>T (rs1045642).	Thai, aged 15-60 years	The ABCB1 c.3435CT and CC genotypes were linked to LTG resistance, with odds ratios of 11.15 (P = 0.001) and 4.38 (P = 0.036), respectively, after adjusting for sex, age, epilepsy syndrome, and AEDs.
Puranik et al., 2013	To evaluate the association of SNPs in genes responsible for CBZ metabolism with CBZ pharmacokinetics profiles in epilepsy patients.	CBZ	ABCB1 (rs1045642, rs1128503, rs2032582, rs4148734, rs4148739, rs4148740).	American, aged 19-87 years	ABCB1 SNP rs1128503 (C>T) was associated with higher carbamazepine clearance in AfricanAmericans. T allele carriers had greater clearance (P = 0.036). Additionally, intronic SNPs (rs4148739 and rs4148740) influenced the CBZ-diol:CBZ-E ratio in African- Americans but not in Caucasians.
Ozgon et al., 2007	To evaluate the link between the C3435T polymorphism in the MDR1 gene and drug resistance in Turkish epilepsy patients, as well as its impact on CBZ plasma levels and dose index.	CBZ	ABCB1/MDR1 exon 26 polymorphism (C>T3435).	Turkish, age not specified	No significant differences were found in genotypes or allelic frequencies between patients and controls, nor in the association between genotypes and CBZ plasma levels.
Hung et al., 2012	To identify the multiple genetic effects and the interactions between genes regarding influences on CBZ dosages, concentrations and concentration-dose ratios in epileptic patients.	CBZ	ABCB1 c.1236C>T (rs1128503), c.2677G>T/A (rs2032582), c.3435C>T (rs1045642).	Taiwanese, age not specified	ABCB1 c.1236C>T (rs1128503), c.2677G>T/A (rs2032582) and c.3435C>T (rs1045642) showed no effect on CBZ maintenance dosages; ABCB1 c.1236C>T (rs1128503), c.2677G>T/A (rs2032582), and c.3435C>T (rs1045642) showed no effect on CDRs of CBZ.
Subenthiran et al., 2013a	To examine a potential relationship between patient response to CBZ monotherapy and the G2677T SNP of the ABCB1 gene.	CBZ	ABCB1: T allele of G2677T	Malaysian, aged 18-60 years	74% of responders had the GG genotype, while 26.5% of nonresponders had GT and 39% had TT genotypes. A significant difference was found between TT and GG genotypes (OR 4.70, 95% CI 2.70-8.20). The T allele of the G2677T SNP may serve as a marker for CBZ resistance in CPS treatment.
Petrenaite et al., 2022	To evaluate how genetic polymorphisms in UGT enzymes (UGT1A4, UGT2B7, UGT2B15, UGT2B17) and ABCB1 affect lamotrigine metabolism in both men and women.	LTG, CLB, GBP, LCM, LEV, OXC, PGB, PB, TPM, VGB, ZNS, VPA.	ABCB1: c.1236 C>T (rs1128503) and c.3435 C>T (rs1045642).	Danish, aged 18-65 years	For ABCB1 c.1236C>T and ABC1B1 c.3435C>T no associations with LTG and 2-N-lamotrigineglucuronide ratios were found.
Meng et al., 2011	To evaluate associations of the C1236T, G2677T/A, and C3435T genotypes of ABCB1 and their haplotypic and diplotypic combinations with CBZ plasma levels and treatment efficacy in Chinese patients with epilepsy.	CBZ	ABCB1: C1236T, G2677T/A, and C3435T.	Chinese, aged 16-77 years	No associations were found between ABCB1 polymorphisms and adjusted CBZ plasma concentrations. However, the 3435-TT genotype had lower adjusted CBZ concentrations compared to 3435-CC, with no significant differences in CBZ resistance.
Wang et al., 2015	The study assessed the effects of genetic polymorphisms in CYP3A4/5 and ABCB1 genes on CBZ plasma concentrations in both monotherapy and bitherapy groups. It was the first to examine the effects of these genetic variations on carbamazepinaepoxide (CBZ-EP) plasma concentration, CBZ + CBZ-EP concentrations, and the CBZ-EP/CBZ ratio in the bitherapy group.	CBZ, PB, PHT, VPA.
	ABCB1: rs1045642, rs2032582, rs10234411, and rs1128503.	Chinese, aged 33 ± 14 years	In the CBZ monotherapy group, no significant associations were found between SNPs and dose-adjusted CBZ concentrations. In the CBZ + PHT/ PB group, rs776746 and rs15524, along with their haplotype, were linked to CBZ concentrations, while rs2032582 and rs10234411 were associated with the CBZE/CBZ ratio.
Zhu et al., 2014	To evaluate the effects of the above genes ABCB1, CYP3A4, CYP3A5, POR and EPHX1 polymorphisms on carbamazepine metabolism in 210 Chinese patients with epilepsy.	CBZ	ABCB1: c.1236C>T, c.2677G>T/A, c.3435C>T.	Chinese, aged 2-86 years	No associations were found between ABCB1 c.1236C>T and c.2677G>T/A polymorphisms and CBZ concentrationdose ratios. However, the 3435CC genotype was linked to higher concentrationdose ratios of carbamazepine, CBZ-epoxide, and CBZ-dihydrodiol compared to the 3435CT genotype.
Wang et al., 2021	To develop a refined population pharmacokinetic model of lamotrigine in pregnant women with epilepsy to identify factors explaining the variability in pharmacokinetics and to establish a model-informed individualized dosing regimen.	LTG	ABCB1: rs1128503, rs1045642, rs2032582.	Chinese, age not specified
	The ABCB1 rs1128503 1236 A > G polymorphism significantly reduces the apparent clearance of lamotrigine. Carriers of the GG genotype have a clearance rate of only 71.9% compared to those with the AA or AG genotypes.
Grover et al., 2010	To evaluate the genetic variability of 19 functional polymorphisms in the northern Indian population, focusing on their known associations with epilepsy pharmacogenetics, and compare these findings with allele frequencies in epilepsy patients from other major ethnic groups.	PB, PHT, CBZ, VPA	ABCB1 ( MDR1 )rs1128503, rs2032582, rs1045642, 3435C>T-2677G>T- 1236C>T.	Indian, age not specified	Sixteen SNPs were polymorphic in northern Indian epilepsy patients, with functional variants in CYP2C19, EPHX1, ABCB1, and SCN1A potentially influencing responses to antiepileptic drugs. Inter-ethnic differences may affect drug levels and dose requirements for treatment.
Vazquez et al., 2020	Investigate the influence of genetic variants in UGT1A1, UGT1A4, UGT2B7, ABCB1, ABCG2, and SLC22A1, along with coadministration of antiepileptic drugs, on plasma LTG concentrations in MM epilepsy patients.	LTG	ABCB1: c.1236T>C (rs1128503).	Mexican, aged 15-73 years	There was no significant association between ABCB1 variants and LTG plasma concentrations.
Domjanović et al., 2018	To evaluate the impact of the suggested polymorphisms in UGT, ABCG2, and MDR1/ABCB1 on the steady-state disposition of LTG.	LTG, VPA	ABCB1/MDR1: 1236C>T	Nationality not identified, aged >16 years	There was no effect of the ABCB1 polymorphisms observed.
Simon et al., 2007	To investigate the impact of genetic variations in CYP3A4, CYP2C9/19, MDR1, and MRP2 on plasma levels and dosing of CBZ and PHT, and explore whether polymorphisms in these genes affect protein expression and drug disposition.	CBZ, PHT	ABCB1/MDR1: 129T, 1236T, 2677 T/A, 3435T	Swiss, aged 21-78 years
	MDR1 expression in the intestine was higher in patients with low CBZ plasma levels. Genotypes at MDR1 positions 2677 and 3435 impacted CBZ and PHT dosing. These variations in MDR1 may explain individual pharmacokinetic differences.
Haerian et al., 2011a	To address whether the ABCB1 C1236T, G2677T/A, and C3435T polymorphisms and PXR G7635A are associated with treatment response in the Malaysian epilepsy population, as well as in the Chinese, Indian, and Malay ethnic subgroups.	CBZ, VPA	ABCB1 (C1236T, G2677T e C3435T)	Malaysian, age not specified	The study found no link between ABCB1 polymorphisms (C1236T, G2677T/A, and C3435T) and the response to CBZ or VPA in epilepsy patients in Malaysia, regardless of ethnicity. These genetic variations did not affect treatment efficacy, suggesting they may not influence drug response in epilepsy.
Subenthiran et al., 2013b	To determine the correlation between patient response to monotherapy with CBZ and the single nucleotide polymorphisms G2677T and C3435T in the ABCB1 gene, as well as G1249A and -24C>T in the ABCC2 gene.
CBZ	ABCB1: G2677T e C3435T	Malaysian, aged 18-60 years	Resistance to CBZ monotherapy was associated with 2677TT and 3435TT genotypes. The GCGC haplotype (2677G>T, 3435C>T, 1249G>A, and -24C>T) predicted positive therapeutic response. These SNPs could be used as screening markers for CBZ treatment outcomes, regardless of ethnicity or sex.
Budikayanti et al., 2023	To investigate the relationship between the MDR1 C3435T polymorphism and the plCBZ level in drug-responsive and drug-resistant patients with epilepsy.	CBZ	ABCB1/ MDR1: C3435T	Indonesian, age not specified	The study found that ABCB1 genotypes affect CBZ response in drug-resistant epilepsy. The CT genotype was linked to lower doses and plasma CBZ levels, while the TT genotype had higher plasma levels, increasing the risk of toxicity.
Glauser et al., 2017	To determine if common polymorphisms in CACNA1G, CACNA1H, CACNA1I, and ABCB1 are associated with differential shortterm seizure outcomes in childhood absence epilepsy (CAE).	EHT, LTG, VPA	ABCB1: (rs2032582, T2677G, S893A)	American, aged 2.5-13 years	The ABCB1 gene polymorphism (rs2032582/ S893A) was found more frequently in individuals without seizures who were treated with lamotrigine. This association (p = 0.015, OR = 2.22, 95% CI = 1.16-4.17) suggests that the variant may influence lamotrigine's effectiveness in preventing seizures.
Milosheska et al., 2016	To develop a population pharmacokinetic model for the quantitative assessment of the influence of genetic variability in LTG-metabolizing enzymes (UGT1A4 and UGT2B7) and transporters (ABCB1 and OCT1) on LTG pharmacokinetics, taking into account the influence of various clinical, biochemical, and demographic factors.	LTG	ABCB1: rs2032582 2677G > T/A, rs1045642 3435C > T, rs1128503 1236C > T	Slovenian, aged 20.7-80.4 years	The study showed no significant impact of the ABCB1 1236C > T polymorphism on LTG pharmacokinetics. A trend for lower LTG clearance was seen in patients with ABCB1 2677 GG and GT genotypes, but this was not statistically significant. No significant associations were found between ABCB1 haplotypes and LTG pharmacokinetics.
Zhou et al., 2015	To identify the multiple genetic impacts of UGT2B7, ABCB1, ABCG2, NR1I2, and HNF4α on LTG concentration in Chinese patients with epilepsy who received LTG as monotherapy.	LTG	ABCB1: rs1128503	Chinese, aged 12-65 years	The ABCB1 rs1128503 polymorphism was associated with the concentration/dose ratio (CDR) of LTG, suggesting that this gene may affect the pharmacokinetics of LTG.
Elmagid et al., 2021	To study the relationship between the MDR1 C3435T SNP and therapy response in Egyptian children.	VPA, CBZ, LEV, OXC, TPM, CLZ, PHT, LCM, LTG	ABCB1/MDR1: C3435T	Egyptian, aged 6.83-8.58 years	No significant association was found between the ABCB1 C3435T polymorphism and the response to carbamazepine, topiramate, and lamotrigine. The study suggests that the ABCB1 C3435T polymorphism may have a specific role in resistance to valproate sodium.
Sterjev et al., 2012	To investigate the influence of the ABCB1 C3435CT SNP on CBZ therapy efficacy in patients with epilepsy in the Republic of North Macedonia.	CBZ	ABCB1: C3435T	Macedonian, aged 53 ± 15.5 years	The study found no significant association between the ABCB1 C3435T polymorphism and the efficacy of CBZ, TPM e LTG. However, individuals with the TT genotype needed higher carbamazepine doses, affecting plasma levels. These results suggest ABCB1 expression may influence treatment response, warranting further research.
Haerian et al., 2011b	To investigate a possible link between the ABCB1 haplotypes rs3789243 C > T, C1236T, G2677T/A, rs6949448 C > T, and C3435T with the response to CBZ or VPA monotherapy in Malaysian patients with epilepsy.	CBZ, VPA	ABCB1: rs3789243 C > T, C1236T, G2677T/A, rs6949448 C > T, and C3435T	Malaysian, age not specified	The study found no association between the polymorphisms and treatment response or interactions with haplotypes in any patient group. These polymorphisms appear not to influence the therapeutic response to CBZ or VPA. Thus, they likely do not affect treatment outcomes.

Year of publication	Title	Journal	References
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2013	Association of carbamazepine major metabolism and transport pathway gene polymorphisms and pharmacokinetics in patients with epilepsy	Pharmacogenomics	Puranik et al., 2013
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2012	Association of polymorphisms in EPHX1, UGT2B7, ABCB1, ABCC2, SCN1A and SCN2A genes with carbamazepine therapy optimization	Pharmacogenomics	Hung et al., 2012
2013	G2677T polymorphism can predict treatment outcome of Malaysians with complex partial seizures being treated with Carbamazepine	Genetics and Molecular Research	Subenthiran et al., 2013b
2022	Effect of UGT1A4, UGT2B7, UGT2B15, UGT2B17 and ABC1B polymorphisms on lamotrigine metabolism in Danish patients	Epilepsy Research	Petrenaite et al., 2022
2011	Effects of ABCB1 polymorphisms on plasma carbamazepine concentrations and pharmacoresistance in Chinese patients with epilepsy	Epilepsy & Behavior	Meng et al., 2011
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2013	Linkage disequilibrium between polymorphisms of ABCB1 and ABCC2 to predict the treatment outcome of Malaysians with complex partial seizures on treatment with carbamazepine mono-therapy at the Kuala Lumpur Hospital	Plos One	Subenthiran et al., 2013a
2023	Multidrug Resistance-1 C3435T Polymorphism and Carbamazepine Plasma Level in Indonesian Temporal Lobe Epilepsy Patients	Current Drug Safety	Budikayanti et al., 2023
2017	Pharmacogenetics of antiepileptic drug efficacy in childhood absence epilepsy	Annals of Neurology	Glauser et al., 2017
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2015	Polymorphisms of ABCG2, ABCB1 and HNF4α are associated with Lamotrigine trough concentrations in epilepsy patients.	Drug Metabolism and Pharmacokinetics	Zhou et al., 2015
2021	The association between MDR1 C3435T genetic polymorphism and the risk of multidrug- resistant epilepsy in Egyptian children	Egyptian Journal of Medical Human Genetics	Elmagid et al., 2021
2012	The association of C3435T single-nucleotide polymorphism, Pgp-glycoprotein gene expression levels and carbamazepine maintenance dose in patients with epilepsy	Neuropsychiatric Disease and Treatment	Sterjev et al., 2012
2011	Lack of association of ABCB1 and PXR polymorphisms with response to treatment in epilepsy	Seizure	Haerian et al., 2011b
2024	The association of ABCB1 gene polymorphism with clinical response to carbamazepine monotherapy in patients with epilepsy	Molecular biology reports	Rashid et al., 2024