TY  - JOUR
T1  - Evaluation of the genotoxicity/mutagenicity of levetiracetam, lamotrigine, and oxcarbazepine using in silico methods
AU  - Yalçın, Can Özgür
AU  - Yılmaz Sarıaltın, Sezen
PY  - 2025
DA  - July
Y2  - 2025
DO  - 10.12991/jrespharm.1734646
JF  - Journal of Research in Pharmacy
JO  - J. Res. Pharm.
PB  - Marmara University
WT  - DergiPark
SN  - 2630-6344
SP  - 1682
EP  - 1692
VL  - 29
IS  - 4
LA  - en
AB  - Epilepsy is a chronic neurological disease affecting approximately 50 million people globally, including pregnant women. The symptoms of epilepsy, obstetric complications, and the adverse effects of antiepileptic drugs on the fetus are problems for pregnant women. Medications prescribed for epilepsy treatment are typically used over an extended period. In this study, the mutagenic and genotoxic potentials of levetiracetam (LEV), lamotrigine (LTG), and oxcarbazepine (OXC), the most widely prescribed new-generation antiepileptic drugs, and their respective metabolites were evaluated using computational methods. The latest treatment protocols indicate that these drugs can be administered during pregnancy with minimal risk to the fetus compared to other antiepileptics. Metabolite analysis of LEV, LTG, and OXG was performed using MetaTox (v.2.0). The selected drugs and their respective known-predicted metabolites were analyzed for potential genotoxic/mutagenic behavior using VEGA (v.1.2.3) and EPA TEST (v.4.2.1 and 5.1.2) in both statistical-based computational methodologies. Molecular structural alerts for genotoxicity/mutagenicity were performed using the OECD QSAR Toolbox (v.4.7) with an expert rule-based approach. Metabolites of LTG and OXC, especially those formed by epoxidation, pose a risk of mutagenicity and genotoxicity. VEGA and EPA mutagenicity consensus models predicted OXC-M10, M11, M12, M13, and M14, which were formed by epoxidation, were predicted as mutagenic. Our findings indicate that LEV might be safer concerning its genotoxicity/mutagenicity potential, whereas OXC warrants cautious prescribing and further research, particularly for use during pregnancy and in long-term treatments. Further in vivo experimental studies are needed to analyze this risk.
KW  - Levetiracetam
KW  - lamotrigine
KW  - oxcarbazepine
KW  - toxicology in silico
KW  - genotoxicity
KW  - mutagenicity
CR  - [1]WHO (2024) https://www.who.int/news-room/fact-sheets/detail/epilepsy (accessed on 1 December 2024)
CR  - [2]Tomson T, Sha L, Chen L. Management of epilepsy in pregnancy: What we still need to learn. Epilepsy Behav Rep. 2023; 24: 100624. https://doi.org/10.1016/j.ebr.2023.100624
CR  - [3]Hernández-Díaz S, Smith CR, Shen A, Mittendorf R, Hauser WA, Yerby M, Holmes LB; North American AED Pregnancy Registry; North American AED Pregnancy Registry. Comparative safety of antiepileptic drugs during pregnancy. Neurology. 2012;78(21):1692-1699. https://doi.org/10.1212/WNL.0b013e3182574f39
CR  - [4]Wlodarczyk BJ, Palacios AM, George TM, Finnell RH. Antiepileptic drugs and pregnancy outcomes. Am J Med Genet A. 2012; 158A: 2071-2090. https://doi.org/10.1002/ajmg.a.35438
CR  - [5]Vajda FJ, O‘Brien TJ, Lander CM, Graham J, Eadie MJ. The teratogenicity of the newer antiepileptic drugs - an update. Acta Neurol Scand. 2014; 130: 234-238. https://doi.org/10.1111/ane.12280
CR  - [6]Campbell E, Kennedy F, Russell A, Smithson WH, Parsons L, Morrison PJ, et al. Malformation risks of antiepileptic drug monotherapies in pregnancy: updated results from the UK and Ireland Epilepsy and Pregnancy Registers. J Neurol Neurosurg Psychiatry. 2014; 85: 1029-1034. https://doi.org/10.1136/jnnp-2013-306318
CR  - [7]Veiby G, Daltveit AK, Engelsen BA, Gilhus NE. Fetal growth restriction and birth defects with newer and older antiepileptic drugs during pregnancy. J Neurol. 2014; 261: 579-588. https://doi.org/10.1007/s00415-013-7239-x
CR  - [8]Weston J, Bromley R, Jackson CF, Adab N, Clayton-Smith J, Greenhalgh J, Hounsome J, McKay AJ, Tudur Smith C, Marson AG. Monotherapy treatment of epilepsy in pregnancy: congenital malformation outcomes in the child. Cochrane Database Syst Rev. 2016; 11: CD010224. https://doi.org/10.1002/14651858.CD010224.pub2
CR  - [9]Thomas SV, Jose M, Divakaran S, Sankara Sarma P. Malformation risk of antiepileptic drug exposure during pregnancy in women with epilepsy: Results from a pregnancy registry in South India. Epilepsia. 2017; 58: 274-281. https://doi.org/10.1111/epi.13632
CR  - [10]Khuda I, Aljaafari D. Epilepsy in pregnancy. A comprehensive literature review and suggestions for saudi practitioners. Neurosciences (Riyadh). 2018; 23(3): 185-193. https://doi.org/10.17712/nsj.2018.3.20180129
CR  - [11]Azarbayjani F. Common Mechanism for Teratogenicity of Antiepileptic Drugs. Acta Universitatis Upsaliensis, Uppsala 2001. https://uu.diva-portal.org/smash/get/diva2:168467/FULLTEXT01.pdf
CR  - [12]Niriayo YL, Mamo A, Kassa TD, Asgedom SW, Atey TM, Gidey K, Demoz GT, Ibrahim S. Treatment outcome and associated factors among patients with epilepsy. Sci Rep. 2018; 8(1): 17354. https://doi.org/10.1038/s41598-018-35906-2
CR  - [13]Klein P, McLachlan R, Foris K, Nondonfaz X, Elmoufti S, Dimova S, Brandt C. Effect of lifetime antiepileptic drug treatment history on efficacy and tolerability of adjunctive brivaracetam in adults with focal seizures: post-hoc analysis of a randomized, placebo-controlled trial. Epilepsy Res. 2020; 167: 106369. https://doi.org/10.1016/j.eplepsyres.2020.106369
CR  - [14]Veroniki AA, Cogo E, Rios P, Straus SE, Finkelstein Y, Kealey R, Reynen E, Soobiah C, Thavorn K, Hutton B, Hemmelgarn BR, Yazdi F, D'Souza J, MacDonald H, Tricco AC. Comparative safety of anti-epileptic drugs during pregnancy: a systematic review and network meta-analysis of congenital malformations and prenatal outcomes. BMC Med. 2017; 15: 95. https://doi.org/10.1186/s12916-017-0845-1
CR  - [15]Tomson T, Battino D, Bromley R, Kochen S, Meador K, Pennell P, Thomas SV. Management of epilepsy in pregnancy: a report from the International League Against Epilepsy Task Force on Women and Pregnancy. Epileptic Disord. 2019; 21(6): 497-517. https://doi.org/10.1684/epd.2019.1105
CR  - [16]Mitra-Ghosh T, Callisto SP, Lamba JK, Remmel RP, Birnbaum AK, Barbarino JM, Klein TE, Altman RB. PharmGKB summary: lamotrigine pathway, pharmacokinetics and pharmacodynamics. Pharmacogenet Genomics. 2020; 30(4): 81-90. https://doi.org/10.1097/FPC.0000000000000397
CR  - [17]Preuss CV, Randhawa G, Wy TJP, Saadabadi A. Oxcarbazepine. [Updated 2023 Aug 28]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. https://www.ncbi.nlm.nih.gov/books/NBK482313/ (accessed on 1 November 2024)
CR  - [18]Kumar A, Maini K, Kadian R. Levetiracetam. [Updated 2023 Dec 3]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. https://www.ncbi.nlm.nih.gov/books/NBK499890/ (accessed on 1 November 2024)
CR  - [19]Leek JC, Arif H. Pregnancy Medications. [Updated 2023 Jul 24]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. https://www.ncbi.nlm.nih.gov/books/NBK507858/ (accessed on 5 November 2024)
CR  - [20]Bank AM, Stowe ZN, Newport DJ, Ritchie JC, Pennell PB. Placental passage of antiepileptic drugs at delivery and neonatal outcomes. Epilepsia. 2017; 58(5): e82-e86. https://doi.org/10.1111/epi.13733
CR  - [21]Finnel RH. Teratology: General considerations and principles. . J Allergy Clin Immunol. 1999;103(2 Pt 2):S337-342. https://doi.org/10.1016/S0091-6749(99)70259-9
[22]Wichard JD. In silico prediction of genotoxicity. Food Chem Toxicol. 2017;106(Pt B):595-599.https://doi.org/10.1016/j.fct.2016.12.013
CR  - [23]Benigni R. In silico assessment of genotoxicity. Combinations of sensitive structural alerts minimize false negative predictions for all genotoxicity endpoints and can single out chemicals for which experimentation can be avoided. Regul Toxicol Pharmacol. 2021;126:105042.https://doi.org/10.1016/j.yrtph.2021.105042
CR  - [24]Tran TTV, Surya-Wibowo A, Tayara H, Chong KT. Artificial Intelligence in Drug Toxicity Prediction: Recent Advances, Challenges, and Future Perspectives. J Chem Inf Model. 2023; 63(9): 2628–2643. https://doi.org/10.1021/acs.jcim.3c00200
CR  - [25]Amorim AMB, Piochi LF, Gaspar AT, Preto AJ, Rosário-Ferreira N, Moreira IS. Advancing Drug Safety in Drug Development: Bridging Computational Predictions for Enhanced Toxicity Prediction. Chem Res Toxicol. 2024; 37(6): 827–849. https://doi.org/10.1021/acs.chemrestox.3c00352
CR  - [26]Kirchmair J, Göller AH, Lang D, Kunze J, Testa B, Wilson ID, Glen RC, Schneider G. Predicting drug metabolism: experiment and/or computation. Nat Rev Drug Discov. 2015; 14: 387-404. https://doi.org/10.1038/nrd4581
CR  - [27]Testa B, Pedretti A, Vistoli G. Reactions and enzymes in the metabolism of drugs and other xenobiotics. Drug Discov Today. 2012; 17: 549-560. https://doi.org/10.1016/j.drudis.2012.01.017
CR  - [28]Guengerich FP. Metabolic activation of carcinogens. Pharmacol Therapeut. 1992; 54(1): 17-61. https://doi.org/10.1016/0163-7258(92)90050-a
CR  - [29]KEPPRA® (Levetiracetam). https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/021035s078s080,021505s021s024lbl.pdf (accessed on 14 December 2024)
CR  - [30]LAMICTAL® (Lamotrigine). https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020241s037s038,020764s030s031lbl.pdf (accessed on 15 December 2024)
CR  - [31]TRILEPTAL® (Oxcarbazepine). https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/021014s036lbl.pdf (accessed on 15 December 2024)
CR  - [32]O’Connor SE, Zupanc ML. Women and epilepsy. J Pediatr Pharmacol Ther. 2009; 14(4): 212-220. https://doi.org/10.5863/1551-6776-14.4.212
CR  - [33]Furness DL, Dekker GA, Roberts CT. DNA damage and health in pregnancy. J Reprod Immunol. 2011; 89(2): 153-162. https://doi.org/10.1016/j.jri.2011.02.004
CR  - [34]Hovinga CA, Pennell PB. Antiepileptic drug therapy in pregnancy II: Fetal and neonatal exposure. Int Rev Neurobiol. 2008; 83: 241–258. https://doi.org/10.1016/S0074-7742(08)00014-7
CR  - [35]REACH Regulation (EC) No 1907/2006 of the European Parliament and of the Council of 18 December 2006 Concerning the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH), Establishing a European Chemicals Agency, Amending Directive 1999/45/EC and Repealing Council Regulation (EEC) No 793/93 and Commission Regulation (EC) No 1488/94 as Well as Council Directive 76/769/EEC and Commission Directives 91/155/EEC, 93/67/EEC, 93/105/EC and 2000/21/EC. 2006. https://eur-lex.europa.eu/legal-content/EN/TXT/?uri=CELEX%3A02006R1907-20140410 (accessed on 17 November 2024)
CR  - [36]Aniceto N, Freitas AA, Bender A, Ghafourian T. A novel applicability domain technique for mapping predictive reliability across the chemical space of a QSAR: Reliability-density neighbourhood. J Cheminf. 2016; 8: 1-20. https://doi.org/10.1186/s13321-016-0182-y
CR  - [37]Kardoost M, Hajizadeh-Saffar E, Ghorbanian MT, Ghezelayagh Z, Pooshang-Bagheri K, Behdani M, Habibi-Anbouhi M. Genotoxicity assessment of antiepileptic drugs (AEDs) in human embryonic stem cells. Epilepsy Res. 2019; 158: 106232. https://doi.org/10.1016/j.eplepsyres.2019.106232
CR  - [38]Tural S, Tekcan A, Elbistan M, Karakuş N, Ozyurek H, Kara N. Genotoxic effects of prenatal exposure to levetiracetam during pregnancy on rat offsprings. In vivo. 2015; 29(1): 77–81.
CR  - [39]Atlı-Şekeroğlu Z, Kefelioğlu H, Kontaş-Yedier S, Şekeroğlu V, Delmecioğlu B. Oxcarbazepine-induced cytotoxicity and genotoxicity in human lymphocyte cultures with or without metabolic activation. Toxicol Mec Methods. 2017; 27(3): 201-206. https://doi.org/10.1080/15376516.2016.1273430
CR  - [40]Sarikaya R, Yüksel M. Genotoxic assessment of oxcarbazepine and carbamazepine in drosophila wing spot test. Food Chem Toxicol. 2008; 46(9): 3159-3162. https://doi.org/10.1016/j.fct.2008.06.089
CR  - [41]Akbar H, Khan A, Mohammadzai I, Khisroon M, Begum I. The genotoxic effect of oxcarbazepine on mice blood lymphocytes. Drug Chem Toxicol. 2018; 41(2): 135-140. https://doi.org/10.1080/01480545.2017.1321011
CR  - [42]Rudik AV, Dmitriev AV, Lagunin AA, Filimonov DA, Poroikov VV. MetaTox 2.0: Estimating the Biological Activity Spectra of Drug-like Compounds Taking into Account Probable Biotransformations. ACS Omega. 2023 ;8(48):45774-45778. https://doi.org/10.1021/acsomega.3c06119
CR  - [43]U.S. EPA. User’s Guide for T.E.S.T. (version 4.2) (Toxicity Estimation Software Tool). 2016. https://cfpub.epa.gov/si/si_public_record_report.cfm?dirEntryId=326210&Lab=NRMRL (accessed on 02 December 2024)
CR  - [44]U.S. EPA. User’s Guide for T.E.S.T. (version 5.1) (Toxicity Estimation Software Tool). 2020. https://www.epa.gov/comptox-tools/toxicity-estimation-software-tool-test (accessed on 02 December 2024)
CR  - [45]Mombelli E, Fernández A, Cester J. Mutagenicity (Ames test) CONSENSUS model-v. 1.0.4. 2022 https://vegahub.eu/vegahub-dwn/qmrf/QMRF_MUTA_CONSENSUS.pdf (accessed on 15 December 2024)
CR  - [46]OECD Toolbox. 2024. https://www.oecd.org/en/data/tools/oecd-qsar-toolbox.html (accessed on 20 December 2024)
CR  - [47]Benfenati E, Manganaro A, Gini GC. VEGA-QSAR: AI inside a platform for predictive toxicology. Workshop on Popularize Artificial Intelligence. 2013. https://hero.epa.gov/hero/index.cfm/reference/details/reference_id/3380800 (accessed on 15 December 2024)
CR  - [48]Toropov AA, Toropova AP, Raitano G, Benfenati E. CORAL: Building up QSAR models for the chromosome aberration test. Saudi J Biol Sci. 2019 26(6):1101-1106. https://doi.org/10.1016/j.sjbs.2018.05.013
CR  - [49]Baderna D, Gadaleta D, Lostaglio E, Selvestrel G, Raitano G, Golbamaki A, Lombardo A, Benfenati E. New in silico models to predict in vitro micronucleus induction as marker of genotoxicity. J Hazard Mater. 2020;385:121638. https://doi.org/10.1016/j.jhazmat.2019.121638
UR  - https://doi.org/10.12991/jrespharm.1734646
L1  - https://dergipark.org.tr/en/download/article-file/5022208
ER  -