Evaluation of the genotoxicity/mutagenicity of levetiracetam, lamotrigine, and oxcarbazepine using in silico methods

Abstract

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.

Keywords

• Levetiracetam
• lamotrigine
• oxcarbazepine
• toxicology in silico
• genotoxicity
• mutagenicity

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