Multi-Omics in Predicting Lamotrigine Neurotoxicity: Current Opportunities (Review)

INTRODUCTION. Lamotrigine (LTG) is among the most commonly prescribed second-generation antiepileptic drugs due to its low teratogenic risk. However, lamotrigine has pronounced neurotoxic, hepatotoxic, dermatotoxic potential (for genetic and metabolic causes) and in some cases can even cause multi-organ failure. Understanding lamotrigine mechanism can help individualise therapy and increase its safety, considering pharmacodynamics and pharmacometabolomics that determine its metabolism, transport, and elimination in a particular patient. AIM. This study aimed to develop an approach to lamotrigine therapy of epilepsy and other neurological and psychiatric diseases reducing neurotoxicity, with due regard to pharmacogenomics and pharmacometabolomics. RESULTS. LTG is metabolised in the liver in two pathways: glucuronidation (major pathway) and P-oxidation (minor pathway). As a result, neutral and toxic (reactive) lamotrigine metabolites are produced that can circulate in blood serum for a long time, penetrate the damaged blood-brain barrier in patients with therapy-resistant seizures and have a neurotoxic effect, triggering or maintaining neurotransmission disorders, impaired synaptic plasticity, neuronal apoptosis and other neurodegeneration mechanisms. An important role in lamotrigine neurotoxicity belongs to transport proteins involved in the efflux (excretion) of reactive (toxic) metabolites from the brain into the systemic circulation, as well as from hepatocytes into the gastrointestinal tract by bile and through the kidneys with urine. Genetically determined delayed efflux through the blood-brain barrier (pharmacogenomics) increases lamotrigine neurotoxic potential. CONCLUSION. To assess the risk of lamotrigine-induced adverse reactions, together with clinically assessing patient’s condition, it is recommended to: 1) monitor drug distribution (blood, hair, saliva, breast milk); 2) analyse potentially toxic metabolites (blood, saliva, hair); 3) perform pharmacogenetic tests for non-functional polymorphisms of genes encoding key transport proteins and enzymes involved in drug metabolism. Results of pharmacogenetic and pharmacometabolic tests applied in the clinical practice of an epileptologist will allow to manage lamotrigine neurotoxiсity.