ВВЕДЕНИЕ

safetyrisk

Безопасность и риск фармакотерапии

Safety and Risk of Pharmacotherapy

2312-78212619-1164

Federal State Budgetary Institution ‘Scientific Centre for Expert Evaluation of Medicinal Products’ of the Ministry of Health of the Russian Federation (FSBI ‘SCEEMP’)

10.30895/2312-7821-2025-498

safetyrisk-498

Research Article

ГЛАВНАЯ ТЕМА: ЭВОЛЮЦИЯ ФАРМАКОНАДЗОРА: ИНТЕГРАЦИЯ НОВЫХ ИСТОЧНИКОВ ДАННЫХ, ПОПУЛЯЦИОННЫХ ИCСЛЕДОВАНИЙ И ПРЕДИКТИВНЫХ ТЕХНОЛОГИЙ

MAIN TOPIC: EVOLUTION OF PHARMACOVIGILANCE: INTEGRATING NEW DATA SOURCES, POPULATION STUDIES AND PREDICTIVE TECHNOLOGIES

Мультиомические технологии в прогнозировании нейротоксичности ламотриджина: современные возможности (обзор)

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

https://orcid.org/0000-0002-2840-837X

Шнайдер

Н. А.

Shnayder

N. A.

Шнайдер Наталья Алексеевна, д-р мед. наук, профессор

ул. Бехтерева, д. 3, Санкт-Петербург, 192019; ул. Партизана Железняка, д. 1, г. Красноярск, 660022

Natalia А. Shnayder, Dr. Sci. (Med.), Professor

3 Bekhterev St., St Petersburg 192019; 1 Partizan Zheleznyak St., Krasnoyarsk 660022

naschnaider@yandex.ru

https://orcid.org/0000-0001-8279-4198

Бадер

В. В.

Bader

V. V.

Бадер Виолетта Владимировна

ул. Бехтерева, д. 3, Санкт-Петербург, 192019; наб. Обводного канала, д. 9, Санкт-Петербург, 191167

Violetta V. Bader

3 Bekhterev St., St Petersburg 192019; 9 Obvodny Canal Emb., St. Petersburg 191167

grechkina.vv@mail.ru

https://orcid.org/0000-0003-1874-9434

Насырова

Р. Ф.

Nasyrova

R. F.

Насырова Регина Фаритовна, д-р мед. наук

ул. Бехтерева, д. 3, Санкт-Петербург, 192019; пр. Ленина, д. 92, г. Тула, 300012

Regina F. Nasyrova, Dr. Sci. (Med.)

3 Bekhterev St., St Petersburg 192019; 92 Lenin Ave., Tula 300012

regina_nmrcpn@mail.ru

https://orcid.org/0000-0002-4186-5911

Киссин

М. Я.

Kissin

M. Ya.

Киссин Михаил Яковлевич, д-р мед. наук, профессор

наб. Обводного канала, д. 9, Санкт-Петербург, 191167; ул. Льва Толстого, д. 6–8, Санкт-Петербург, 197022

Mikhail Ya. Kissin, Dr. Sci. (Med.), Professor

9 Obvodny Canal Emb., St. Petersburg 191167; 6–8, Lev Tolstoy St., St Petersburg 197022

kissin.m@yandex.ru

Институт персонализированной психиатрии и неврологии, федеральное государственное бюджетное учреждение «Национальный медицинский исследовательский центр психиатрии и неврологии им. В.М. Бехтерева» Министерства здравоохранения Российской Федерации; Центр коллективного пользования «Молекулярные и клеточные технологии», федеральное государственное бюджетное образовательное учреждение высшего образования «Красноярский государственный медицинский университет имени профессора В.Ф. Войно-Ясенецкого» Министерства здравоохранения Российской ФедерацииРоссияInstitute of Personalized Psychiatry and Neurology, V.M. Bekhterev National Medical Research Center for Psychiatry and Neurology; Shared Core Facilities Molecular and Cell Technologies Krasnoyarsk State Medical UniversityRussian Federation

Институт персонализированной психиатрии и неврологии, федеральное государственное бюджетное учреждение «Национальный медицинский исследовательский центр психиатрии и неврологии им. В.М. Бехтерева» Министерства здравоохранения Российской Федерации; Городской эпилептологический центр, Санкт-Петербургское государственное казенное учреждение здравоохранения «Городская психиатрическая больница № 6 (стационар с диспансером)»РоссияInstitute of Personalized Psychiatry and Neurology, V.M. Bekhterev National Medical Research Center for Psychiatry and Neurology; City Epileptology Centre, City Psychiatric Hospital No. 6Russian Federation

Городской эпилептологический центр, Санкт-Петербургское государственное казенное учреждение здравоохранения «Городская психиатрическая больница № 6 (стационар с диспансером)»; Федеральное государственное бюджетное образовательного учреждение высшего образования «Первый Санкт-Петербургский государственный медицинский университет имени академика И.П. Павлова»РоссияCity Epileptology Centre, City Psychiatric Hospital No. 6; Pavlov First St. Petersburg State Medical UniversityRussian Federation

2026

31032026

1415165

2026

Шнайдер Н.А., Бадер В.В., Насырова Р.Ф., Киссин М.Я.

Shnayder N.A., Bader V.V., Nasyrova R.F., Kissin M.Y.

Данная работа распространяется под лицензией Creative Commons Attribution 4.0.

This work is licensed under a Creative Commons Attribution 4.0 License.

https://www.risksafety.ru/jour/article/view/498

ВВЕДЕНИЕ

ВВЕДЕНИЕ. Ламотриджин (ЛТД) — один из наиболее часто назначаемых противоэпилептических препаратов второго поколения. Препарат имеет низкий тератогенный потенциал, однако обладает генетически и метаболически детерминированными нейротоксическим, гепатотоксическим, дерматотоксическим эффектами и в некоторых случаях может вызвать полиорганную недостаточность. Понимание механизмов действия ЛТД с учетом фармакогеномики и фармакометаболомики, определяющих особенности его метаболизма, транспорта и элиминации у конкретного пациента позволит обеспечить индивидуализацию терапии и повысить ее безопасность.

ЦЕЛЬ

ЦЕЛЬ. Разработка подхода к терапии ламотриджином эпилепсии и других неврологических и психических заболеваний с учетом фармакогеномики и фармакометаболомики для снижения риска нейротоксичности препарата.

ОБСУЖДЕНИЕ

ОБСУЖДЕНИЕ. Метаболизм ЛТД осуществляется в печени глюкуронидацией (основной путь) и Р-окислением (второстепенный путь). В результате образуются как нейтральные, так и токсические (реактивные) метаболиты ЛТД, которые могут длительно циркулировать в крови, проникать через поврежденный гематоэнцефалический барьер у пациентов с терапевтически резистентными эпилептическими приступами и оказывать нейротоксический эффект, запуская или поддерживая механизмы нейродегенерации: нарушение нейротрансмиссии, синаптической пластичности, апоптоз нейронов. Большое значение в нейротоксичности ЛТД играют транспортные белки, участвующие в эффлюксе (выведении) токсических метаболитов из головного мозга в системный кровоток, а также из гепатоцитов в желудочно-кишечный тракт с желчью и через почки с мочой. Генетически детерминированное замедление эффлюкса препарата через гематоэнцефалический барьер (фармакогеномика) повышает нейротоксический потенциал ЛТД.

ВЫВОДЫ

ВЫВОДЫ. Для оценки риска ЛТД-индуцированных нежелательных реакций наряду с клинической оценкой состояния пациента целесообразно проводить: 1) терапевтический лекарственный мониторинг (кровь, волосы, слюна, грудное молоко); 2) анализ потенциально токсичных метаболитов (кровь, слюна, волосы); 3) фармакогенетическое тестирование носительства нефункциональных полиморфизмов генов, кодирующих ключевые белки-транспортеры и ферменты, участвующие в метаболизме ЛТД. Внедрение результатов фармакогенетического и фармакометаболического тестирования в клиническую практику эпилептолога позволит снизить риск нейротоксичности ЛТД.

INTRODUCTION

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

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

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

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.

ламотриджинпротивоэпилептический препаратметаболизмглюкуронидацияР-окислениеметаболиты ламотриджиналамотриджин-N-оксидламотриджин-N-метилфармакогеномикафармакометаболомиканежелательная реакциянейротоксичность

lamotrigineantiepileptic druglamotrigine metabolismglucuronidationP-oxidationlamotrigine metabolitespharmacogenomicspharmacometabolomicsadverse drug reactionneurotoxicity

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The authors declare that there are no conflicts of interest present.