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

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

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. 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.

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