safetyriskБезопасность и риск фармакотерапииSafety and Risk of Pharmacotherapy2312-78212619-1164Federal State Budgetary Institution ‘Scientific Centre for Expert Evaluation of Medicinal Products’ of the Ministry of Health of the Russian Federation (FSBI ‘SCEEMP’)10.30895/2312-7821-2018-6-2-78-85safetyrisk-104Research ArticleОРИГИНАЛЬНЫЕ СТАТЬИORIGINAL ARTICLESФАРМАКОГЕНЕТИКА ОСНОВНЫХ ПРЕДСТАВИТЕЛЕЙ ТРАНСПОРТЕРОВ ОРГАНИЧЕСКИХ КАТИОНОВPHARMACOGENETICS OF ORGANIC CATION TRANSPORTERSЕвтеевВ. А.EvteevV. A.

Евтеев Владимир Александрович. Младший научный сотрудник Центра клинической фармакологии. 

Петровский б-р, д. 8, стр. 2, Москва, 127051

Evteev Vladimir A. Junior researcher, Clinical Pharmacology Center. 

8/2 Petrovsky Blvd, Moscow 127051

Evteev@expmed.ruКазаковР. Е.KazakovR. E.

Казаков Руслан Евгеньевич. Начальник отдела персонализированной медицины и клинической фармакогенетики Центра клинической фармакологии. 

Петровский б-р, д. 8, стр. 2, Москва, 127051

Kazakov Ruslan E. Head of the Department of personalised medicine and clinical pharmacogenetics of the Clinical Pharmacology Center.

8/2 Petrovsky Blvd, Moscow 127051

МуслимоваО. А.MuslimovaO. A.

Муслимова Ольга Валерьевна. Старший научный сотрудник Центра клинической фармакологии

Петровский б-р, д. 8, стр. 2, Москва, 127051

 

Muslimova Olga V. Senior researcher, Clinical Pharmacology Center.

8/2 Petrovsky Blvd, Moscow 127051 

ДемченковаЕ. Ю.DemchenkovaE. Yu.

Демченкова Елена Юрьевна. Старший научный сотрудник Центра клинической фармакологии  

Петровский б-р, д. 8, стр. 2, Москва, 127051

Demchenkova Еlena Yu. Senior researcher, Clinical Pharmacology Center. 

8/2 Petrovsky Blvd, Moscow 127051

Федеральное государственное бюджетное учреждение «Научный центр экспертизы средств медицинского применения» Министерства здравоохранения Российской ФедерацииРоссияScientific Centre for Expert Evaluation of Medicinal ProductsRussian Federation201821062018627885Copyright © Евтеев В.А., Казаков Р.Е., Муслимова О.А., Демченкова Е.Ю., 20182018Евтеев В.А., Казаков Р.Е., Муслимова О.А., Демченкова Е.Ю.Evteev V.A., Kazakov R.E., Muslimova O.A., Demchenkova E.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/104

В статье представлены основные сведения о классификации, строении, субстратной специфичности и экспрессии транспортеров органических катионов. Более подробно рассмотрены фармакокинетические и фармакогенетические аспекты транспортеров, а также их участие во взаимодействии лекарств. Транспортеры органических катионов входят в семейство SLC-транспортеров и представлены тремя основными изоформами: ОСТ1, ОСТ2, ОСТ3. По строению они аналогичны другим представителям этого семейства и имеют 12 трансмембранных доменов. ОСТ1 экспрессируется преимущественно в печени, ОСТ2 — в почках, а ОСТ3 имеет наиболее широкую распространенность среди всех транспортеров этого семейства и экспрессируется в печени, плаценте, почках, скелетных мышцах, сердце и мозге. Регуляция экспрессии транспортеров осуществляется главным образом за счет наличия сайтов гликозилирования и фосфорилирования в больших петлях между 1,2 и 6,7 доменами соответственно. Среди эндогенных субстратов ОСТ — катехоламины, нейротрансмиттеры, стероидные гормоны и др. Среди лекарственных препаратов субстратами ОСТ являются: метформин, ганцикловир, прокаинамид, цисплатин, циметидин и др. Гены ОСТ располагаются в одном кластере протяженностью 300000 п.н. на длинном плече 6-й хромосомы. Для ОСТ1 известно 4 наиболее изученных полиморфизма: rs12208357, rs34130495, rs72552763 и rs34059508. Для ОСТ2 единственным клинически значимым полиморфизмом является rs316019. Для ОСТ3 на данный момент известно 4 полиморфизма: A116S, T400I, A439V, и M370I. Лекарственные взаимодействия при участии ОСТ возникают при приеме субстратов, являющихся ингибиторами транспортеров. Наиболее изучено влияние на фармакокинетику ЛС циметидина и препаратов платины. Транспортеры органических катионов в настоящее время продолжают активно изучаться. С каждым годом увеличивается количество ЛС, на фармакокинетику которых эти транспортеры оказывают влияние.

This article describes basic information about the classification, structure, substrate specificity and expression of organic cation transporters. The pharmacokinetic and pharmacogenetic aspects of transporters are discussed in more detail, as well as their participation in drug-drug interactions. Organic cation transporters are members of the SLC family which include three isoforms: OCT1, OCT2, OCT3. They are similar in structure to other members of this family and have 12 transmembrane domains. OCT1 is expressed predominantly in the liver, OCT2 in the kidneys, and OCT3 is the most common among all transports of this family and is expressed in the liver, placenta, kidneys, skeletal muscles, heart and brain. The regulation of transporter expression is mainly due to the presence of glycosylation and phosphorylation sites in large loops between 1,2 and 6,7 transmembrane domains, respectively. Among the endogenous substrates OCT — catecholamines, neurotransmitters, steroid hormones, etc. Among drugs, substrates of OCT are: metformin, ganciclovir, procainamide, cisplatin, cimetidine, etc. All three OCT genes are located in one cluster with a length of 300,000 bp. on the long arm of the 6th chromosome. For OCT1 the four most studied polymorphisms are known: rs12208357, rs34130495, rs72552763 and rs34059508. For OCT2, the only clinically relevant polymorphism is rs316019. For OCT3 at the moment, there are 4 polymorphisms: A116S, T400I, A439V, and M370I. Drug-drug interactions involving OCT occur when the substrate is inhibitor of the transporter. The effect of cimetidine and platinum drugs on the pharmacokinetics of drugs has been most studied. Organic cation transporters are currently being actively studied. Every year the number of drugs that are substrates of OCT is growing.

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