vedomostiregmedРегуляторные исследования и экспертиза лекарственных средствRegulatory Research and Medicine Evaluation3034-30623034-3453Federal State Budgetary Institution ‘Scientific Centre for Expert Evaluation of Medicinal Products’ of the Ministry of Health of the Russian Federation (FSBI ‘SCEEMP’)10.30895/1991-2919-2020-10-3-177-183vedomostiregmed-308Research ArticleОБЗОРЫREVIEWSβ-лактамные антибиотики – межлекарственное взаимодействие на уровне транспортеров органических анионов ОАТ1 и ОАТ3β-Lactam Antibiotics—Drug-Drug Interaction Mediated by Organic Anion Transporters OAT1 and OAT3https://orcid.org/0000-0002-3733-6822МазеркинаИ. А.MazerkinaI. A.

Мазеркина Ирина Анатольевна, канд. мед. наук

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

Irina A. Mazerkina, Cand. Sci

8/2 Petrovsky Blvd, Moscow 127051

mazerkina@expmed.ruhttps://orcid.org/0000-0002-6150-5796ЕвтеевВ. А.EvteevV. A.

Евтеев Владимир Александрович

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

Vladimir A. Evteev

8/2 Petrovsky Blvd, Moscow 127051

evteev@expmed.ruhttps://orcid.org/0000-0001-7024-5546ПрокофьевА. Б.ProkofievA. B.

Прокофьев Алексей Борисович, д-р мед. наук

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

Aleksey B. Prokofiev, Dr. Sci. (Med.)

8/2 Petrovsky Blvd, Moscow 127051

prokofiev@expmed.ruhttps://orcid.org/0000-0003-1009-9609МуслимоваО. В.MuslimovaO. V.

Муслимова Ольга Валерьевна, канд. мед. наук

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

Olga V. Muslimova, Cand. Sci. (Med.)

8/2 Petrovsky Blvd, Moscow 127051

muslimova@expmed.ruhttps://orcid.org/0000-0003-1972-4386ДемченковаЕ. Ю.DemchenkovaE. Yu.

Демченкова Елена Юрьевна, канд. фарм. наук

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

Elena Yu. Demchenkova, Cand. Sci. (Pharm.)

8/2 Petrovsky Blvd, Moscow 127051

demchenkova@expmed.ruФедеральное государственное бюджетное учреждение «Научный центр экспертизы средств медицинского применения» Министерства здравоохранения Российской ФедерацииРоссияScientific Centre for Expert Evaluation of Medicinal ProductsRussian Federation202028062020103177183Copyright © Мазеркина И.А., Евтеев В.А., Прокофьев А.Б., Муслимова О.В., Демченкова Е.Ю., 20202020Мазеркина И.А., Евтеев В.А., Прокофьев А.Б., Муслимова О.В., Демченкова Е.Ю.Mazerkina I.A., Evteev V.A., Prokofiev A.B., Muslimova O.V., 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.vedomostincesmp.ru/jour/article/view/308

Транспортеры органических анионов (ОАТ1/3) играют ключевую роль в выведении большинства β-лактамных антибиотиков из организма. Поскольку субстратами ОАТ1/3 являются также нестероидные противовоспалительные средства, противовирусные, противоопухолевые и другие препараты, это создает условия для межлекарственного взаимодействия (МЛВ). Цель работы — определить на основании данных научной литературы вероятность и значимость, а также возможность прогнозирования МЛВ β-лактамных антибиотиков на уровне транспортеров органических анионов. Показано, что в клинической практике ингибирование выведения β-лактамных антибиотиков используют для повышения их системной экспозиции и снижения стоимости антибиотикотерапии. Ингибиторы ОАТ циластатин и бетамипрон используются в комбинированных препаратах для снижения нефротоксичности карбапенемов. С другой стороны, отмечено, что повышение концентрации β-лактамных антибиотиков вследствие ингибирования ОАТ может привести к появлению нежелательных реакций. В связи с этим Европейское агентство по лекарственным средствам и Управление по контролю за качеством продуктов питания и лекарственных средств рекомендуют при разработке новых лекарственных средств в случае значимого почечного выведения (≥25%) проводить исследования их транспорта ОАТ1/3 in vitro с вычислением константы ингибирования Ki и/или концентрации полумаксимального ингибирования IC50 для прогнозирования МЛВ. Выявлено, что одной из основных проблем при этом является вариабельность значений Ki и IC50 между лабораториями и необходима разработка единых общих рекомендаций по методикам определения данных показателей для различных транспортеров.

Organic anion transporters OAT1 and OAT3 play a key role in elimination of most β-lactam antibiotics. Since nonsteroidal anti-inflammatory drugs, antivirals, antitumor agents, and some other drugs are also substrates of OAT1/3, this enables drug-drug interaction (DDI). The aim of the study was to analyze scientific literature to determine the likelihood and significance of β-lactam antibiotic DDI mediated by organic anion transporters, as well as potential for predicting it. In clinical practice, inhibition of β-lactam antibiotic elimination is used to increase systemic exposition and reduce the cost of antibiotic therapy. OAT inhibitors (cilastatin, betamipron) are used in combination drugs to reduce nephrotoxicity of carbapenems. On the other hand, an increase in the concentration of β-lactams due to OAT inhibition may lead to adverse drug reactions. Therefore, the European Medicines Agency and the Food and Drug Administration recommendations for the development of new drugs state that in the case of significant renal excretion (≥25%) it is necessary to investigate OAT1/3 transport in vitro and calculate inhibition constant Ki and/or half maximal inhibitory concentration IC50 for predicting DDI. One of the main problems is the variability of Ki and IC50 values between laboratories, which requires the development of general recommendations for different transporters as regards methods of determination of these parameters.

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