Ethylmethylhydroxypyridine Succinate Is an Inhibitor but Not a Substrate of ABCB1 and SLCO1B1
2-Ethyl-6-methyl-3-hydroxypyridine succinate (EMHPS, Mexidol) is an original antioxidant and an anti-ischemic drug with the possibility of wide applications in the complex therapy of diseases, accompanied by the development of oxidative stress and ischemia; for example, ischemic stroke, chronic cere...
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Published in | Pharmaceuticals (Basel, Switzerland) Vol. 16; no. 11; p. 1529 |
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Abstract | 2-Ethyl-6-methyl-3-hydroxypyridine succinate (EMHPS, Mexidol) is an original antioxidant and an anti-ischemic drug with the possibility of wide applications in the complex therapy of diseases, accompanied by the development of oxidative stress and ischemia; for example, ischemic stroke, chronic cerebral ischemia, and chronic heart failure. The use of EMHPS in the complex therapy of the above diseases may cause the development of drug–drug interactions, particularly pharmacokinetic interactions at the level of transporter proteins. In the present study, we evaluated the interaction of EMHPS with ABCB1 and SLCO1B1. In Caco-2 cells, it was shown that EMHPS is not a substrate of ABCB1 and that it does not affect its expression, but at the same time, it inhibits the activity of this transporter. Its inhibitory activity was inferior to verapamil—a classic inhibitor of ABCB1. In HEK293 and HEK293-SLCO1B1 cells, it was shown that EMHPS is not a substrate of SLCO1B1 either, but that it inhibited the activity of the transporter. However, its inhibitory activity was inferior to the classic inhibitor of SLCO1B1-rifampicin. Furthermore, it was found out that EMHPS does not affect SLCO1B1 expression in HepG2 cells. The approach proposed by the FDA (2020) and the International Transporter Consortium (2010) was used to assess the clinical significance of the study results. The effect of EMHPS on SLCO1B1 and the systemic inhibition of ABCB1 by EMPHS are not clinically significant, but ABCB1 inhibition by EMHPS in the gastrointestinal tract should be tested in vivo through clinical trials. |
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AbstractList | 2-Ethyl-6-methyl-3-hydroxypyridine succinate (EMHPS, Mexidol) is an original antioxidant and an anti-ischemic drug with the possibility of wide applications in the complex therapy of diseases, accompanied by the development of oxidative stress and ischemia; for example, ischemic stroke, chronic cerebral ischemia, and chronic heart failure. The use of EMHPS in the complex therapy of the above diseases may cause the development of drug–drug interactions, particularly pharmacokinetic interactions at the level of transporter proteins. In the present study, we evaluated the interaction of EMHPS with ABCB1 and SLCO1B1. In Caco-2 cells, it was shown that EMHPS is not a substrate of ABCB1 and that it does not affect its expression, but at the same time, it inhibits the activity of this transporter. Its inhibitory activity was inferior to verapamil—a classic inhibitor of ABCB1. In HEK293 and HEK293-SLCO1B1 cells, it was shown that EMHPS is not a substrate of SLCO1B1 either, but that it inhibited the activity of the transporter. However, its inhibitory activity was inferior to the classic inhibitor of SLCO1B1-rifampicin. Furthermore, it was found out that EMHPS does not affect SLCO1B1 expression in HepG2 cells. The approach proposed by the FDA (2020) and the International Transporter Consortium (2010) was used to assess the clinical significance of the study results. The effect of EMHPS on SLCO1B1 and the systemic inhibition of ABCB1 by EMPHS are not clinically significant, but ABCB1 inhibition by EMHPS in the gastrointestinal tract should be tested in vivo through clinical trials. |
Audience | Academic |
Author | Kotliarova, Maria S Shchulkin, Aleksey V Mylnikov, Pavel Yu Abalenikhina, Yulia V Yakusheva, Elena N Goncharenko, Anna V Chernykh, Ivan V Erokhina, Pelageya D |
Author_xml | – sequence: 1 fullname: Shchulkin, Aleksey V – sequence: 2 fullname: Erokhina, Pelageya D – sequence: 3 fullname: Goncharenko, Anna V – sequence: 4 fullname: Mylnikov, Pavel Yu – sequence: 5 fullname: Chernykh, Ivan V – sequence: 6 fullname: Abalenikhina, Yulia V – sequence: 7 fullname: Kotliarova, Maria S – sequence: 8 fullname: Yakusheva, Elena N |
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Title | Ethylmethylhydroxypyridine Succinate Is an Inhibitor but Not a Substrate of ABCB1 and SLCO1B1 |
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