Evaluation of the effect of ethylmethylhydroxypyridine succinate on the activity of the BCRP transporter protein in vitro

Relevance. Breast cancer resistance protein (BCRP) is one of the main clinically significant transporter proteins that play an important role in the pharmacokinetics of drugs. To predict the development of drug interactions at the level of this transporter, it is recommended to test drugs for belonging to substrates and BCRP inhibitors.

Objective. Comparative assessment of the effect of ethylmethylhydroxypyridine succinate (EMHPS) on the activity of the BCRP transporter protein under in vitro conditions using sulfasalazine as a substrate.

Materials and methods. The study was performed in vitro on Caco-2 cells that were cultured in a transwell-system. Sulfasalazine was used as a BCRP substrate. EMHPS was used in the concentration range of 0.1 — 500 µM. A classic BCRP inhibitor, quercetin, was used as a comparison drug. The concentration of sulfasalazine in the transport medium was determined by HPLC-MS/MS.

Results. During the study, it was shown that EMHPS inhibited BCRP activity in the concentration range of 50–500 µM. In terms of inhibitory activity, the tested drug was inferior to the comparison drug quercetin — the IC₅₀ of quercetin was 0.2 µM, the IC₅₀ of EMHPS was 37.5 µM. To study the clinical significance of the inhibitory ability of EMHPS, the ratio C_max of EMHPS/IC₅₀ (predicts systemic inhibition of BCRP in the liver, kidneys, and histohematic barriers) and the ratio dose of EMHPS/ 250 ml / IC₅₀ (predicts inhibition of BCRP in the intestine) were calculated. It has been shown that EMHPS can clinically significantly inhibit BCRP in the intestine.

Conclusion. Thus, EMHPS is an inhibitor of BCRP in vitro. To confirm the significance of the obtained results for the development of drug-drug interactions, it is necessary to conduct clinical studies.

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