Assessment of drugs belonging to inhibitors and inductors of p-glycoprotein in vitro

Abstract

The article describes modern approaches for testing of drugs belonging to substrates and inhibitors of P-glycoprotein (Pgp, ABCB1-protein, MDR1-protein) according to the recommendations of Food and Drug Administration (United States) and European Medicines Agency. In vitro methods on cell lines with hyperexpression of the transporter are presented. The same analysis was done on human colon adenocarcinoma cell line (Caco-2).

Keywords

P-glycoprotein / ABCB1 protein / substrates / inhibitors / in vitro testing / Caco-2 cell line

References

[1] Якушева Е.Н., Титов Д.С. Структура и функционирование белка множественной лекарственной устойчивости 1 // Биохимия. – 2018. – Т. 83. – № 8. – С. 1148–1172. [Yakusheva EN, Titov DS. Structure and Function of Multidrug Resistance Protein 1. Biochemistry. 2018;83(8):1148–1172. (In Russ.)] https://doi.org/10.1134/S 0320972518080043.

[2] Якушева Е.Н., Щулькин А.В., Попова Н.М., и др. Структура, функции гликопротеина-Р и его значение для рациональной фармакотерапии // Обзоры по клинической фармакологии и лекарственной терапии. – 2014. – Т. 12. – № 2. – С. 3–11. [Yakusheva EN, Shulkin AV, Popova NM, et al. Structure, functions of P-glycoprotein and its role in rational pharmacotherapy. Reviews on clinical pharmacology and drug therapy. 2014;12(2):3-11. (In Russ.)]. https://doi.org/10.17816/RCF1223-11.

[3] Agarwal S, Arya V, Zhang L. Review of P-gp inhibition data in recently approved new drug applications: utility of the proposed [I(1)]/IC(50) and [I(2)]/IC(50) criteria in the P-gp decision tree. J Clin Pharmacol. 2013;53(2):228-233. https://doi.org/10.1177/0091270011436344.

[4] Elsby R, Surry DD, Smith VN, Gray AJ. Validation and application of Caco-2 assays for the in vitro evaluation of development candidate drugs as substrates or inhibitors of P-glycoprotein to support regulatory submissions. Xenobiotica. 2008;38(7-8):1140-1164.https://doi.org/10.1080/00498250802050880.

[5] European medicines agency. Guideline on the investigation of drug interactions [Internet]. 2012 [cited 2019 Mar 20]. Available from: https://www.ema.europa.eu/documents/scientific-guideline/guideline-investigation-drug-interactions_en.pdf.

[6] Giacomini KM, Huang SM, Tweedie DJ, et al. Membrane transporters in drug development. Nat Rev Drug Discov. 2010;9(3):215-236. https://doi.org/10.1038/nrd3028.

[7] Al Hamid A, Ghaleb M, Aljadhey H, Aslanpour Z. A systematic review of hospitalization resulting from medicine-related problems in adult patients. Br J Clin Pharmacol. 2014;78(2):202-217. https://doi.org/10.1111/bcp.12293.

[8] Hilgers AR, Conradi RA, Burton PS. Caco-2 Cell Monolayers as a Model for Drug Transport Across the Intestinal Mucosa. Pharm Res. 1990;7(9):902-910. https://doi.org/10.1023/a:1015937605100.

[9] Huang SM, Zhang L, Giacomini KM. The International Transporter Consortium: a collaborative group of scientists from academia, industry, and the FDA. Clin Pharmacol Ther. 2010;87(1):32-36. https://doi.org/10.1038/clpt.2009.236.

[10] Petri N, Tannergren C, Rungstad D, Lennernäs H. Transport Characteristics of Fexofenadine in the Caco-2 Cell Model. Pharm Res. 2004;21(8):1398-1404. https://doi.org/10.1023/B: PHAM.0000036913.90332.b1.

[11] Srinivasan B, Kolli AR, Esch MB, et al. TEER measurement techniques for in vitro barrier model systems. J Lab Autom. 2015;20(2):107-126. https://doi.org/10.1177/2211068214561025.

[12] U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research. In Vitro Metabolism and Transporter-Mediated Drug-Drug Interaction Studies Guidance for Industry [Internet]. 2017 [cited 2019 Mar 20]. Available from: https://www.fda.gov/downloads/Drugs/Guidances/UCM581965.pdf.

RIGHTS & PERMISSIONS

Yakusheva E.N., Shchulkin A.V., Chernykh I.V., Popova N.M., Kotlyarova A.A., Slepnev A.A.