Effect of four ABCB1 genetic polymorphisms on the accumulation of darunavir in HEK293 recombinant cell lines

Abstract The intracellular penetration of darunavir, a second-generation HIV protease inhibitor, is limited by the activity of the efflux P-glycoprotein (ABCB1). ABCB1 expression and/or activity levels can vary between individuals due to genetic polymorphisms including the c.1199G>A, c.1236C>T...

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Autores principales:	Gabriel Stillemans, Happy Phanio Djokoto, Kévin-Alexandre Delongie, Halima El-Hamdaoui, Nadtha Panin, Vincent Haufroid, Laure Elens
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/a78aedce85a04099871be76d5f19ff7d
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spelling	oai:doaj.org-article:a78aedce85a04099871be76d5f19ff7d2021-12-02T13:41:10ZEffect of four ABCB1 genetic polymorphisms on the accumulation of darunavir in HEK293 recombinant cell lines10.1038/s41598-021-88365-72045-2322https://doaj.org/article/a78aedce85a04099871be76d5f19ff7d2021-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-88365-7https://doaj.org/toc/2045-2322Abstract The intracellular penetration of darunavir, a second-generation HIV protease inhibitor, is limited by the activity of the efflux P-glycoprotein (ABCB1). ABCB1 expression and/or activity levels can vary between individuals due to genetic polymorphisms including the c.1199G>A, c.1236C>T, c.2677G>T and c.3435C>T variants, which could in part explain why the pharmacokinetics of darunavir are so variable from one individual to another. While a few clinical studies have failed to demonstrate an influence of these polymorphisms on darunavir pharmacokinetics, drug-drug interactions and methodological limitations may have prevented them from revealing the true influence of ABCB1 variants. In this work, we report on the intracellular accumulation of darunavir in recombinant HEK293 cell lines expressing wild-type ABCB1 or one of several variants: ABCB1 1199A, ABCB1 3435T, and ABCB1 1236T/2677T/3435T. We demonstrate that while ABCB1 expression limits intracellular accumulation of darunavir, there is no significant difference in efflux activity between cells expressing wild-type ABCB1 and those that express any of the studied variants.Gabriel StillemansHappy Phanio DjokotoKévin-Alexandre DelongieHalima El-HamdaouiNadtha PaninVincent HaufroidLaure ElensNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-7 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Gabriel Stillemans Happy Phanio Djokoto Kévin-Alexandre Delongie Halima El-Hamdaoui Nadtha Panin Vincent Haufroid Laure Elens Effect of four ABCB1 genetic polymorphisms on the accumulation of darunavir in HEK293 recombinant cell lines
description	Abstract The intracellular penetration of darunavir, a second-generation HIV protease inhibitor, is limited by the activity of the efflux P-glycoprotein (ABCB1). ABCB1 expression and/or activity levels can vary between individuals due to genetic polymorphisms including the c.1199G>A, c.1236C>T, c.2677G>T and c.3435C>T variants, which could in part explain why the pharmacokinetics of darunavir are so variable from one individual to another. While a few clinical studies have failed to demonstrate an influence of these polymorphisms on darunavir pharmacokinetics, drug-drug interactions and methodological limitations may have prevented them from revealing the true influence of ABCB1 variants. In this work, we report on the intracellular accumulation of darunavir in recombinant HEK293 cell lines expressing wild-type ABCB1 or one of several variants: ABCB1 1199A, ABCB1 3435T, and ABCB1 1236T/2677T/3435T. We demonstrate that while ABCB1 expression limits intracellular accumulation of darunavir, there is no significant difference in efflux activity between cells expressing wild-type ABCB1 and those that express any of the studied variants.
format	article
author	Gabriel Stillemans Happy Phanio Djokoto Kévin-Alexandre Delongie Halima El-Hamdaoui Nadtha Panin Vincent Haufroid Laure Elens
author_facet	Gabriel Stillemans Happy Phanio Djokoto Kévin-Alexandre Delongie Halima El-Hamdaoui Nadtha Panin Vincent Haufroid Laure Elens
author_sort	Gabriel Stillemans
title	Effect of four ABCB1 genetic polymorphisms on the accumulation of darunavir in HEK293 recombinant cell lines
title_short	Effect of four ABCB1 genetic polymorphisms on the accumulation of darunavir in HEK293 recombinant cell lines
title_full	Effect of four ABCB1 genetic polymorphisms on the accumulation of darunavir in HEK293 recombinant cell lines
title_fullStr	Effect of four ABCB1 genetic polymorphisms on the accumulation of darunavir in HEK293 recombinant cell lines
title_full_unstemmed	Effect of four ABCB1 genetic polymorphisms on the accumulation of darunavir in HEK293 recombinant cell lines
title_sort	effect of four abcb1 genetic polymorphisms on the accumulation of darunavir in hek293 recombinant cell lines
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/a78aedce85a04099871be76d5f19ff7d
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Effect of four ABCB1 genetic polymorphisms on the accumulation of darunavir in HEK293 recombinant cell lines

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