In vitro identification of decreased function genetic variants of ABCB1

IF 4.7 3区医学 Q1 PHARMACOLOGY & PHARMACY European Journal of Pharmaceutical Sciences Pub Date : 2025-03-18 DOI:10.1016/j.ejps.2025.107078

Laura Suominen, Hatam Rashidpour, Noora Sjöstedt, Heidi Kidron

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Abstract

The efflux transporter ABCB1 (P-glycoprotein, P-gp) has an important role in drug disposition, and thus, genetic variants that lead to decreased transport function might increase drug exposure. Complete loss of function of ABCB1 is rare but a few nonfunctional variants have been found. We studied the transport activity of the common S893A/T (c.2677T>G/A) variants and a set of 14 other naturally occurring non-synonymous single nucleotide variants to find new decreased function variants. The reference ABCB1 (c.1236T, c.2677T, c.3435T haplotype) and variants (N21D, H61Y, Y116C, N183S, I261V, L305P, R580P, C717Y, S795C, I836V, Y853N, S893A, S893T, V907F, Y928S, and A980P) were expressed in Sf9 cells. These cells were then used to prepare membrane vesicles, which were used to study N-methyl-quinidine (NMQ) and aliskiren transport. Aliskiren kinetics were characterised, as it has not previously been used in vesicle transport assays. Compared to the reference, C717Y caused a complete loss of NMQ and aliskiren transport, and L305P and V907F decreased transport to <25 % of the reference. In addition, R580P and A980P decreased the transport of both substrates to ≤50 %, while S795C affected only NMQ transport. Based on our results, carriers of the C717Y, L305P, or V907F variants may experience altered distribution and exposure of ABCB1 substrate drugs.

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ABCB1功能下降基因变异的体外鉴定。

外排转运蛋白ABCB1 （p -糖蛋白，P-gp）在药物处置中起重要作用，因此，导致转运功能下降的遗传变异可能会增加药物暴露。完全丧失ABCB1的功能是罕见的，但一些无功能的变体已被发现。我们研究了常见的S893A/T （c.2677T>G/A）变异和其他14种自然发生的非同义单核苷酸变异的运输活性，以发现新的功能下降的变异。参考ABCB1 （c.1236T、c.2677T、c.3435T单倍型）和变异（N21D、H61Y、Y116C、N183S、I261V、L305P、R580P、C717Y、S795C、I836V、Y853N、S893A、S893T、V907F、Y928S、A980P）在Sf9细胞中表达。然后用这些细胞制备膜囊泡，用于研究n -甲基奎尼丁（NMQ）和阿利斯基仑（aliskiren）的转运。Aliskiren动力学被表征，因为它以前没有被用于囊泡运输测定。与参考相比，C717Y导致NMQ和aliskiren传输完全丧失，L305P和V907F的传输减少至

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来源期刊

European Journal of Pharmaceutical Sciences 医学-药学

CiteScore

9.60

自引率

2.20%

发文量

248

审稿时长

50 days

期刊介绍： The journal publishes research articles, review articles and scientific commentaries on all aspects of the pharmaceutical sciences with emphasis on conceptual novelty and scientific quality. The Editors welcome articles in this multidisciplinary field, with a focus on topics relevant for drug discovery and development. More specifically, the Journal publishes reports on medicinal chemistry, pharmacology, drug absorption and metabolism, pharmacokinetics and pharmacodynamics, pharmaceutical and biomedical analysis, drug delivery (including gene delivery), drug targeting, pharmaceutical technology, pharmaceutical biotechnology and clinical drug evaluation. The journal will typically not give priority to manuscripts focusing primarily on organic synthesis, natural products, adaptation of analytical approaches, or discussions pertaining to drug policy making. Scientific commentaries and review articles are generally by invitation only or by consent of the Editors. Proceedings of scientific meetings may be published as special issues or supplements to the Journal.