Inhibition of P-glycoprotein-mediated efflux by thiolated cyclodextrins

Florina Veider; Soheil Haddadzadegan; Eva Sanchez Armengol; Flavia Laffleur; Gergely Kali; Andreas Bernkop-Schnürch

doi:10.1016/j.carbpol.2023.121648

Inhibition of P-glycoprotein-mediated efflux by thiolated cyclodextrins

Carbohydr Polym. 2024 Mar 1:327:121648. doi: 10.1016/j.carbpol.2023.121648. Epub 2023 Nov 30.

Authors

Florina Veider¹, Soheil Haddadzadegan², Eva Sanchez Armengol³, Flavia Laffleur⁴, Gergely Kali⁵, Andreas Bernkop-Schnürch⁶

Affiliations

¹ Center for Chemistry and Biomedicine, Department of Pharmaceutical Technology, Institute of Pharmacy, University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria. Electronic address: [email protected].
² Center for Chemistry and Biomedicine, Department of Pharmaceutical Technology, Institute of Pharmacy, University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria. Electronic address: [email protected].
³ Center for Chemistry and Biomedicine, Department of Pharmaceutical Technology, Institute of Pharmacy, University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria. Electronic address: [email protected].
⁴ Center for Chemistry and Biomedicine, Department of Pharmaceutical Technology, Institute of Pharmacy, University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria. Electronic address: [email protected].
⁵ Center for Chemistry and Biomedicine, Department of Pharmaceutical Technology, Institute of Pharmacy, University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria. Electronic address: [email protected].
⁶ Center for Chemistry and Biomedicine, Department of Pharmaceutical Technology, Institute of Pharmacy, University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria. Electronic address: [email protected].

PMID: 38171673
DOI: 10.1016/j.carbpol.2023.121648

Abstract

Overcoming P-glycoprotein (P-gp)-mediated efflux poses a significant challenge for the pharmaceutical industry. This study investigates the potential of thiolated β-cyclodextrins (β-CD-SHs) as inhibitors of P-gp-mediated efflux in Caco-2 cells. Through a series of transport assays, intracellular accumulation, and efflux of the P-gp substrates Rhodamine 123 (Rh123) and Calcein-AM with and without co-administration of β-CD-SHs were assessed. The results revealed that the cellular uptake of Rh123 and Calcein-AM were enhanced up to 7- and 3-fold, compared to the control, respectively. In efflux studies an up to 2.5-fold reduction of the Rh123 efflux was reached compared the control, indicating a substantial decrease of Rh123 efflux by β-CD-SHs. Furthermore, it was observed that β-CD-SHs led to a decrease in the reactivity of fluorescence-labeled anti-P-gp, suggesting additional effects on the conformation of P-gp. Overall, this study demonstrates the potential of β-CD-SHs as effective modulator of P-gp-mediated drug efflux in Caco-2 cells.

Keywords: Calcein-AM; Cellular uptake; Efflux; Inhibitors; Rhodamine 123; Thiolated cyclodextrins; Thiomers.

MeSH terms

ATP Binding Cassette Transporter, Subfamily B, Member 1*
Caco-2 Cells
Cyclodextrins* / pharmacology
Humans
Rhodamine 123

Substances

ATP Binding Cassette Transporter, Subfamily B, Member 1
calcein AM
Cyclodextrins
Rhodamine 123