Inhibition of P-glycoprotein-mediated efflux by thiolated cyclodextrins

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.