Evaluation of P-glycoprotein activity mediated by fiscalin derivatives at the rat intestinal barrier

Background: P-glycoprotein (P-gp) is an active efflux pump that reduces xenobiotics’ accumulation inside cells, and which activity can be modulated by inhibitors, inducers and activators [1,2]. The first ones have been used to counteract the multidrug resistance (MDR) phenomena and the inducers and activators have been proposed as a therapeutic approach in intoxication scenarios. In fact, P-gp binds several unrelated hydrophobic drugs and its activity can be changed in order to increase or decrease drugs intracellular accumulation. Previous in vitro studies showed that fiscalins, marine-derived compounds, are able to alter P-gp transport activity in differentiated neuronal SH-SY5Y cells. Interestingly, some fiscalin derivatives showed to act as inhibitors, whether others were activators of P-gp expressed in SH-SY5Y cells [3]. Objective: Considering the fact that P-gp is a major efflux pump expressed in barrier tissues, influencing xenobiotics’ pharmacokinetics and bioavailability, the main purpose of this study is to investigate the modulatory effects of two fiscalin derivatives, FISC 1 and FISC 2, on P-gp activity in the rat intestinal barrier, using ex vivo approaches. Methods: The study was performed at the distal portion of the rat ileum, using everted intestinal sacs as an ex vivo model, aiming to evaluate the potential immediate effects of the fiscalin derivatives on P-gp transport activity, as a result of a direct inhibition or activation of this pump. P-gp activity was evaluated in rat everted intestinal sacs after a direct and short contact of the tested fiscalin derivatives (5 µM), in the presence and absence of ZOS (5 µM). A fluorescent P-gp substrate widely used in these assays is rhodamine 123 (RHO 123), which allows for the direct evaluation of P-gp activity by measuring RHO 123 fluorescence in samples of mucosal medium, determined by spectrofluorometry. Results and Conclusions: The findings revealed that FISC 1 is able to activate P-gp activity at rat intestinal barrier, highlighting the pharmaco(toxico)kinetic relevance of this efflux protein.