Flavonoid compounds as reversal agents of the P-glycoprotein-mediated multidrug resistance: biology, chemistry and pharmacology

Multidrug resistance (MDR) represents one of the major problems in pharmacotherapy of important diseases (e.g., cancer, epilepsy). Although many factors may contribute to the development of MDR phenotype, the increased expression and/or functional activity of P-glycoprotein (P-gp; active drug efflux transporter) across the cell membrane has been recognized as the main one. Therefore, a great attention has been given to the search of P-gp inhibitors as therapeutic agents to reverse the MDR mediated by P-gp. Since the chemical entities identified over the last three decades as potential P-gp inhibitors did not show suitable pharmacological properties, more recently herbal components, such as flavonoid compounds, have gained a great interest as safe P-gp inhibitors. The interest in flavonoids as P-gp inhibitors is increasing due to their potential favourable characteristics, including selectivity and non-cytotoxic effects. Flavonoids integrate the third-generation non-pharmaceutical category of P-gp inhibitors, and some of them exhibited effects comparable to those of the classic P-gp inhibitors. In fact, some flavonoids found in foods and beverages of herbal origin appear to be quite promising to inhibit the P-gp–mediated drug efflux, indicating their potential value to enhance the systemic/cellular bioavailability of P-gp drug substrates when administrated in co-therapy. This review paper summarizes the current evidence of P-gp inhibitory effects produced by flavonoids, taking into account studies performed in cell-based in vitro models, in vivo animal models and clinical trials.