Effect of five novel 5-substituted tetrandrine derivatives on P-glycoprotein-mediated inhibition and transport in Caco-2 cells.

Tetrandrine (Tet) is a potent inhibitor that reverses P-glycoprotein-mediated multidrug resistance (MDR). A number of novel 5-substituted tetrandrine derivatives were synthesized by the authors. The present study aimed at identifying potential P-gp inhibitor candidates, and intracellular uptake and efflux experiments and Caco-2 cell-based Transwell transport studies were performed. It was demonstrated that all five test compounds were able to inhibit efflux and increase intracellular uptake of the P-gp substrate, rhodamine-123 (Rho-123); the test compounds were P-gp inhibitors. The transepithelial transport experiment indicated that the secretory (basolateral-to-apical) of Rho-123 decreased, the absorption (apical-to-basolateral) increased and the transport efflux ratio (ER) reduced in the presence of the five compounds. Among the compounds, fluobenzene-Tet (TF) exhibited similar inhibitory effect as Tet. Although the other four test compounds exhibited weaker inhibitory effects than Tet and TF, the compounds exhibited stronger inhibitory effects compared with the reference compound verapamil. The study demonstrated that the five novel 5-substituted tetrandrine derivatives are able to act as inhibitors of P-gp to overcome P-gp-mediated drug resistance.