stilbenes and fexofenadine

Arsenic trioxide (As2O3) has been verified as a breakthrough in the management of acute promyelocytic leukemia in recent decades. However, cardiotoxicity, especially long QT syndrome (LQTS) has become the most important issue during As2O3 treatment. The characterized mechanisms behind this adverse effect are inhibition of cardiac hERG channel trafficking and increase of cardiac calcium currents. In our study, we found a new pathway underlying As2O3-induced cardiotoxicity that As2O3 accelerates lysosomal degradation of hERG on plasma membrane after using brefeldin A (BFA) to block protein trafficking. Then we explored pharmacological rescue strategies on As2O3-induced LQTS, and found that 4 therapeutic agents exert rescue efficacy via 3 different pathways: fexofenadine and astemizole facilitate hERG trafficking via promotion of channel-chaperone formation after As2O3 incubation; ranolazine slows hERG degradation in the presence of As2O3; and resveratrol shows significant attenuation on calcium current increase triggered by As2O3. Moreover, we used human-induced pluripotent stem cell derived cardiomyocytes (hiPS-CMs) to evaluate the rescue effects of the above agents on As2O3-induced prolongation of action potential duration (APD) and demonstrated that fexofenadine and resveratrol significantly ameliorate the prolonged APD. These observations suggested that pharmacological chaperone like fexofenadine and resveratrol might have the potential to protect against the cardiotoxicity of As2O3.

Topics: Action Potentials; Antineoplastic Agents; Arsenic Trioxide; Arsenicals; ERG1 Potassium Channel; HEK293 Cells; Humans; Induced Pluripotent Stem Cells; Leukemia, Promyelocytic, Acute; Long QT Syndrome; Lysosomes; Myocytes, Cardiac; Oxides; Patch-Clamp Techniques; Proteolysis; Resveratrol; Stilbenes; Terfenadine

Resveratrol (RSV) is a natural occurring antioxidant has been found to possess P-glycoprotein (P-gp) inhibition activity in vitro and in vivo, which may have the potential to cause drug-phytochemical interactions. The purpose of the present study was to evaluate the effect of RSV on the pharmacokinetics of fexofenadine (FEX), P-gp substrate in rats.. A mechanistic evaluation was undertaken using in vitro non-everted sac and in situ intestinal perfusion studies to determine the FEX intestinal transport and permeability. These results were confirmed by an in vivo pharmacokinetic study of oral administered FEX (10mg/kg) in rats.. The intestinal transport and apparent permeability (Papp) of FEX were increased significantly in duodenum, jejunum and ileum of RSV and verapamil (VER) pretreated groups when compared to FEX alone group. Similarly absorption rate constant (Ka), fraction absorbed (Fab) and effective permeability (Peff) of FEX were increased significantly in ileum of RSV and VER pretreated groups when compared to FEX alone group. In comparison with FEX alone, RSV pretreatment significantly increased maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC), while there was no significant change was observed in T1/2 and Tmax of FEX.. RSV significantly enhanced the exposure of FEX in rats likely by the inhibition of P-glycoprotein (P-gp) mediated efflux during the intestinal absorption, suggesting that there is a potential pharmacokinetic interaction between RSV and FEX. Therefore, further studies are recommended to evaluate the potential drug-phytochemical interactions in humans.

Topics: Administration, Oral; Animals; ATP Binding Cassette Transporter, Subfamily B; Biological Transport; Drug Interactions; Intestinal Absorption; Intestinal Mucosa; Intestines; Male; Permeability; Rats; Rats, Wistar; Resveratrol; Stilbenes; Terfenadine; Verapamil

Berberine (BBR), an isoquinoline alkaloid mainly isolated from plants of Berberidaceae family, is extensively used to treat gastrointestinal infections in clinics. It has been reported that BBR can block human ether-a-go-go-related gene (hERG) potassium channel and inhibit its membrane expression. The hERG channel plays crucial role in cardiac repolarization and is the target of diverse proarrhythmic drugs. Dysfunction of hERG channel can cause long QT syndrome. However, the regulatory mechanisms of BBR effects on hERG at cell membrane level remain unknown. This study was designed to investigate in detail how BBR decreased hERG expression on cell surface and further explore its pharmacological rescue strategies. In this study, BBR decreases caveolin-1 expression in a concentration-dependent manner in human embryonic kidney 293 (HEK293) cells stably expressing hERG channel. Knocking down the basal expression of caveolin-1 alleviates BBR-induced hERG reduction. In addition, we found that aromatic tyrosine (Tyr652) and phenylalanine (Phe656) in S6 domain mediate the long-term effect of BBR on hERG by using mutation techniques. Considering both our previous and present work, we propose that BBR reduces hERG membrane stability with multiple mechanisms. Furthermore, we found that fexofenadine and resveratrol shorten action potential duration prolongated by BBR, thus having the potential effects of alleviating the cardiotoxicity of BBR.

Topics: Action Potentials; Berberine; Caveolin 1; Cell Membrane; Dose-Response Relationship, Drug; ERG1 Potassium Channel; Ether-A-Go-Go Potassium Channels; HEK293 Cells; Humans; Kinetics; Mutation; Phenylalanine; Potassium Channel Blockers; Resveratrol; RNA Interference; Stilbenes; Terfenadine; Transfection; Tyrosine