Tetrandrine Potentiates the Hypoglycemic Efficacy of Berberine by Inhibiting P-Glycoprotein Function

Abstract

This study was designed to improve the absorption and hypoglycemic efficacy of berberine (BBR), which is a substrate of P-glycoprotein (P-gp), by combination with a P-gp inhibitor tetrandrine (Tet). Flow cytometry and LC-MS/MS were used to determine the cellular efflux or retention of chemicals. Pharmacokinetic study was performed in ICR mice following oral administration of the study compounds. The hypoglycemic efficacies of the compounds were evaluated in diabetic KK-Ay mice. In the in vitro experiments, Tet significantly inhibited the efflux and increased the uptake of P-gp substrates rhodamine-123 as well as BBR in MCF7/DOX cells and Caco-2 intestinal cells. Meanwhile, Tet greatly reduced the expression of P-gp in Caco-2 cells. The inhibition of BBR efflux by Tet was translated into improved pharmacokinetics in vivo. When co-administered, Tet dose-dependently increased the average maximum concentration (C max ) and area under concentration-time curve (AUC 0-24 ) of BBR in mice. Tet itself had no impact on glucose metabolism. However, it greatly potentiated the hypoglycemic efficacy of BBR in diabetic KK-Ay mice. In addition, we found that Tet had moderate inhibitory effect on the catalytic activity of CYP3A4, which played a role in the bio-transformation of BBR, and this may also take part in the improvement of the pharmacokinetics of BBR. In summary, combination with P-gp inhibitors such as Tet can improve the pharmacokinetics and hypoglycemic efficacy of BBR greatly; this implicates a feasible strategy for exploring the therapeutic effects of BBR and other pharmaceuticals which are substrates of P-gp.

Antioxidant and Anti‐Inflammatory Activities of Berberine in the Treatment of Diabetes Mellitus

“…This finding could partially explain the pharmacological activities of BBR in various tissues despite its low blood concentration [117, 122]. Our previous work showed that the metabolites of BBR could activate AMPK, as well [123].…”

“…In addition to what was mentioned above, recent studies indicated that the anti-inflammatory activity of BBR was also associated with its beneficial effects in the gut [114–116]. Due to the possible low bioavailability [117], high concentration of BBR in the gut after oral administration could modulate the structure of gut microbiota, resulting in the enrichment of short-chain fatty acid (SCFA)-producing bacteria in the gut [114]. SCFA could improve intestinal barrier function and prevent inflammation by blocking exogenous antigen or endotoxin to enter into the blood [118].…”

Current knowledge and pharmacological profile of berberine: An update

“…Tetrandine P-gp efflux of berberine is inhibited by tetrandine Potentiation of hypoglycemic activity of berberine (Zhang et al, 2014) L-DOPA Berberine leads to degeneration of dopaminergic neuronal Antagonistic action (Shan et al, 2013) cells …”

Roles of Chemical Complexity and Evolutionary Theory in Some Hepatic and Intestinal Enzymatic Systems in Chemical Reproducibility and Clinical Efficiency of Herbal Derivatives

“…Both substances interact with P-glycoprotein, and the performance of berberine is affected negatively by P-glycoprotein-mediated intestinal extrusion. P-glycoprotein antagonists, whether synthetic [99] or natural like silymarin [100], improve both berberine bioavailability and efficacy.…”