A 2021 article examined the potential transporter-mediated interactions of the botanical natural product goldenseal using a comprehensive in vitro-in vivo approach. The study was meticulously designed to assess the inhibitory effects of a goldenseal extract, standardized to its major alkaloid berberine, on various transporters with clinical relevance. In vitro assays utilized transporter-expressing cell systems to evaluate the extract’s inhibitory potency across a range of transporters, including BCRP, OATP1B1/3, and P-gp. These findings were integrated into basic predictive models to anticipate potential clinical interactions, representing an advanced convergence of pharmacokinetic modeling and experimental data. The subsequent clinical evaluation, presented in the 2021 publication, involved 16 healthy volunteers administered with a transporter probe cocktail to elucidate the effects of goldenseal in a controlled setting. Participants received a probe cocktail containing 50 mg of metformin, a substrate for organic cation transporters and multidrug and toxin extrusion (MATE) proteins, following five days of goldenseal supplementation. While basic models predicted no renal interaction based on systemic berberine concentrations, the clinical results revealed that goldenseal significantly reduced metformin systemic exposure, decreasing the area under the curve (AUC) by 23% and maximum concentration by 27%. Notably, metformin renal clearance and half-life were unaffected, indicating that the interaction did not occur during renal elimination as expected from the in vitro renal transporter inhibition, suggesting alterations in intestinal permeability and transporter interactions, reducing the bioavailability of metformin. Consequently, the co-administration of goldenseal could negatively impact glucose control in patients with type 2 diabetes. This underscores the complexity of predicting natural product-drug interactions and highlights the necessity for refined modeling approaches that incorporate differential transporter expression and potential degradation processes. [1]
The 2018 study investigated the pharmacokinetic interaction between metformin and berberine using Sprague–Dawley rats, intestinal sac assays, and OCT/MATE transporter-expressing MDCK cell models. Co-administration of berberine significantly reduced metformin exposure, lowering both Cmax and AUC₀–₄h, an effect attributed to inhibition of OCT1-mediated intestinal uptake of metformin. Consistent with this mechanism, berberine inhibited metformin transport in OCT1-, OCT2-, and MATE1-transfected MDCK cells in a dose-dependent manner, and non-everted intestinal sac experiments confirmed impaired drug absorption. Conversely, metformin produced a modest increase in berberine plasma concentrations and notably increased berberine tissue levels in the liver and kidney, likely through inhibition of berberine efflux via OCT/MATE pathways. Overall, the study demonstrates a bidirectional pharmacokinetic interaction driven by shared transporter systems (OCT1/2 and MATE1), though clinical relevance remains unknown because the data are limited to animal and in-vitro models. [2]