Different structures of berberine and five other protoberberine alkaloids that affect P-glycoprotein-mediated efflux capacity

Abstract

Berberine, berberrubine, thalifendine, demethyleneberberine, jatrorrhizine, and columbamine are six natural protoberberine alkaloid (PA) compounds that display extensive pharmacological properties and share the same protoberberine molecular skeleton with only slight substitution differences. The oral delivery of most PAs is hindered by their poor bioavailability, which is largely caused by P-glycoprotein (P-gp)-mediated drug efflux. Meanwhile, P-gp undergoes large-scale conformational changes (from an inward-facing to an outward-facing state) when transporting substrates, and these changes might strongly affect the P-gp-binding specificity. To confirm whether these six compounds are substrates of P-gp, to investigate the differences in efflux capacity caused by their trivial structural differences and to reveal the key to increasing their binding affinity to P-gp, we conducted a series of in vivo, in vitro, and in silico assays. Here, we first confirmed that all six compounds were substrates of P-gp by comparing the drug concentrations in wild-type and P-gp-knockout mice in vivo. The efflux capacity (net efflux) ranked as berberrubine > berberine > columbamine~jatrorrhizine > thalifendine > demethyleneberberine based on in vitro transport studies in Caco-2 monolayers. Using molecular dynamics simulation and molecular docking techniques, we determined the transport pathways of the six compounds and their binding affinities to P-gp. The results suggested that at the early binding stage, different hydrophobic and electrostatic interactions collectively differentiate the binding affinities of the compounds to P-gp, whereas electrostatic interactions are the main determinant at the late release stage. In addition to hydrophobic interactions, hydrogen bonds play an important role in discriminating the binding affinities.

Rhizoma coptidis as a Potential Treatment Agent for Type 2 Diabetes Mellitus and the Underlying Mechanisms: A Review

“…Cmax, t 1/2 , and AUC (17.35 ± 3.24 vs 34.41 ± 4.25 μg/L, 3.95 ± 1.27 vs 9.29 ± 2.75 h, 151.21 ± 23.96 vs 283.81 ± 53.92 μg⋅h/L, respectively) and oral clearance rates (134.73 ± 32.15 vs 62.55 ± 16.34 L/h/kg) were decreased significantly. Intestinal ATP-dependent efflux pump P-glycoprotein (PGP) is distributed widely in the intestinal epithelium and hepatocytes, and it reduces drug efficiency of protoberberine alkaloid (Pan et al, 2010; Zhang et al, 2019b). A study revealed that intestinal P-GP was impaired in STZ-induced T2DM model, which partly enhanced the absorption of the five protoberberine alkaloids (berberine, palmatine, coptisine, epiberberine, and jatrorrhizine) (Yu et al, 2010).…”

“…A study revealed that intestinal P-GP was impaired in STZ-induced T2DM model, which partly enhanced the absorption of the five protoberberine alkaloids (berberine, palmatine, coptisine, epiberberine, and jatrorrhizine) (Yu et al, 2010). Small structural differences (e.g., the location and number of hydroxyl groups) led to different binding affinities to P-GP (e.g., berberine and coptisine) (Cui et al, 2015; Zhang et al, 2019b). In normal rats, berberine was quickly distributed in organs, and the concentrations in organs were higher than that in blood (Tan et al, 2013).…”

Co-Delivery of Berberine Chloride and Tariquidar in Nanoliposomes Enhanced Intracellular Berberine Chloride in a Doxorubicin-Resistant K562 Cell Line Due to P-gp Overexpression

“…Finally, BRB- plus TAR-loaded nanoliposomes were investigated for the ability to enhance BRB uptake in K562/DOXO cell lines. Due to its fluorescent properties, the BRB is a suitable probe for evaluating directly the uptake by flow cytometry [ 20 ].…”

Recent Advances in Berberine Inspired Anticancer Approaches: From Drug Combination to Novel Formulation Technology and Derivatization

“…As with other diseases, the therapeutic potential of berberine for cancer is also mediated through effect on diverse cellular targets and signalling processes (see Section 2 below). Despite its promise, however, berberine is known for its relatively poor anticancer efficacy and poor bioavailability resulting from low intestinal permeability and absorption [20] and efflux due to the action of intestinal permeabilityglycoprotein (P-gp) [21]. Furthermore, berberine is extensively metabolised in the liver by the action of enzymes which are also active in intestinal cells [22].…”

“…Strategies highlighted include using berberine in combination with other chemotherapeutic agents either to reduce toxic side effects or enhance their anticancer effects; the various novel formulation approaches which by order of magnitude improved the pharmacokinetics of berberine; and semisynthetic approaches that enhanced potency by up to 100-fold.Molecules 2020, 25, 1426 2 of 31 cellular targets and signalling processes (see Section 2 below). Despite its promise, however, berberine is known for its relatively poor anticancer efficacy and poor bioavailability resulting from low intestinal permeability and absorption [20] and efflux due to the action of intestinal permeability-glycoprotein (P-gp) [21]. Furthermore, berberine is extensively metabolised in the liver by the action of enzymes which are also active in intestinal cells [22].…”