Structure of berberine

Berberine’s varied positive effects on many metabolic outcomes make it particularly of interest in treating the modern obesity-related condition known as “metabolic disorder”. Unfortunately, bioavailability for this compound is low – estimated at less than 5% of the orally-administered dose – the compound itself being poorly soluble, and the gram-plus doses necessary for a physiologically-relevant effect cause major gastrointestinal side-effects.

Super-Berberine^TM
Super-Berberine^TM solves these problems in two ways.

Firstly, in Super-Berberine^TMthe berberine is complexed with cyclodextrins.
Cyclodextrins are sugar molecules bound into a ring- or doughnut-shape, which can be used to increase the solubility of other compounds by the formation of inclusion complexes. The insoluble compound is held in the hydrophobic cavity, and the cyclodextrin acts as a “carrier” molecule.

Berberin-cyclodextrin complexes are not only more soluble, and therefore more bioavailable, than plain berberine, but also sweeter and less bitter due to the natural sugary taste of cyclodextrins and because complexed molecules cannot fully interact with taste buds.

Dissolution profiles of berberine and berberine-beta-cyclodextrin inclusion complex (a) in simulated gastric fluid and (b) in simulated intestinal juice.

The improvements in solubility seen in the graphs above may be improved further by use of 2 hydroxypropyl-β-cyclodextrin (HPβCD) instead of the less-soluble β-cyclodextrin.

Secondly, in Super-Berberine^TMthe berberine-cyclodextrins are co-administered with the penetration-enhancer sodium caprate.

Structure of sodium caprate

Sodium caprate is an absorption promoter, increasing the oral bioavailability of poorly permeable compounds across the gut wall. Many bioavailability enhancers work by increasing cellular permeability, allowing greater transcellular movement (through the epithelial cells) by diffusion or active transport.
Sodium caprate dilates tight junctions (TJs) in the intestinal epithelium, increasing their permeability, facilitating paracellular transport (between the cells). Sodium caprate also inhibits the excretion pump function of P-glycoprotein, of which berberine is a substrate.
As a sodium salt of a medium chain fatty acid, sodium caprate is Generally Recognized As Safe (GRAS) as a food additive.

When sodium caprate is co-administered with berberine, intestinal absorption of berberine increases significantly, leading to bioavailability improvements of 1.5 to 2.3-fold.

• In in vitro experiments, berberine has a stronger effect on the phosphorylation of AMPK than AICAR.
• Berberine reduces bodyweight in test animals fed a high-fat diet, as well as improving triglycerides, total cholesterol, and glucose tolerance.
• Berberine induces an increase in muscle glucose uptake via AMPK, and inhibits glucose production in the liver.

Combining cyclodextrin-complexed berberine with sodium caprate results in a berberine product of never-before-seen potency: Super-Berberine^TM.

References and further reading:

Aungst BJ. Absorption Enhancers: Applications and Advances. AAPS J. 2011 Nov 22;14(1):10–8.

Chen Y, Wang Y, Zhang J, Sun C, Lopez A. Berberine improves glucose homeostasis in streptozotocin-induced diabetic rats in association with multiple factors of insulin resistance. ISRN Endocrinol. 2011;2011:519371.

Zhang Y, Cui Y-L, Gao L-N, Jiang H-L. Effects of β-cyclodextrin on the intestinal absorption of berberine hydrochloride, a P-glycoprotein substrate. International Journal of Biological Macromolecules. 2013 Aug;59:363–71.

Lv X-Y, Li J, Zhang M, Wang C-M, Fan Z, Wang C-Y, et al. Enhancement of sodium caprate on intestine absorption and antidiabetic action of berberine. AAPS PharmSciTech. 2010 Mar;11(1):372–82.

Maher S, Leonard TW, Jacobsen J, Brayden DJ. Safety and efficacy of sodium caprate in promoting oral drug absorption: from in vitro to the clinic. Adv Drug Deliv Rev. 2009 Dec 17;61(15):1427–49.

Krug SM, Amasheh M, Dittmann I, Christoffel I, Fromm M, Amasheh S. Sodium caprate as an enhancer of macromolecule permeation across tricellular tight junctions of intestinal cells. Biomaterials. 2013 Jan;34(1):275–82.

Zhang M, Lv X, Li J, Meng Z, Wang Q, Chang W, et al. Sodium caprate augments the hypoglycemic effect of berberine via AMPK in inhibiting hepatic gluconeogenesis. Mol Cell Endocrinol. 2012 Nov 5;363(1-2):122–30.

Also known as pyrimidinecarboxylic acid, orotic acid is an intermediate in pyrimidine synthesis, which is required for DNA and RNA synthesis. It is naturally occurring in the diet; particularly in cow, goat, and sheep’s milk. Orotic acid is ultimately converted to betaalanine, which can subsequently be incorporated in anserine and carnosine.

Orotic acid enhances pyrimidine pools.

The body stores pools of pyrimidines and purines (such as ATP, GTP, CTP and UTP) and for use as energy sources, in cell signalling, and to participate in enzymatic reactions, and these pools can be taxed by intense and/or repeated exercise. [1]
Supplemental orotic acid may serve to replenish depleted pyrimidine pools.

Orotic acid may be nootropic

As a precursor of uridine monophosphate, orotic acid represents a source of bioavailable uridine. Although uridine is present in the diet, it is mainly in the form of RNA and not bioavailable. Several studies show nootropic effects of uridine, often in combination with choline and/or DHA

Orotic acid increases glycogen synthesis in muscle.

Orotic acid is also precursor of uridine triphosphate (UTP). UTP is converted by the enzyme UDP–glucose pyrophosphorylase to uridine diphosphate glucose (UDPG). Glycogen synthase then combines the glucose residues from UDPG into long chains of glycogen; the remaining UDP molecules can then be recycled back into the process. Skeletal muscle uses glycogen as a fuel source during strenuous and prolonged exercise. Experiments from the 1970s demonstrated that additional uridine increased the rate of glycogen synthesis (and thus that glycogen synthase was not the only rate-limiting step in the process). [2]

Orotic acid converts to beta-alanine, and may thus increase carnosine stores

Beta alanine is a product of the catabolism of uracil, a metabolite of uridine, of which orotic acid is a precursor. This process isn’t instant, but begins within minutes of absorption. [3] Orotic acid administration may therefore be viable alternative to beta-alanine, to avoid the paresthesia (‘pins-and-needles’) side effect associated with large doses (>750mg) of betaalanine. [4]

“Supplementation with mineral orotates or orotic acid may represent a practical strategy for boosting the level of carnosine and carnosine derivatives within the body.” [4]

Carnosine acts as a buffer to lactic acid, boosting muscle performance and reducing fatigue.

References:

[1] Yamamoto T, Moriwaki Y, Takahashi S, Tsutsumi Z, Yamakita J, Higashino K. Effect of muscular exercise on the concentration of uridine and purine bases in plasma–adenosine triphosphate consumption-induced pyrimidine degradation. Metab Clin Exp. 1997 Nov;46(11):1339–42.

[2] Haugaard ES, Frantz KB, Haugaard N. Effect of uridine on cellular UTP and glycogen synthesis in skeletal muscle: stimulation of UTP formation by insulin. Proc Natl Acad Sci U S A. 1977 Jun;74(6):2339–42.

[3] Aonuma S, Hama T, Tamaki N, Okumura H. Orotate as a β-Alanine Donor for Anserine and Carnosine Biosynthesis, and Effects of Actinomycin D and Azauracil on Their Pathway. The Journal of Biochemistry. 1969;66(2):123–32.

[4] McCarty MF, DiNicolantonio JJ. β-Alanine and orotate as supplements for cardiac protection. Open Heart. 2014 Jan 8;1(1):e000119.

These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure, or prevent any disease.