Bioavailability: Is It A Concern With Nutritional Supplements?

Bioavailability is a large word that is hard to spell and probably even harder to understand. Human nature being what it is, we tend to ignore things we don’t understand, unless it is impacting our lives in a meaningful way. In the world of prescription and over-the-counter drug products, bioavailability concerns are addressed by the pharmaceutical research staff of the drug company, and with the possible exception of Advil LiquiGels, these concerns seldom reach the conscious level of the average consumer. In the dietary supplement world, bioavailability of natural substances is largely ignored, with only CoQ10 products focusing significant attention on the bioavailability issue.

A Simple Definition of Bioavailability.

Bioavailability has been defined as “the extent to which the active moiety enters the circulation, thereby gaining access to the site of action”. In simpler terms, it is a measure of how much of a dose of orally administered product is absorbed from the intestines, enters the bloodstream, and is delivered to the cells (the site of action). It is intuitively obvious that a drug or nutraceutical substance will not be effective if it is not absorbed into the blood and delivered to the cell where it exerts its biological effect. This is fully recognized by drug companies, and the necessary formulation and pharmacokinetic studies are undertaken to assure maximum absorption and the desired biological effect. This is generally not the case with nutraceuticals, but is beginning to be addressed by ingredient suppliers and a few research-oriented supplement manufacturers.

Because It’s Natural Doesn’t Mean It’s Easily Absorbed By The Body.

I have been actively engaged in the world of dietary supplements for about 10 years and am beginning to understand the ever-changing dynamics of this marketplace, but am still baffled by the practices of many of the market participants. It is not uncommon for manufacturers to identify a natural substance that has been shown to have beneficial properties and undertake to develop a simple capsule or tablet formulation, with little regard, and probably little understanding, of the absorption and bioavailability profile for their product formulation. This could be because they assume that all natural substances are bioavailable, but more likely because the cost structure of the nutraceutical market doesn’t support expensive formulation research.

Notwithstanding this general disregard for the bioavailability of natural products, there are a number of extremely valuable natural substances that are poorly soluble in water, not easily absorbed from the intestines, and demonstrate low bioavailability in conventional formulations. One of these extremely valuable substances is alpha lipoic acid, which is poorly soluble in water and has low bioavailability in powder-based (i.e. hard gelatin capsules and tablets) formulations. Another example is coenzyme Q10 (ubiquinone), which has been the subject of intense scrutiny in the United States and Japan. The importance of achieving and maintaining high blood levels of CoQ10 to achieve a desired clinical effect has been well-documented in the scientific and lay literature. The importance of achieving high blood levels of alpha lipoic acid to achieve a desired biological/clinical effect has received little scientific attention, and is virtually unknown in the marketplace.

Alpha Lipoic Acid: A Remarkable Multi-Faceted Molecule.

Alpha lipoic acid in its molecular form is soluble in both the aqueous and lipid compartments of the body, earning it the nickname the “universal anti-oxidant” because it is soluble in both compartments, and has the added benefit of regenerating these Vit C and Vit E, along with the naturally occurring anti-oxidants, most notably “glutathione”. Because alpha lipoic acid very effectively neutralizes free radicals in vitro (i.e. in a test-tube), it is generally believed that alpha lipoic acid acts primarily as an anti-oxidant free radical scavenger in vivo (i.e. inside the body). There is accumulating evidence that alpha lipoic acid has multiple biological activities that may not be mediated through its anti-oxidant properties.

A good example of this is reflected in the beneficial effects of alpha lipoic acid in retarding the progression of liver disease in compromised individuals. This beneficial effect had been almost universally attributed to its anti-oxidant effect on lipid peroxidation of the liver cell membrane, but recent studies suggest that alpha lipoic acid also inhibits the hepatic plasminogen activator pathway toward liver fibrosis. The change in scientific thinking regarding the mode of action of alpha lipoic acid is best summarized by the researchers at the Linus Pauling Institute who state that “although LA is a potent antioxidant in the test tube, LA supplementation may affect health by stimulating glutathione synthesis, enhancing insulin signaling and modulating the activity of other cell signaling molecules and transcription factors”.

Maximizing Cellular Uptake Of ALA Can Be Critically Important.

Regardless of the mechanisms by which alpha lipoic acid exerts its many biological properties, it is essential that adequate quantities of the alpha lipoic acid molecules reach the cells. We don’t really know what constitutes an effective dose of alpha lipoic acid, nor how much of that dose actually reaches the various cells in the body. Because studies aimed at answering these questions would be exceedingly complex and prohibitively expensive, we are limited to making assumptions based on clinical experience with arbitrary dose levels. Clinical studies on the use of alpha lipoic acid in the treatment of diabetic neuropathy give us perhaps the best clue as to the levels of alpha lipoic acid required to achieve a measurable biological/clinical effect, and whether oral dosage forms can deliver adequate quantities of alpha lipoic acid to the cells. Clinical studies performed in Germany and the United States have confirmed that intravenous doses of 600 mg of alpha lipoic acid were effective in relieving the symptoms of diabetic neuropathy, but equivalent oral doses were only marginally effective. This outcome is not surprising, considering the poor solubility of alpha lipoic acid oral dosage forms and the rapid clearance of alpha lipoic acid from the bloodstream. It is this clinical experience that forms the basis for suggesting that commonly used oral dosage forms do not deliver adequate quantities of alpha lipoic acid to the cells to achieve the desired clinical effect.

Introducing a Solubilized Formulation.

At the time of the German clinical studies, all oral dosage forms contained crystalline alpha lipoic acid powder that was poorly soluble in water, and thus poorly absorbed into the bloodstream from the GI tract. Based on the premise that the effectiveness of oral dosage forms could be enhanced by solubilizing the crystalline powder, a startup discovery company embarked on a research project to develop an oral dosage form that would deliver alpha lipoic acid blood levels that approached intravenous dosing. Using advanced formulation techniques, a solubilized alpha lipoic acid dosage form was developed that was similar to the high bioavailability formulations used for poorly soluble substances like ibuprofen (Advil) and coenzyme Q10. This solubilized, enhanced bioavailability product was made commercially available about 10 years ago under the brand name ThioGel.

Studies were conducted in animals and humans that demonstrated a 2–3 fold
increase in plasma levels of alpha lipoic acid using the ThioGel solubilized product versus powder based products marketed at that time. In the intervening 10 years, ThioGel has been successfully used by integrative medicine physicians, holistic practitioners, and individual consumers to treat a broad array of conditions that are beneficially influenced by the biological properties of alpha lipoic acid.

As with all nutraceuticals and drug substances, adequate levels of alpha lipoic acid must reach the cells to achieve a clinically significant effect. Based on the diabetic neuropathy clinical studies, it appears that adequate cellular levels of alpha lipoic acid cannot be achieved, or are only marginally achieved at best, with common powder based oral products. The inadequate or marginal cellular uptake of alpha lipoic acid can be substantially increased with solubilized alpha lipoic acid, shifting the cellular uptake equation to a more substantial clinical effect.

Enhancing Bioavailability To Achieve the Desired Clinical Effect.

It is possible to increase the absorption and bioavailability of alpha lipoic acid administered in oral dosage forms by employing advanced formulation techniques to solubilize poorly water soluble alpha lipoic acid powder. Unfortunately, studies demonstrating clinical effectiveness are rare in the nutraceutical world, and we are left with extrapolation from laboratory data, anecdotal reports, and comparative kinesiology testing. While these approaches do not measure up to controlled clinical studies, they do provide a measure of confidence in selecting a product formulation that will deliver the best clinical result. The solubilized formulation of alpha lipoic acid is based on solid laboratory data, has been used successfully for many years by respected clinicians, and always tests in the top level in comparative kinesiology testing.

Returning to the question posed in the title of this article, it is indeed critically important to understand the absorption and bioavailability profile of natural substances to assure adequate absorption into the circulation and adequate uptake in the cells to exert the desired biological effect. Consumption of powder-based formulations delivers substantially lower and variable amounts of alpha lipoic acid to the site of action in the cells, and these amounts my not be adequate to realize the desired biological effect. Alpha lipoic acid and CoQ10 are two of the more important supplement products where bioavailability concerns are strongly justified.