New Lab Studies Show Creatine Ethyl Ester & Kre-Alkalyn Ineffective

At the recent International Society of Sports Nutrition, two new studies were released showing that both Creatine Ethyl Ester (CEE) and Kre-Alkalyn were ineffective in vitro. The studies were conducted by The Division of Sport Sciences at Northumbria University, Newcastle UK and Kingston University London, Department of Life Sciences by Dr. MJ. Tallon Dr. R. Child.

Both studies used similar methods to compare the rates of conversion of CEE and Kre-Alkalyn to the waste by-product creatinine when compared to Creapure brand micronized creatine monohydrate. "Each product was incubated in 900ml of pH 1 HCL [hydrochloric acid] at 37º +/- 1ºC and samples where drawn at 5, 30 and 120 minutes and immediately analyzed by HPLC [high-performance liquid chromatography] (UV) for creatine and creatinine." [1,2] This occured in both product studies. Although this test was conducted in a laboratory, it was meant to mimic conditions that would be present in the human stomach.

Creatine Ethyl Ester

"Creatine ethyl ester is merely creatine monohydrate with an added ester attached to make the creatine molecule more lipophilic [having an ability to be absorbed by lipids, or fats]." [3] Adding an ester to compounds is nothing new, but until this point, there has been no real data indicating that creatine ethyl ester was any better than any other form of creatine on the market - particularly the most studied form, creatine monohydrate. By adding an ester to a compound for oral consumption, it attempts to allow it to pass through the harsh acidic stomach content and be taken up by lymphatic absorption. Esterification is the process that allows an acid molecule to combine with an alcohol molecule, which removes water from the equation. This makes it more soluble in an oil or fat - similar to esterfied steroids.

Creatine Ethyl Ester has a long history - longer than I actually imagined, with studies dating back to the 1920s. [3] However, this most recent form, which was originally conceived to be used as a dietary supplement was first introduced by The University of Nebraska, which holds patent #6897334: Production of creatine esters using in situ acid production. This patent does not specify the usage of CEE, but only it's production and manufacturer. Initially, CEE was submitted to the FDA for review to market it as an OTC dietary supplement, CE2™, it was rejected by the FDA (PDF) following safety concerns. However, that didn't stop every other supplement company on the planet from picking up the ingredient and selling it, despite the lack of pre-market approval by the FDA of from its patent holders.

The new study involving CEE uses two products, SAN CM2 Alpha - a blended product that includes Di-L-Arginine-L-Malate, Beta-Alanine, and CEE HCL. SAN previously sold a version of CEE that was methylated, a molecular change to the creatine in an attempt to enhance absorption by avoiding breakdown in the stomach and liver. However, this version was removed at concerns about it's potential conversion to methanol. The second brand tested was MRI CE2, which is the original Medical Research Institute that requested approval to market CEE from the FDA. MRI is the company that was founded by Ed Byrd, who also popularized NO2 products. CE2 contains only creatine ethyl ester HCl.

Creatine ethyl ester rapidly degrades to creatinine in stomach acid

Child R and Tallon MJ

Department of Life Sciences, Kingston University, Penrhyn Rd, Kingston-upon-Thames, United Kingdom. University of Northumbria, Sport Sciences, Northumbria University, Northumberland Building, Newcastle upon Tyne, United Kingdom, DrChild@CR-Technologies.net

Creatine ethyl ester (CEE) is a commercially available synthetic creatine that is now widely used in dietary supplements. It comprises of creatine with an ethyl group attached and this molecular configuration is reported to provide several advantages over creatine monohydrate (CM). The Medical Research Institute (CA, USA) claim that the CEE in their product (CE2) provides greater solubility in lipids, leading to improved absorption. Similarly San (San Corporation, CA, USA) claim that the CEE in their product (San CM2 Alpha) avoids the breakdown of creatine to creatinine in stomach acids. Ultimately it is claimed that CEE products provide greater absorption and efficacy than CM. To date, none of these claims have been evaluated by an independent, or university laboratory and no comparative data are available on CEE and CM.

This study assessed the availability of creatine from three commercial creatine products during degradation in acidic conditions similar to those that occur in the stomach. They comprised of two products containing CEE (San CM2 Alpha and CE2) and commercially available CM (Creapure™). An independent laboratory, using testing guidelines recommended by the United States Pharmacopeia (USP), performed the analysis. Each product was incubated in 900ml of pH 1 HCL at 37º +/- 1ºC and samples where drawn at 5, 30 and 120 minutes and immediately analyzed by HPLC (UV).

After 30 minutes incubation only 73% of the initial CEE present was available from CE2, while the amount of CEE available from San CM2 Alpha was even lower at only 62%. In contrast, more than 99% of the creatine remained available from the CM product. These reductions in CEE availability were accompanied by substantial creatinine formation, without the appearance of free creatine. After 120 minutes incubation 72% of the CEE was available from CE2 with only 11% available from San CM2 Alpha, while more than 99% of the creatine remained available from CM.

CEE is claimed to provide several advantages over CM because of increased solubility and stability. In practice, the addition of the ethyl group to creatine actually reduces acid stability and accelerates its breakdown to creatinine. This substantially reduces creatine availability in its esterified form and as a consequence creatines such as San CM2 and CE2 are inferior to CM as a source of free creatine.

As indicated by the study, the products tested in the sample under performed that of regular micronized creatine monohydrate. In real world terms this would equate to purchasing a product that itself advertises to be superior to "regular" creatine by withstanding breakdown in the stomach and other common problems, yet it turns out that it does not perform as advertised, at least in the lab. The conversion of creatine into creatinine is an unwanted effect of the compound, as creatine needs to make it's way into skeletal muscle cells to be effective. Creatinine is not effective at anything, and high levels in individuals with kidney problems can be hazardous. In fact, creatinine is one of the markers doctors check for when doing routine blood tests to determine if renal failure is occurring.

Kre-Alkalyn

Kre-Alkalyn [KA] is not a modification to creatine itself, but an alternative delivery system for the compound. However, the claims made for Kre-Alkalyn have generally been viewed with skepticism due to the fact that there has been no clinical research performed on it, and the claims made about KA are similar to those made in the past by products such as the well known and bunk liquid creatine.

Here is a partial description taken from an advertisement for a KA product:

Kre-Alkalyn...a patented Creatine in a pharmaceutical delivery system providing maximum stability and absorption. Creatine Monohydrate has been proven through a decade and more of research to enhance strength, endurance, and subsequent athletic performance. The only disadvantages of traditional Creatine Monohydrate are the extremely short term stability, rapid conversation into the bi-product Creatinine when exposed to liquid, and subsequent poor absorption into the bloodstream. Kre-Alkalyn...which is buffered for maximum absorption and stability, solves this dilemma. Kre-Alkalyn...offers the athlete Creatine which is 100% stable, will not break down into Creatinine, and will absorb efficiently into the bloodstream. In fact, each 1 gram of Kre-Alkalyn is equivalent to ingesting 10 grams of Creatine powder allowing the athlete to take far less product while experiencing even more explosive results.

Kre-Alkalyn is covered under several patents for it's usage as a creatine supplement delivery system. Patent #6,399,661 details some of the inner workings of KA:

Abstract
The present invention relates to an oral creatine supplement and the method of making this supplement which includes mixing an alkaline powder with a powdered creatine until the pH of the mixture is in the range between 7-14. A powdered additive is added to the mixture for improving sweetness and taste. Finally, a further alkaline powder is added to the mixture to adjust the pH of the mixture to a range between 7-14. This mixture is then mixed with water prior to ingestion.

What is claimed is:

1. A process for producing a creatine mixture for ingestion comprising the steps of:

mixing an alkaline powder with a powdered creatine to adjust the pH of the mixture to a range between 7-14;
adding a powdered additive to the mixture for improving sweetness and taste; and
adding a further alkaline powder to the mixture to adjust the pH of the mixture to a range between 7-14.
2. The method according to claim 1 wherein the alkaline powder is comprised of soda ash.

3. The method according to claim 1 wherein the alkaline powder is comprised of magnesium glycerol phosphate.

4. The method according to claim 1 wherein the alkaline powder is selected from a hydroxide, carbonate, bicarbonate, chloride, tree latex or a phosphate.

5-8. The method according to claim 1 wherein the creatine powder is comprised of creatine monohydrate, creatine phosphate, creatine pyruvate, creatine citrate.

The patent itself includes tests demonstrating KA's ability to defeat conversion to creatinine and the reasoning behind how it works. Like CEE, Kre-Alkalyn is a higher priced creatine product that has less total creatine per dose than standard the monohydrate version. Unfortunately, as with the previous study for CEE, this new study, using the same methods, successfully demonstrates that KA doesn't live up to it's claims and that micronized creatine monohydrate still wins out.

Kre-alkalyn® supplementation has no beneficial effect on creatine-to-creatinine conversion rates.

Tallon MJ and Child R

University of Northumbria, Sport Sciences, Northumbria University, Northumberland Building, Newcastle upon Tyne, United Kingdom, Department of Life Sciences, Kingston University, Penrhyn Rd, Kingston-upon-Thames, United Kingdom. DrTallon@CR-Technologies.net

All American Pharmaceutical and Natural Foods Corp. (Billings, MT, USA) claim that Kre-alkalyn® (KA) a "Buffered" creatine, is 100% stable in stomach acid and does not convert to creatinine. In contrast, they also claim that creatine monohydrate (CM) is highly pH labile with more than 90% of the creatine converting to the degradation product creatinine in stomach acids. To date, no independent or university laboratory has evaluated the stability of KA in stomach acids, assessed its possible conversion to creatinine, or made direct comparisons of acid stability with CM.

This study examined whether KA supplementation reduced the rate of creatine conversion to creatinine, relative to commercially available CM (Creapure™). Creatine products were analyzed by an independent commercial laboratory using testing guidelines recommended by the United States Pharmacopeia (USP). Each product was incubated in 900ml of pH 1 HCL at 37º +/- 1ºC and samples where drawn at 5, 30 and 120 minutes and immediately analyzed by HPLC (UV) for creatine and creatinine.

In contrast to the claims of All American Pharmaceutical and Natural Foods Corp., the rate of creatinine formation from CM was found to be less than 1% of the initial dose, demonstrating that CM is extremely stable under acidic conditions that replicate those of the stomach. This study also showed that KA supplementation actually resulted in 35% greater conversion of creatine to creatinine than CM. In conclusion the conversion of creatine to creatinine is not a limitation in the delivery of creatine from CM and KA is less stable than CM in the acid conditions of the stomach.

Conclusions

Both studies demonstrate that two new and very highly-touted creatine products do not live up to their claims in lab conditions. Contrary to claims made by both products that they can withstand the supposed problems of regular creatine conversion to creatinine in the body, the in fact work less well than the regular versions. However, it should be emphasized that both of these test are performed in vitro and more studies need to be done, especially on male athletes and weight lifters, to see how they stack up in real world conditions. It is also important to make the determination as to whether or not they have a real effect on strength and body composition. Another factor that is noticeable is the email addresses of the two doctors that conducted the study. Although I am not personally familiar with either of them or their ties to CR-Technologies.net, it does appear that the web page for that domain sells a product called Creasafe™, which claims to be "the worlds safest and most advance [sic] creatine", bringing up the possibility of a conflict of interest. UPDATE: Dr. Tallon has responded to this criticism.

Still, for now, it appears that the best bet for people supplementing with creatine is what has been recommended all along - micronized creatine monohydrate.

References

Thanks to Anssi Manninen for clearing up some confusion in the studies text.

1. Child R and Tallon MJ. Creatine ethyl ester rapidly degrades to creatinine in stomach acid. Department of Life Sciences, Kingston University, Penrhyn Rd, Kingston-upon-Thames, United Kingdom. University of Northumbria, Sport Sciences, Northumbria University, Northumberland Building, Newcastle upon Tyne, United Kingdom, DrChild@CR-Technologies.net

2. Tallon MJ and Child R. Kre-alkalyn® supplementation has no beneficial effect on creatine-to-creatinine conversion rates. University of Northumbria, Sport Sciences, Northumbria University, Northumberland Building, Newcastle upon Tyne, United Kingdom, Department of Life Sciences, Kingston University, Penrhyn Rd, Kingston-upon-Thames, United Kingdom. DrTallon@CR-Technologies.net

NOTE: The original abstracts of these studies have been posted online at NPICenter. The abstracts which are in this blog were copied and after Layne Norton (str8flexed) posted them on bodybuilding.com, which lead to some of the characters showing up incorrectly.

3. Creatine Ethyl Ester…Reviewing the Literature by Deserusan