Ask Dr. Andro: The Pharmacokinetics of Creatine (Part I/II) - How Is Creatine Absorbed into the Bloodstream?

Illustration 1: There is a bunch of things that could potentially go wrong with creatine uptake: The creatine from dietary sources could be mal-absorbed (1) in the small intestine, (2) not make it into the cell, or (3) be excreted too readily either before or immediately after it was transported into the muscle.

Question from Lerner (via comments): Do Creatine Transporters behave the same as glucose transporters? (I.e., serum insulin binds to cellular insulin receptors, which causes Transporters to migrate from inside the cell to the plasma membrane - and the Transporters then pull in the external glucose.)

Answer Dr. Andro: As you may have noticed, I took the freedom to set Learner's question into a broader context. A context I broached in my dissertations on Athletic Edge Nutrition's new creatine product Creatine RT on Tuesday, Aug 16, 2011. Thus, the questions I will be trying to answer (unfortunately, I have to rely on existing studies and do not have my own lab, here ;-) are the following ones:

1. How does creatine get into the blood?
2. How does creatine get into the muscle? (cf. Part II)
3. What can influence these processes?
   

In view of the fact that this is quite an extensive topic, I decided to tackle it in a two part series, where in part 1 (today) I will focus on the issue of creatine absorption into the bloodstream, a putative problem the clever researchers from the supplement industry pretend to have solved, already. Creatine ethyl-ester, Creatine malate, Creatine citrate, Creatine HCL, Creatine whatever, and Krealkalyn(TM)... are the names of the "solutions" to the purported inferiority of creatine monohydrate, the shelves of your local supplement story have to offer.

How does Creatine Get into Your Blood?

In essence all these esters, acids, chlorides and other "creatine + X"-combinations have been designed to mug you... ah, I mean to increase the amount of creatine that makes it into your bloodstream, or in other words, to increase bioavailability. Now, as Wesley Mc Call and Adam Persky state in chapter 13 of Creatine and Creatine Kinase in Health and Disease, there are four potential reasons why creatine bioavailability could be less than 100%, in the first place:

1. Degradation (to creatinine) in the stomach
2. Insufficient dissolution, i.e. passing the intestines "unsolved"
3. Problems with creatine uptake by the epithelial cells
4. Degradation by gut bacteria

1. Creatine could degrade when it reaches your stomach:

We know for certain that creatine degradation is maximal at pH 3 (Cannon. 1927, cf. figure 1). Now, a healthy stomach should have a pH of 1 and for about 84 years everybody (supplement producers included) would have been able to take a look at the data of the 1927 study by Cannon and Shore, who found that after 25 h in a solution with a pH of 1 only ~2% of the creatine would have "degraded" into its dehydration product creatinine and that the often cited "breakdown" of creatine monohydrate in the acidic milieu of your stomach is not really an issue, after all.

Figure 1: Percent creatinine in solution of previously pure creatine after 25, 50, 125 and 1903h at a certain pH (data adapted from Cannon. 1927).

Moreover, the data in figure 1 clearly shows that you would have to have the creatine sit in your stomach for more than 2h before it would make a statistically significant difference (25h: pH1=2%, pH6=2%; 125h ph1=9%, pH6=3%) whether your stomach had a pH 1 or a pH that is greater 6. Now, that certainly sounds ridiculously long, still in conjunction with food (Mc Call. 2008) and outside of the petri dish these effects are, as we are about to see further down, still physiological relevant.

Image 2: You probably expected that it ain't advisable to take your creatine with a Big Mac, but would you have guessed that juices are counter-indicated, as well?

Did you know that the ingestion of a meal will increase the PH of your stomach drastically? Dressman, et al. report an increase to pH ~6 after consuming a hamburger and a glass of milk (Dressman. 1990). After no more than 30 minutes, however, gastric secretion had reduced the pH to 4-3 and after roughly 90 minutes, the stomach of the subjects was the same "acid pit" (pH 1.3) as it was before the ingestion of the meal. This goes to tell you that taking creatine with a meal or even worse right after a meal could be counter-indicated.

Tip: You better wait at least 90 minutes after your last meal, before you flush down your creatine with water, as even the presence of carbohydrates from juices has been shown to "delay the time to peak concentration", which usually is less than 2h and to decrease the maximal concentration at peak concentration (Mc Call. 2008).

What you certainly want to avoid, though, is a pH somewhere between 3-4. However, even in this "worst" case scenario less than 10% of the creatine would undergo the (at higher pH partly reversible!) reaction from creatine to creatinine. So, as Mc Call and Persky point out, the "relatively short time the creatine actually spends in the stomach means that very little of the oral dose of creatine should be lost" (Mc Call. 2008) - at least, if you take it on an empty (and healthy, i.e. highly acidic) stomach.

2. Creatine (Monohydrate) could not dissolve and thus be not absorbed

Illustration 2: Creatine is taken up by enterocytes in the jejunum and the illeum.

The issue of undissolved creatine monohydrate crystals, has been discussed on bulletin-boards and in the ads of several supplement companies ever since the first "advanced" creatine products hit the market. Yet, while it is beyond debate that the enterocytes of your small intestines (in rats creatine has been found to be absorbed in the ileum (Peral. 2005) and the jejenum (Tosco. 2004), cf. image 2) cannot absorb bulky creatine crystals, the solubility of creatine monohydrate in water at 20°C is 14 g/L at a neutral pH of 7. Now, with lower pHs and higher temperatures (as mentioned before your stomach should have a pH of about 1-2 and your body temperature obviously is ~37°C) it is absolutely unlikely that the creatine would not dissolve. Using creatine citrate, which, due to its lower pH (solution has pH 3.5), has a 1.5x higher solubility, or other highly soluble forms of creatine is thus not necessary, if your stomach is the warm acid pit it is supposed to be.

Interestingly, a study by Harris et al. suggests that the creatine from meat such as the paddies of the burger in image 2 (I am assuming here that there is still some meat in McDonalds burgers / here in Germany they have recently begun advertising their meat quality ;-) is more readily absorbed (this refers to absolute amounts, not to the time-course) than either creatine suspended (=more creatine in water than can be solved) in water or creatine tablets / lozenges (Harris. 2002). A probable explanation for this phenomenon could be that the creatine is safely contained in the meat, until the latter is broken down by enzymes that are activated as  the pH of the stomach is decreasing. Thus only very limited amounts of free creatine will be exposed to pH levels in the detrimental3-4 range.

3. Creatine could simply not be taken up by the enterocytes in the small intestine

Obviously, any general digestive problem related to nutrient transport across the epithelial barrier in the intestines could compromise creatine uptake, as well. As mentioned earlier the presence of large (180g) amounts of carbohydrates have been shown to slow gastric emptying and consequently creatine absorption, considerably (Vist. 1995). In addition several other meal-constituents could also increase the pH temporarily and thus initially decrease solubility (when pH is still very high) and consequently increase creatine to creatinine breakdown (when the pH passes the critical 3-4 range, see above).

4. Creatine could be degraded by bacteria in the gut

Image 2: Biridobacterium tongum is a probiotic and a natural enemy of putrefective bacteria, who "suffocate" from the lactic acid, acetic acid and bacteriocins (image from dophilus.com)

Even if the creatine survives passage through the stomach, is dissolved and the enerocytes are ready to absorb it, it could still be taken up by putrefective bacteria (bacteria that break down organic material) of which William C. Rose in a paper in the Annual Review of Biochem. writes that they transform creatine  into methylhydantoin, which previously had been shown to yield sarcosine under the influence of micro-organisms" (Rose. 1933) Unless you want Patrick Arnolds sarcosine as an adjunct to d-aspartic acid (as in TestForce 2), I would say this is another good reason to keep your gut clean and tidy ;-)

Conclusion: Absorption should not be an issue

If your gut is healthy, acidic and free of pathogenic amounts of putrefective bacteria there is absolutely no reason you could have problems absorbing creatine - especially if you stick to my recommendations and

• do not escalate single dosages beyond 5g, 
• take your creatine on an empty stomach (or at least 90 min after your last meal)*
  (taking creatine with carbs + protein will increase breakdown to creatinine, and decrease the maximal serum levels, but, on the other hand, it will increase muscular creatine retention, cf. Part II)
• do not take creatine with a meal or protein or large amounts of carbohydrates**
  (read more on the carb issue in the 2nd part of this installment of "Ask Dr. Andro", tomorrow)

A tweak to this general guideline resolves around the "mysterious" issue of alkaline creatine. The results from the Cannon study show that you have the choice:

• increase your stomach pH beyond 6, or 
• decrease your stomach pH below 2 

 if you want to avoid the breakdown of creatine to creatinine.

Figure 2: Relative increase in creatine in dry muscle mass of horses, after supplementation with creatine monohydrate, kre-alkalyn or Gastner's patented creatine + sodium carbonate +sodium hydrogen carbonate formula (Gastner. 2010)

Timing creatine away from meals would be option #2, option #1, on the other hand, would entail supplementing with some strong alkalizing agent such as sodium or potassium bicarbonate, and in fact, this is exactly what KreAlkalyn, the purported "super-creatine" is - a ph-buffered creatine-monohydrate product. Thomas Gastner holds the patent to a formula of which had a higher stability than KreAlkalyn and consists of nothing else but 2.98g creatine monohydrate + 150mg sodium carbonate + 118mg sodium hydrogen carbonate. According to self-conducted animal experiments (horses= the increased stability entailed a statistically significant improvement in muscular creatine retention after 4 weeks on creatine enriched feed pellets (+7% over creatine monohydrate and +10% over KreAlkalyn).

Image 3: Kre-Alkalyn - expensive, but probably
useless - at least when taken with food.

The results of Gastner's experiment should obviously be taken with some skepticism. Nevertheless, the picture we are seeing here is conclusive, because either you rely on the acidity of your stomach (using plain creatine monohydrate) or you put enough alkaline buffers into your product so that the acidity of the stomach remains greater than pH 6 for a long enough amount of time. With Kre-Alkalyn (and horse stomachs) it appears that Jeffrey Gollini who holds the patent for KreAlkalyn managed to hit exactly that most unfavorable pH range, where the overall pH of the food + KreAlkalyn solution in the (horse-)stomach falls back into the 3-4 range very quickly and the creatine uptake is reduced due to the increased breakdown of  creatine to creatinine.

In summary, this is a clear points win for creatine monohydrate taken on an empty stomach (or, alternatively with a significant amount of buffers + food). Fidgeting with citrates, malates, and esters which will eventually be cleaved (if you are unlucky at the very same moment your gastric pH has returned to the "danger zone" of 3-4), may be promotional, but either is not likely to be superior (citrate, malate & co) or has been shown (creatine ethyl ester, cf. Spillane. 2009) to be inferior to the undefeated 'top dog' creatine monohydrate.

Click here to read Part II: How Does Creatine Get into the Muscle

Supercharging Creatine With Baking Soda: Study Shows Increased Peak Power and Endurance - Plus: How Bicarbonate Could Help You Lose Fat & Build Muscle

The pH of your urine is not a reliable measure of your bodies acid base-status

I have written about the "love affair" of creatine and baking soda before. Once, in the "The Pharmacokinetics of Creatine" series (Part I, Part II), where I outlined how you can "brew" your own KreAlkalyn replacement using creatine and NaHCO3, and another time back in 2010, when I discussed the data from a dissertation by James J Barber, who had conducted a preliminary investigation into the joint ergogenic effects of N-Amidinosarkosin (creatine) and NaHCO3 (baking soda) on the repeated sprint performance of recreational athletes.

You can learn more about beta alanine & bicarbonate at the SuppVersity

The Hazards of Acidosis

Build Bigger Legs W/ Bicarbonate

HIIT it Hard W/ NaCHO3

BA + Bicarb are Synergists

Bicarb Buffers Creatine

Beta Alanine Fails to HIIT Back

The complete results of a follow up investigation by Barber, who now works at the Human Performance Laboratory at the California Polytech State University, are going to be published in the next issue of the Journal of Strength and Conditioning Research (Barber. 2012); and they underline what you, as a diligent student of the SuppVersity, knew all along: Baking soda is not only cheaper than 99% of the commercially available supplements, it is also more ergogenic than the average junk the guy at GNC is trying to sell to you.

Soda? But that must be bad for you?! False!

For their study, the researchers recruited a group of 13 healthy previously trained (>5h of aerobic and >2h of HIT per week) young men (age 21.1 ± 0.6 yrs, BMI 23.5 ± 0.5 kg/m²; VO2Max 66.7 ± 5.7 ml/kg-min). In a double-blinded crossover fashion (meaning that each participant had to complete every condition, i.e. "crossover", and neither he, nor the researchers knew whether he had been given the active or the placebo treatment, i.e. "double-blinded"), the men had to consume a supplement containing either

• placebo: 20g maltodextrin + 0.5g/kg maltodextrin,
   
• creatine (only): 20g creatine + 0.5g/kg maltodextrin, or
   
• creatine + NaHCO3: 20g creatine + 0.5g/kg baking soda*
  
  * for all supplement the total dosage was divided into four smaller doses, which were to be taken at 9:00 a.m., 12:00 p.m., 6:00 p.m., and 10:00 p.m.; the subjects also completed a 48h dietary recall and were asked to consume identical foods during each condition

before their peak power, mean power, relative peak power, and bicarbonate concentrations were assessed during six subsequent 10-second repeated Wingate sprint tests on a cycle ergometer with 60s rest periods between each sprint. To preclude any carry-over effects from previous tests, or rather supplementation, each experiment was followed by a three-week washout period.

Figure 1: Total and relative peak power output (left) and relative peak power output in the individual trials (right; data adapted from Barber. 2012)

As you can see in figure 1, Barber et al. were able to confirm his initial results. Interestingly, only the creatine + NaHCO3, yet not the creatine only regimen elicited statistically significant increases in both the relative power output (in W/kg; p < 0.05 for both) and the total power output (p < 0.05 only in the creatine + NaHCO3 trial; cf. figure 1, left). Moreover, the creatine + NaHCO3 supplementation lead to "the greatest attenuation of decline in relative peak power over the 6 repeated sprints." (cf. figure 1, right).

Creatine + baking soda: Additive or synergistic effects

An interesting question the scientists probably ignored, because their GNC guy did not yet tell them about the "extraordinary superiority of buffered creatine", is whether the ~37g of sodium bicarbonate the subjects ingested simply added to the beneficial effects the 20g of creatine had on the repeated sprint performance of the athletes, or whether the baking soda also decreased the breakdown and facilitated the uptake of creatine (cf. figure 2)

Figure 2: Relative increase in creatine in dry muscle mass of horses, after supplementation with creatine monohydrate, Kre-Alkalyn or Gastner's patented creatine + sodium carbonate +sodium hydrogen carbonate formula (posted first in "The Pharmacokinetics of Creatine: Part 1/2" based on Gastner. 2010)

And while it may not be important for your HIIT sessions, whether the mechanism behind the performance increase is additive of synergistic, it could well make the one-rep difference on a deadlift or bench press competition, in the course of which each additional phosphocreatine molecule counts.

"Cholesterol is the devil and sodium is his little brother!" Everyone who still believes everything the medical orthodoxy says, please raise your hands!

A note on the dangers of "salt": Firstly, baking soda is "only" ~28% sodium, which means that for every 4 grams you ingest you get roughly 1 g of sodium. Secondly, it is arguable how much of the sodium is effectively taken up and will be floating around in your blood. As T. Lakhanisky points out in his dossier for the Belgian government: "The uptake of sodium, via exposure to sodium carbonate, is much less than the uptake of sodium via food. Therefore, sodium carbonate is not expected to be systemically available in the body." (Lakhanisky. 2002) And thirdly, there is more and more evidence that suggests that the chloride rather than the sodium content of common table salt (NaCl = NatriumChloride) is the root cause of "sodium induced hypertension" in "sodium sensitive" individuals / animal models. Only recently, a study by Schmidlin et al. showed that chloride loading induced hypertension in the stroke-prone spontaneously hypertensive rat despite profound sodium depletion (Schmidlin. 2010). So, if you asked me, rather than pointing at salt as the #2 on the list of greatest evils (obviously cholesterol is still #1, here) the medical orthodoxy would be better advised to address the imbalances between sodium and potassium, which are so characteristic of the western diet, instead of painting yet another black and white picture where sodium is the bad guy and potassium the dangerous mineral that cannot be sold OTC in dosages >80mg.... but hey, this would be the topic for a whole new blogpost and as gross as it may sound, the chance that you get diarrhea from the baking soda is probably 1000x higher than the remote possibility of increases in blood pressure. A 1990 study by Luft et al. even found that the blood pressure of 10 mildly hypertensive and normal subjects decreased by 5mmHg after 7 days in the course of which they drank 3 liters of sodium bicarbonate containing water per day (Luft. 1990)

If you add to that all the previously reported benefits you can derive from a few tablespoons of baking soda

• +34% time to exhaustion and +91% total work during HIIT (Feb 29, 2012)
• synergistic and superior effects compared to beta alanine (Feb 20, 2012)
• protection against stress induced oxidative damage to white blood cells (Nov 28, 2011)
• increased performance in tennis players (Nov 4, 2010)

and obviously Barber's own previously reported results, you may understand why I urged our common friend Adelfo Cerame Jr to supplement with bicarbonate throughout his whole contest prep.

Latent metabolic acidosis hampers weight loss and muscle gains

Figure 3: The contribution of latent acidoses to the obesity epidemic and maybe even your inability to build muscle and/or lose weight
(based on Berkemeyer. 2009)

And even when you are not interested in your performance, a 2009 paper by Shoma Berkemeyer is by no means the only, nor the first article that linking an increased hydrogen ion concentrations (latent acidity, which can be countered by dietary bicarbonate) to weight gain and the obesity epidemic (Berkemeyer. 2009, cf. my summary in figure 3).

In view of the fact that even a latent H+ surplus could apparently compromise your efforts to lose fat and build muscle, it should be obvious that you better make sure to have enough alkalizing greens (and optional supplemental bicarbonate; not necessarily 30g, though ;-) in your diet - no matter if the whole acid/base balance issue, esp. the role of a high protein intake, is still very controversial.

More scientific evidence for the combination of bicarbonate & creatine in a more recent article | read it!

Practically speaking, what do I do? Since loading is not necessary unless you have a competition right ahead and this is the first time you take creatine you just take 3-5g of creatine monohydrate with approximately the same amount of sodium bicarbonate per day.

Larger doses of sodium bicarbonate as they would be used for acute performance enhancing effects are (almost certainly) not necessary to increase the efficacy of creatine. If you want the acute benefits, but get diarrhea from 15-20g of bicarbonate, I suggest you try to serial load.