Sunday, August 28, 2011

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.

27 comments:

  1. Nice and useful article as always.Thanks for the effort,and i guess it could be more complete if you could present some data on creatine absorption in relation with caffeine.

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  2. wtf....we gotta take creatine on an empty stomach? I thought that was the dark ages?....

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  3. if you also read part II than you will

    a) get the information on caffeine
    b) realize that taking it on empty stomach is advantageous when it comes to increasing blood levels, but taking it with food could be beneficial in terms of increasing muscle retention

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    Replies
    1. Yep... well done. Done and Done...

      Take the info of an empty stomach on an empty mind and cease the mental resistance.

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  4. Thank you for the best critical analysis of creatine products that I have read, and the only critical analysis of kre-alkalyn. I confess that I bought into the hype!
    - Rick

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  5. In the Cannon study Fig. 1 shows time in solution in hours not in minutes.
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1252207/?page=6

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    1. damn you are right. thanks for the headsup

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    2. My pleasure!
      Ridiculous how much time you are investing in this very interesting but surely time robbing blog besides your regular work.

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    3. true, sometimes I wonder why I am doing all that, but then there are those days when someone says he did X or Y and that really worked for him that make it all worthwhile

      Delete
  6. hello, like the articles and the site, though I would have to admit Im not the smartest of guys when it comes to all the science bits (you should have a 'for dummies' paragraph at the bottom of the articles somewhere) So would a post workout drink of 25g whey protein, 3g creatine, 3g bicarbonate of soda and 20g of oats be o.k to stop the creatine becoming creatinine?
    musa123

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  7. hello, find these articles really interesting but like the guy above, im not the smartest of people when it comes to the science, was just wondering if my postworkout shake would be effective, i have 30g whey protein with 5g creatine 45g dextrose and 4g bicarbonate of soda, could you tell me if theirs something im not doing right with my post workout shake please

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    Replies
    1. you need to take the bicarbonate pre workout like 45min at least (better 1h) if you want an immediate benefit. And personally I like to split the creatine up - so just down 2.5g of it with the NaHCO3 preworkout

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  8. thanks, id been taking it pre work out also but just 5g creatine, 45g dextrose, 4g NaHCO3 about 45 - 60 min before work out, will cut the dose of creatine to 2.5g but is the dextrose a benefit or is not really helping with the absorption ?, would prefer not to use the dextrose because when it comes to cutting time i'd rather get my carbs from a more nutritous source, just want to make sure im getting the maximum effects possible from my supplementation. thanks again for your response

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  9. I'm confused. Which do I want, to take it on empty stomach or with protein + carbs?

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  10. Will the enhanced absorption, from taking it on an empty stomach, not mean greater retention, as more is available to retain????

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    Replies
    1. the problem is the breakdown due to stomach acid. Take is with some sodium bicarbonate, that's like "kre alklyn" if you want to maximize absorption. In the end, it will work this way or aonther

      Delete
  11. Which works greater for a gym goer supplementing with creatine.

    Ss I said, will the enhanced absorption, from taking it on an empty stomach, not mean greater retention anyway?

    Thanks

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    Replies
    1. Absorption and retention are two separate things. Just because you absorb a lot of something does not mean you will retain it. Consuming a large bolus of whey protein is a perfect example. You will absorb all the protein, but most will just be oxidized and wasted.

      Also I fail to see how Adel's response failed to answer your question. He states "in the end, it will work this way or another" implying that you will retain the needed creatine so don't worry about it.

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    2. This comment has been removed by the author.

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  12. Thanks primalkid. I'm still confused though.

    Dr Andro say's above "taking it on empty stomach is advantageous when it comes to increasing blood levels, but taking it with food could be beneficial in terms of increasing muscle retention"

    What is the advantage of increasing blood levels?

    Will It matter, in terms of retention/saturation, if I take 3g a day with a meal or on an empty stomach?

    Will one of these two options increase urine output? (I have nocturia)

    Finally, I've read that creatine on an empty stomach causes GI distress (I have GERD)

    Please correct me where I've gone wrong

    Thanks

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    Replies
    1. The typical creatine amount of 3-5g is so small that how you take it is borderline irrelevant. Your body will retain 99% if not all of it. Perhaps if you were loading for a week with 20g doses it might make a difference, but I doubt it would do much.

      Furthermore, assuming you have been taking creatine daily for a while now, your muscles and organs are going to be saturated with it. Which means at this point taking creatine is more about maintaining saturation and preventing a return to baseline levels. Thus your naturally going to have more be excreted then if you were just beginning to use creatine. This is expected though and you need not worry.

      With regard to GERD and GI distress, I have not met anyone who has issues with creatine. However this type of thing is very individualistic so generalizing claims becomes pointless. If you don't have symptoms with creatine then don't worry about what it *might* do in someone else.

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  13. Also, isn't 97 grams of carbohydrates high GI, and not very good for overall health

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    Replies
    1. No. Carbohydrates are not intrinsically bad. You need to take everything in context.

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    2. well said on both this and your previous post pertaining the absoprtion issues with small doses. The latter is by the way another good reason not to waste a single cent on any of the "advanced creatine formulas" - they WONT MAKE A DIFFERENCE

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    3. By your name, I thought you were Kiefer from Dangerously Hardcore. After that comment, I don't think so....

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    4. John Kiefer (from DH) doesn't read blogs and doesn't comment on anything that isn't an article of his own.

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