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Title: Creatine  
Author: World Heritage Encyclopedia
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Subject: WikiProject Pharmacology/Cleanup listing, Creatine kinase, Sarcosine, Dietary supplement, Creatine supplements
Collection: Amino Acids, Bodybuilding Supplements, Dietary Supplements, Guanidines
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Skeletal formula of creatine
Ball and stick model of creatine
Systematic IUPAC name
2-[Carbamimidoyl(methyl)amino]acetic acid
Other names
N-Carbamimidoyl-N-methylglycine; Methylguanidoacetic acid
ATC code C01
ChemSpider  Y
DrugBank  Y
EC number 200-306-6
Jmol-3D images Image
RTECS number MB7706000
Molar mass 131.14 g·mol−1
Appearance White crystals
Odor Odourless
Melting point 255 °C (491 °F; 528 K)
13.3 g L−1 (at 18 °C)
log P −1.258
Acidity (pKa) 3.429
Basicity (pKb) 10.568
Isoelectric point 8.47
171.1 J K−1 mol−1 (at 23.2 °C)
189.5 J K−1 mol−1
−538.06–−536.30 kJ mol−1
−2.3239–−2.3223 MJ mol−1
3 hours
GHS pictograms The exclamation-mark pictogram in the Globally Harmonized System of Classification and Labelling of Chemicals (GHS)
GHS signal word WARNING
H315, H319, H335
P261, P305+351+338
Irritant Xi
R-phrases R36/37/38
S-phrases S26, S36
Related compounds
Related alkanoic acids
Related compounds
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
 N  (: Y/N?)

Creatine ( or [1][2]) is a vertebrates and helps to supply energy to all cells in the body, primarily muscle. This is achieved by increasing the formation of adenosine triphosphate (ATP). Creatine was identified in 1832 when Michel Eugène Chevreul isolated it from the basified water-extract of skeletal muscle. He later named the crystallized precipitate after the Greek word for meat, κρέας (kreas). Early analysis showed that human blood is approximately 1% creatine, and the highest concentrations are found in animal blood, brain (0.14%), muscle (0.50%), and testes (0.18%). The liver and kidney contain approximately 0.01% creatine. Today, creatine content (as a percentage of crude protein) can be used as an indicator of meat quality.[3]

In solution, creatine is in equilibrium with creatinine.[4]

Creatine is a derivative of the guanidinium cation.


  • Biosynthesis 1
  • The phosphocreatine system 2
  • Health effects 3
    • Supplements 3.1
    • Pharmacokinetics 3.2
    • Pregnancy and breastfeeding 3.3
    • Muscle disorders 3.4
    • Cancer 3.5
      • Testicular Cancer 3.5.1
  • See also 4
  • References 5
  • External links 6


Creatine is not an essential nutrient[5] as it is naturally produced in the human body from the amino acids glycine and arginine. In the first step of the biosynthesis these two amino acids are combined by the enzyme arginine:glycine amidinotransferase (AGAT, EC: to form guanidinoacetate, this is then methylated by guanidinoacetate N-methyltransferase (GAMT,EC:, using S-adenosyl methionine as the methyl donor. Creatine itself can be phosphorylated by creatine kinase to form phosphocreatine, which is used as an energy reserve in skeletal muscles and the brain.

Synthesis primarily takes place in the kidney and liver, with creatine then being transported to the muscles via the blood. Approximately 95% of the human body's total creatine is located in skeletal muscle.[6] In humans and animals, approximately half of stored creatine originates from food (about 1 g/day, mainly from meat).[5] A study involving 18 vegetarians and 24 non-vegetarians on the effect of creatine in vegetarians showed that total creatine was significantly lower than in non-vegetarians. Since vegetables are not the primary source of creatine, vegetarians can be expected to show lower levels of directly derived muscle creatine. However, the subjects happened to show the same levels after using supplements.[7] Given the fact that creatine can be synthesized from the above-mentioned amino acids, protein sources rich in these amino acids can be expected to provide adequate capability of native biosynthesis in the human body.[5]

Genetic deficiencies in the creatine biosynthetic pathway lead to various severe neurological defects.[8] Clinically, there are three distinct disorders of creatine metabolism. Deficiencies of the two synthetic enzymes can cause L-arginine:glycine amidinotransferase deficiency and guanidinoacetate methyltransferase deficiency. Both biosynthetic defects are inherited in an autosomal recessive manner. A third defect, creatine transporter defect is caused by mutations in SLC6A8 and inherited in a X-linked manner. This condition is related to the transport of creatine into the brain.[9]

The phosphocreatine system

Creatine, synthesized in the liver and kidney, is transported through the blood and taken up by tissues with high energy demands, such as the brain and skeletal muscle, through an active transport system. The concentration of ATP in skeletal muscle is usually 2-5 mM, which would result in a muscle contraction of only a few seconds.[10] Fortunately, during times of increased energy demands, the phosphagen (or ATP/PCr) system rapidly resynthesizes ATP from ADP with the use of phosphocreatine (PCr) through a reversible reaction with the enzyme creatine kinase (CK). In skeletal muscle, PCr concentrations may reach 20-35 mM or more. Additionally, in most muscles, the ATP regeneration capacity of CK is very high and is therefore not a limiting factor. Although the cellular concentrations of ATP are small, changes are difficult to detect because ATP is continuously and efficiently replenished from the large pools of PCr and CK.[10] Creatine has the ability to increase muscle stores of PCr, potentially increasing the muscle’s ability to resynthesize ATP from ADP to meet increased energy demands.[11] For a review of the creatine kinase system and the pleiotropic actions of creatine and creatine supplementation see.[12][13]

The pathway for the synthesis of creatine
Arg - Arginine; GATM - Glycine amidinotransferase; GAMT - Guanidinoacetate N-methyltransferase; Gly - Glycine; Met - Methionine; SAH - S-adenosyl homocysteine; SAM - S-adenosyl methionine.
The color scheme is as follows:enzymes, coenzymes and the Met part, substrate names, the Gly part, the Arg part

Health effects


Creatine supplements are used by athletes, bodybuilders, wrestlers, sprinters, and others who wish to gain muscle mass. The Mayo Clinic states that creatine has been associated with asthmatic symptoms and warns against consumption by persons with known allergies to creatine.[14]

A 2009 systematic review discredited concerns that creatine supplementation could affect hydration status and heat tolerance and lead to muscle cramping and diarrhea.[15][16]

There are reports of kidney damage with creatine use, such as interstitial nephritis; patients with kidney disease should avoid use of this supplement.[14] In similar manner, liver function may be altered, and caution is advised in those with underlying liver disease, although studies have shown little or no adverse impact on kidney or liver function from oral creatine supplementation.[17] In 2004 the European Food Safety Authority (EFSA) published a record which stated that oral long-term intake of 3g pure creatine per day is risk-free.[18] A 2003 study on athletes who took creatine for 21 months, found no significant changes in markers of renal function;[19] a 2008 study on athletes who took creatine for 3 months, found no evidence of kidney damage during that time.[20]

Long-term administration of large quantities of creatine is reported to increase the production of formaldehyde, which has the potential to cause serious unwanted side effects. However, this risk is largely theoretical because urinary excretion of formaldehyde, even under heavy creatine supplementation, does not exceed normal limits.[21][22]

Extensive research has shown that oral creatine supplementation at a rate of five to 20 grams per day appears to be very safe and largely devoid of adverse side-effects,[23] while at the same time effectively improving the physiological response to resistance exercise, increasing the maximal force production of muscles in both men and women.[24][25]

Many meta analyses found that creatine treatment resulted in no abnormal renal, hepatic, cardiac, or muscle function.[26][27]

While some research indicates that supplementation with pure creatine is safe, a survey of 33 commercially available in Italy supplements found that over 50% of them exceeded the European Food Safety Authority recommendations in at least one contaminant. The most prevalent of these contaminants was creatinine, a breakdown product of creatine also produced by the body.[28] Creatinine was present in higher concentrations than the European Food Safety Authority recommendations in 44% of the samples. About 15% of the samples had detectable levels of dihydro-1,3,5-triazine or a high dicyandiamide concentration. Heavy metals contamination was not found to be a concern, with only minor levels of mercury being detectable. Both two studies reviewd in 2007 found no impurities.[26]


Endogenous serum or plasma creatine concentrations in healthy adults are normally in a range of 2–12 mg/L. A single 5 g (5000 mg) oral dose in healthy adults results in a peak plasma creatine level of approximately 120 mg/L at 1–2 hours post-ingestion. Creatine has a fairly short elimination half-life, averaging just less than 3 hours, so to maintain an elevated plasma level it would be necessary to take small oral doses every 3–6 hours throughout the day. After the "loading dose" period (1–2 weeks, 12-24 g a day), it is no longer necessary to maintain a consistently high serum level of creatine. As with most supplements, each person has their own genetic "preset" amount of creatine they can hold. The rest is eliminated as waste. A typical post-loading dose is 2-5 g daily.[29][30][31]

Pregnancy and breastfeeding

There is a lack of scientific information on the effects of creatine supplementation during pregnancy and breastfeeding. As of 2014 it is not clear if taking creatine during pregnancy affects the rate of cerebral palsy or other neurological problems.[32]

Pasteurized cow's milk contains higher levels of creatine than human milk.[33][34]

Muscle disorders

A meta analysis found that creatine treatment increased muscle strength in muscular dystrophies, and potentially improved functional performance.[35] It has also been implicated in decreasing mutagenesis in DNA[36]


When creatine is mixed with protein and sugar at high temperatures (above 148 °C), the resulting reaction produces heterocyclic amines (HCAs). Such a reaction happens when grilling or pan frying meat. HCAs are known to cause cancer in animals and may cause cancer in humans as well.[37] This could be a mechanism why consumption of meat increases risk of colon, breast and prostate cancer.[38] Metaanalysis from 2011 concluded that "search for the excretion of heterocyclic amines remains a future task to definitively exclude the unproved allegation made by some national agencies".[27] Study from 2015 indicated that "diet rather than creatine supplementation was the main responsible factor for HCA".[39]

Testicular Cancer

In March 2015, a study published by the British Journal of Cancer found that men using supplements containing creatine may have a higher risk of getting testicular cancer [40][41]

See also


  1. ^ Entry "creatine" in Merriam-Webster Online Dictionary.
  2. ^ Wells, J. C. (2000). Longman Pronunciation Dictionary. Harlow, England: Pearson Education Ltd.
  3. ^
  4. ^ Cannan, R. K.; Shore, A. (1928). "The creatine-creatinine equilibrium. The apparent dissociation constants of creatine and creatinine" (PDF). Biochem. J. 22 (4): 920–29.  
  5. ^ a b c "Creatine".  
  6. ^ "Creatine". MedLine Plus Supplements.  
  7. ^ Burke DG, Chilibeck PD, Parise G, Candow DG, Mahoney D, Tarnopolsky M; Chilibeck; Parise; Candow; Mahoney; Tarnopolsky (2003). "Effect of creatine and weight training on muscle creatine and performance in vegetarians". Medicine and science in sports and exercise 35 (11): 1946–55.  
  8. ^ "L-Arginine:Glycine Amidinotransferase". Retrieved 2010-08-16. 
  9. ^ Braissant, O; Henry, H; Béard, E; Uldry, J (May 2011). "Creatine deficiency syndromes and the importance of creatine synthesis in the brain.". Amino Acids 40 (5): 1315–24.  
  10. ^ a b Wallimann, T; Wyss, M; Brdiczka, D; Nicolay, K; Eppenberger, HM (January 1992). "Intracellular compartmentation, structure and function of creatine kinase isoenzymes in tissues with high and fluctuating energy demands: the 'phosphocreatine circuit' for cellular energy homeostasis". The Biochemical journal 281 (Pt 1): 21–40.  
  11. ^ Spillane, M; Schoch, R; Cooke, M; Harvey, T; Greenwood, M; Kreider, R; Willoughby, DS (2009). "The effects of creatine ethyl ester supplementation combined with heavy resistance training on body composition, muscle performance, and serum and muscle creatine levels". Journal of the International Society of Sports Nutrition 6 (1): 6.  
  12. ^ "The creatine kinase system and pleiotropic effects of creatine". Amino Acids 40 (5): 1271–96. May 2011.  .
  13. ^ T. Wallimann, M. Tokarska-Schlattner, D. Neumann u. a.: The Phosphocreatine Circuit: Molecular and Cellular Physiology of Creatine Kinases, Sensitivity to Free Radicals, and Enhancement by Creatine Supplementation. In: Molecular System Bioenergetics: Energy for Life. 22. November 2007. doi:10.1002/9783527621095.ch7C
  14. ^ a b "Creatine: Safety". Retrieved 2010-08-16. 
  15. ^ Lopez RM, Casa DJ, McDermott BP, Ganio MS, Armstrong LE, Maresh CM; Casa; McDermott; Ganio; Armstrong; Maresh (2009). "Does Creatine Supplementation Hinder Exercise Heat Tolerance or Hydration Status? A Systematic Review With Meta-Analyses". Journal of Athletic Training 44 (2): 215–23.  
  16. ^ Dalbo VJ, Roberts MD, Stout JR, Kerksick CM; Roberts; Stout; Kerksick (July 2008). "Putting to rest the myth of creatine supplementation leading to muscle cramps and dehydration". British Journal of Sports Medicine 42 (7): 567–73.  
  17. ^ Poortmans JR, Francaux M; Francaux (September 2000). "Adverse effects of creatine supplementation: fact or fiction?". Sports Medicine 30 (3): 155–70.  
  18. ^
  19. ^ Kreider, Richard B.; Melton, Charles; Rasmussen, Christopher J.; Greenwood, Michael; Lancaster, Stacy; Cantler, Edward C.; Milnor, Pervis; Almada, Anthony L. (2003). "Long-term creatine supplementation does not significantly affect clinical markers of health in athletes". Molecular and Cellular Biochemistry 244 (1–2): 95–104.  
  20. ^ Gualano, Bruno; Ugrinowitsch, Carlos; Novaes, Rafael Batista; Artioli, Guilherme Gianini; Shimizu, Maria Heloisa; Seguro, Antonio Carlos; Harris, Roger Charles; Lancha, Antonio Herbert (2008). "Effects of creatine supplementation on renal function: A randomized, double-blind, placebo-controlled clinical trial". European Journal of Applied Physiology 103 (1): 33–40.  
  21. ^ Francaux M, Poortmans JR; Poortmans (December 2006). "Side effects of creatine supplementation in athletes". International Journal of Sports Physiology and Performance 1 (4): 311–23.  
  22. ^ "International Society of Sports Nutrition position stand: creatine supplementation and exercise". jissn. Retrieved 19 January 2012. 
  23. ^ Bizzarini E, De Angelis L; De Angelis (December 2004). "Is the use of oral creatine supplementation safe?". The Journal of Sports Medicine and Physical Fitness 44 (4): 411–6.  
  24. ^ Bemben MG, Lamont HS; Lamont (2005). "Creatine supplementation and exercise performance: recent findings". Sports Medicine 35 (2): 107–25.  
  25. ^ Kreider RB (February 2003). "Effects of creatine supplementation on performance and training adaptations" (PDF). Molecular and Cellular Biochemistry 244 (1–2): 89–94.  
  26. ^ a b Persky, AM; Rawson, ES (2007). "Safety of creatine supplementation.". Sub-cellular biochemistry 46: 275–89.  
  27. ^ a b
  28. ^ Moreta S, Prevarin A, Tubaro F.; Prevarin; Tubaro (June 2011). "Levels of creatine, organic contaminants and heavy metals in creatine dietary supplements". Food Chemistry 126 (3): 1232–1238.  
  29. ^ Kamber M, Koster M, Kreis R, Walker G, Boesch C, Hoppeler H. Creatine supplementation--part I: performance, clinical chemistry, and muscle volume. Med. Sci. Sports Exer. 31: 1763-1769, 1999.
  30. ^ Deldicque, L; Décombaz, J; Zbinden Foncea, H; Vuichoud, J; Poortmans, JR; Francaux, M (2008). "Kinetics of creatine ingested as a food ingredient". Eur. J. Appl. Physiol 102: 133–143.  
  31. ^ R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 8th edition, Biomedical Publications, Foster City, CA, 2008, pp. 366-368.
  32. ^ Dickinson, H; Bain, E; Wilkinson, D; Middleton, P; Crowther, CA; Walker, DW (19 December 2014). "Creatine for women in pregnancy for neuroprotection of the fetus.". The Cochrane database of systematic reviews 12: CD010846.  
  33. ^ Hülsemann J, Manz F, Wember T, Schöch G; Manz; Wember; Schöch (1987). "[Administration of creatine and creatinine with breast milk and infant milk preparations]". Klinische Pädiatrie (in German) 199 (4): 292–5.  
  34. ^ Wallimann, Theo; Tokarska-Schlattner, Malgorzata; Schlattner, Uwe (1 May 2011). "The creatine kinase system and pleiotropic effects of creatine". Amino Acids (Springer Wien) 40 (5): 1271–1296.  
  35. ^ Kley, R. A.; Tarnopolsky, M. A.; Vorgerd, M. (2011). Kley, Rudolf A, ed. "Creatine for treating muscle disorders". The Cochrane Library (2): CD004760.  
  36. ^ Rahimi, R. (2011). "Creatine Supplementation Decreases Oxidative DNA Damage and Lipid Peroxidation Induced by a Single Bout of Resistance Exercise". Journal of Strength and Conditioning Research 25 (12): 3448–3455.  
  37. ^ "Chemicals in Meat Cooked at High Temperatures and Cancer Risk".  
  38. ^ "Meat Consumption and Cancer Risk".  
  39. ^
  40. ^ "Muscle-building supplement use and increased risk of testicular germ cell cancer in men from Connecticut and Massachusetts".  
  41. ^ "Creatine Linked to Testicular Cancer".  

External links

  • Creatine bound to proteins in the PDB
  • International Society of Sports Nutrition position stand: Creatine
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