CoChat
Sign Up
Cited by 30Muscle metabolism and nutritionDrug Solubulity and Delivery SystemsAnalytical Methods in Pharmaceuticals

Absolute Oral Bioavailability of Creatine Monohydrate in Rats: Debunking a Myth

Open access
Alraddadi, Eman, Lillico, Ryan, Vennerstrom, Jonathan, Lakowski, Ted, Miller, Donald·2018·Pharmaceutics
DOI 10.3390/pharmaceutics10010031PMC PMC5874844
Open this paper in CoChat — free accountOpen PDF

Abstract

Creatine is an ergogenic compound used by athletes to enhance performance. Supplementation with creatine monohydrate (CM) has been suggested for musculoskeletal and neurological disorders. Until now, little is known about its pharmacokinetic profile. Our objective was to determine the oral bioavailability of CM and the influence of dose on oral absorption. Rats were dosed orally with low dose (10 mg/kg) or high dose (70 mg/kg) 13C-labeled CM. Blood samples were removed at various time points. Muscle and brain tissue were collected at the conclusion of the study. Plasma and tissue levels of 13C-labeled creatine were determined using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Physiologically based pharmacokinetic (PBPK) models of CM were built using GastroPlus™. These models were used to predict the plasma concentration–time profiles of creatine hydrochloride (CHCL), which has improved aqueous solubility compared to CM. Absolute oral bioavailability for low dose CM was 53% while high dose CM was only 16%. The simulated Cmax of 70 mg/kg CHCL was around 35 μg/mL compared to 14 μg/mL for CM with a predicted oral bioavailability of 66% with CHCL compared to 17% with CM. Our results suggest that the oral bioavailability of CM is less than complete and subject to dose and that further examination of improved dosage formulations of creatine is warranted.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.3390/pharmaceutics10010031

Cites

4 of 4 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • The Alraddadi et al. study is only a theoretical modeling study and did not directly compare Cr-HCl to CrM intake on plasma or tissue creatine content.

    “First, this is only a theoretical modeling study. The researchers did not directly compare Cr-HCl to CrM intake on plasma or tissue creatine content.”

    From Bioavailability, Efficacy, Safety, and Regulatory Status of Creatine and Related Compounds: A Critical Review (2022) · cites this paper as [199]

    The Methods (§2.2) describe an experimental rat study that administered creatine monohydrate and measured plasma and tissue samples, so the paper was not only a theoretical modeling study. The Results (§3.4) show that the creatine hydrochloride versus monohydrate comparison was simulated rather than directly tested, supporting the second sentence. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 42

  1. [2]Persky A.M. Brazeau G.A. Clinical pharmacology of the dietary supplement creatine monohydrate Pharmacol. Rev. 2001 53 161 176 11356982
  2. [3]Wallimann T. Wyss M. Brdiczka D. Nicolay K. Eppenberger H.M. Intracellular compartmentation, structure and function of creatine kinase isoenzymes in tissues with high and fluctuating energy demands: The ‘phosphocreatine circuit’ for cellular energy homeostasis Biochem. J. 1992 281 21 40 10.1042/bj2810021 1731757 PMC1130636 · DOI · Paper page
  3. [4]Williams M.H. Branch J.D. Creatine supplementation and exercise performance: An update J. Am. Coll. Nutr. 1998 17 216 234 10.1080/07315724.1998.10718751 9627907 · DOI
  4. [5]Beal M.F. Neuroprotective effects of creatine Amino Acids 2011 40 1305 1313 10.1007/s00726-011-0851-0 21448659 · DOI
  5. [6]Rosas H.D. Doros G. Gevorkian S. Malarick K. Reuter M. Coutu J.P. Triggs T.D. Wilkens P.J. Matson W. Salat D.H. PRECREST: A phase II prevention and biomarker trial of creatine in at-risk Huntington disease Neurology 2014 82 850 857 10.1212/WNL.0000000000000187 24510496 PMC3959748 · DOI
  6. [8]Vis J.C. de Boer-van Huizen R.T. Verbeek M.M. de Waal R.M.W. ten Donkelaar H.J. Kremer B. Creatine protects against 3-nitropropionic acid-induced cell death in murine corticostriatal slice cultures Brain Res. 2004 1024 16 24 10.1016/j.brainres.2004.06.087 15451363 · DOI
  7. [9]Matthews R.T. Yang L.C. Jenkins B.G. Ferrante R.J. Rosen B.R. Kaddurah-Daouk R. Beal M.F. Neuroprotective effects of creatine and cyclocreatine in animal models of Huntington’s disease J. Neurosci. 1998 18 156 163 9412496 PMC6793381
  8. [10]Matthews R.T. Ferrante R.J. Klivenyi P. Yang L.C. Klein A.M. Mueller G. Kaddurah-Daouk R. Kaddurah-Daouk M.F. Creatine and cyclocreatine attenuate MPTP neurotoxicity Exp. Neurol. 1999 157 142 149 10.1006/exnr.1999.7049 10222117 · DOI
  9. [11]Juhn M.S. Tarnopolsky M. Oral creatine supplementation and athletic performance: A critical review Clin. J. Sport Med. 1998 8 286 297 10.1097/00042752-199810000-00006 9884793 · DOI
  10. [12]Balsom P.D. Soderlund K. Sjodin B. Ekblom B. Skeletal muscle metabolism during short duration high-intensity exercise: Influence of creatine supplementation Acta Physiol. Scand. 1995 154 303 310 10.1111/j.1748-1716.1995.tb09914.x 7572228 · DOI
  11. [13]Greenhaff P.L. Bodin K. Soderlund K. Hultman E. Effect of oral creatine supplementation on skeletal muscle phosphocreatine resynthesis Am. J. Physiol. 1994 266 E725 E730 10.1152/ajpendo.1994.266.5.E725 8203511 · DOI · Paper page
  12. [14]Gufford B.T. Sriraghavan K. Miller N.J. Miller D.W. Gu X.C. Vennerstrom J.L. Robinson D.H. Physicochemical characterization of creatine N-methylguanidinium salts J. Diet. Suppl. 2010 7 240 252 10.3109/19390211.2010.491507 22432515 · DOI · Paper page
  13. [15]Deldicque L. Décombaz J. Foncea H.Z. Vuichoud J. Poortmans J.R. Francaux M. Kinetics of creatine ingested as a food ingredient Eur. J. Appl. Physiol. 2008 102 133 143 10.1007/s00421-007-0558-9 17851680 · DOI · Paper page
  14. [16]Dash A.K. Miller D.W. Han H.Y. Carnazzo J. Stout J.R. Evaluation of creatine transport using Caco-2 monolayers as an in vitro model for intestinal absorption J. Pharm. Sci. 2001 90 1593 1598 10.1002/jps.1109 11745717 · DOI
  15. [17]Gufford B.T. Ezell E.L. Robinson D.H. Miller D.W. Miller N.J. Gu X.C. Vennerstrom J.L. pH-dependent stability of creatine ethyl ester: Relevance to oral absorption J. Diet. Suppl. 2013 10 241 251 10.3109/19390211.2013.822453 23957855 PMC4469200 · DOI · Paper page
  16. [18]Boenzi S. Rizzo C. Ciommo V.M.D. Martinelli D. Goffredo B.M. Marca G.I. Dionisi-Vici C. Simultaneous determination of creatine and guanidinoacetate in plasma by liquid chromatography-tandem mass spectrometry (LC-MS/MS) J. Pharm. Biomed. Anal. 2011 56 792 798 10.1016/j.jpba.2011.06.006 21742455 · DOI
  17. [19]Carling R.S. Hogg S.L. Wood T.C. Calvin J. Simultaneous determination of guanidinoacetate, creatine and creatinine in urine and plasma by un-derivatized liquid chromatography-tandem mass spectrometry Ann. Clin. Biochem. 2008 45 575 584 10.1258/acb.2008.008029 18782816 · DOI
  18. [21]Miller D.W. Augustine S. Robinson D.H. Vennerstrom J.L. Wagner J.C. Oral Bioavailability of Creatine Supplements: Insights into Mechanism and Implications for Improved Absorption Nutrition and Enhanced Sports Performance: Muscle Biulding, Endurance, and Strength 1st ed. Academic Press Cambridge, MA, USA 2013
  19. [22]McCall W. Persky A.M. Pharmacokinetics of creatine Subcell. Biochem. 2007 46 261 273 18652081
  20. [24]Davies N.M. Takemoto J.K. Brocks D.R. Yáñez J.A. Multiple peaking phenomena in pharmacokinetic disposition Clin. Pharmacokinet. 2010 49 351 377 10.2165/11319320-000000000-00000 20481648 · DOI
  21. [25]Deminice R. Jordao A.A. Creatine supplementation reduces oxidative stress biomarkers after acute exercise in rats Amino Acids 2012 43 709 715 10.1007/s00726-011-1121-x 22009139 · DOI
  22. [26]Harris R.C. Nevill M. Harris D.B. Fallowfield J.L. Bogdanis G.C. Wise J.A. Absorption of creatine supplied as a drink, in meat or in solid form J. Sports Sci. 2002 20 147 151 10.1080/026404102317200855 11811571 · DOI · Paper page
  23. [27]Schedel J.M. Tanaka H. Kiyonaga A. Shindo M. Schutz Y. Acute creatine ingestion in human: Consequences on serum creatine and creatinine concentrations Life Sci. 1999 65 2463 2470 10.1016/S0024-3205(99)00512-3 10622230 · DOI · Paper page
  24. [28]Sale C. Harris R.C. Florance J. Kumps A. Sanvura R. Poortmans J.R. Urinary creatine and methylamine excretion following 4 × 5 g day−1 or 20 × 1 g day−1 of creatine monohydrate for 5 days J. Sports Sci. 2009 27 759 766 10.1080/02640410902838237 19437189 · DOI
  25. [29]Atassi N. Ratai E.M. Greenblatt D.J. Pulley D. Zhao Y.L. Bombardier J. Wallace S. Eckenrode J. Cudkowicz M. Dibernardo A. A phase I, pharmacokinetic, dosage escalation study of creatine monohydrate in subjects with amyotrophic lateral sclerosis Amyotroph. Lateral Scler. 2010 11 508 513 10.3109/17482961003797130 20698808 PMC3045755 · DOI
  26. [30]Snow R.J. Murphy R.M. Creatine and the creatine transporter: A review Mol. Cell. Biochem. 2001 224 169 181 10.1023/A:1011908606819 11693194 · DOI
  27. [31]Braissant O. Creatine and guanidinoacetate transport at blood-brain and blood-cerebrospinal fluid barriers J. Inherit. Metab. Dis. 2012 35 655 664 10.1007/s10545-011-9433-2 22252611 · DOI · Paper page
  28. [32]Nash S.R. Giros B. Kingsmore S.F. Rochelle J.M. Suter S.T. Gregor P. Seldin M.F. Caron M.G. Cloning, pharmacological characterization, and genomic localization of the human creatine transporter Recept. Channels 1994 2 165 174 7953292
  29. [33]Sora I. Richman J. Santoro G. Wei H.B. Wang Y. Vanderah T. Horvath R. Nguyen M. Waite S. Roeske W.R. The cloning and expression of a human creatine transporter Biochem. Biophys. Res. Commun. 1994 204 419 427 10.1006/bbrc.1994.2475 7945388 · DOI
  30. [34]Salomons G.S. van Dooren S.J.M. Verhoeven N.M. Cecil K.M. Ball W.S. Degrauw T.J. Jakobs C. X-linked creatine-transporter gene (SLC6A8) defect: A new creatine-deficiency syndrome Am. J. Hum. Genet. 2001 68 1497 1500 10.1086/320595 11326334 PMC1226136 · DOI
  31. [35]Tachikawa M. Tachikawa M. Fukaya M. Terasaki T. Ohtsuki S. Watanabe M. Distinct cellular expressions of creatine synthetic enzyme GAMT and creatine kinases uCK-Mi and CK-B suggest a novel neuron-glial relationship for brain energy homeostasis Eur. J. Neurosci. 2004 20 144 160 10.1111/j.1460-9568.2004.03478.x 15245487 · DOI
  32. [36]Ohtsuki S. Tachikawa M. Takanaga H. Shimizu H. Watanabe M. Hosoya K. Terasaki T. The blood-brain barrier creatine transporter is a major pathway for supplying creatine to the brain J. Cereb. Blood Flow Metab. 2002 22 1327 1335 10.1097/01.WCB.0000033966.83623.7D 12439290 · DOI
  33. [37]Salomons G.S. Wyss M. Creatine and Creatine Kinase in Health and Disease: From Cell Deconstruction to System Reconstruction Subcellular Biochemistry Springer Berlin, Germany 2007 Volume 46 99 113
  34. [38]Jager R. Harris R.C. Purpura M. Francaux M. Comparison of new forms of creatine in raising plasma creatine levels J. Int. Soc. Sports Nutr. 2007 4 17 10.1186/1550-2783-4-17 17997838 PMC2206055 · DOI · Paper page
  35. [39]Allan G. Davis J. Dickins M. Garder I. Jenkins T. Jones H. Webster R. Westgate H. Pre-clinical pharmacokinetics of UK-453,061, a novel non-nucleoside reverse transcriptase inhibitor (NNRTI), and use of in silico physiologically based prediction tools to predict the oral pharmacokinetics of UK-453,061 in man Xenobiotica 2008 38 620 640 10.1080/00498250802069088 18570162 · DOI
  36. [40]Bungay P.J. Tweedy S. Howe D.C. Gibson K.R. Jones H.M. Mount N.M. Preclinical and clinical pharmacokinetics of PF-02413873, a nonsteroidal progesterone receptor antagonist Drug Metab. Dispos. 2011 39 1396 1405 10.1124/dmd.110.037234 21543556 · DOI
  37. [41]De Buck S.S. Sinha V.K. Fenu L.A. Nijsen M.J. Mackie C.E. Gilissen R.A.H.J. Prediction of human pharmacokinetics using physiologically based modeling: A retrospective analysis of 26 clinically tested drugs Drug Metab. Dispos. 2007 35 1766 1780 10.1124/dmd.107.015644 17620347 · DOI · Paper page
  38. [43]Jones H.M. Dickins M. Youdim K. Gosset J.R. Attkins N. Hay T.L. Gurrell I.K. Logan Y.R. Bungay P.J. Jones B.C. Application of PBPK modelling in drug discovery and development at Pfizer Xenobiotica 2012 42 94 106 10.3109/00498254.2011.627477 22035569 · DOI
  39. [44]Sinha V.K. Snoeys J. Osselaer N.V. Peer A.V. Mackie C. Heald D. From preclinical to human—Prediction of oral absorption and drug-drug interaction potential using physiologically based pharmacokinetic (PBPK) modeling approach in an industrial setting: A workflow by using case example Biopharm. Drug Dispos. 2012 33 111 121 10.1002/bdd.1782 22383166 · DOI
  40. [45]Xia B. Heimbach T. He H. Lin T.H. Nilotinib preclinical pharmacokinetics and practical application toward clinical projections of oral absorption and systemic availability Biopharm. Drug Dispos. 2012 33 536 549 10.1002/bdd.1821 23097199 · DOI
  41. [46]Yamazaki S. Skaptason J. Romero D. Vekich S. Jones H.M. Tan W.W. Wilner K.D. Koudriakova T. Prediction of oral pharmacokinetics of cMet kinase inhibitors in humans: Physiologically based pharmacokinetic model versus traditional one-compartment model Drug Metab. Dispos. 2011 39 383 393 10.1124/dmd.110.035857 21098644 · DOI
  42. [47]Tuckfield C. First use of creatine hydrochloride in premanifest Huntington disease Med. J. Aust. 2015 202 378 380 10.5694/mja14.01070 25877121 · DOI

Cited by

Sorted by citations

Authors
Alraddadi, E., Lillico, R., Vennerstrom, J., Lakowski, T., & Miller, D.
Affiliations
  • University of Manitoba (CA)
  • University of Nebraska Medical Center (US)
Corresponding author
Miller, Donald
ORCID
Venue
Pharmaceutics
Publisher
MDPI AG
Published
2018-03-08
Volume
10
Issue
1
Pages
31
ISSN
1999-4923 (ISSN-L)
DOI
10.3390/pharmaceutics10010031
PMC
PMC5874844
OpenAlex
W2792694658
Cited by
30
References
4
Citations by year
2026: 6 · 2025: 4 · 2024: 5 · 2023: 4 · 2022: 7 · 2021: 2 · 2019: 1 · 2018: 1
FWCI
0.55
Type
journal article
Language
en
Open access
Licence
Locations
  • Pharmaceutics (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DigitalCommons@UNMC (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • University of Nebraska Medical Center
  • King Saud bin Abdulaziz University for Health Science
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Muscle metabolism and nutrition
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Drug Solubulity and Delivery Systems
  • Physical Sciences › Chemistry › Analytical Chemistry › Analytical Methods in Pharmaceuticals
Keywords
creatine monohydrate, absolute oral bioavailability, dose-dependent absorption, physiologically based pharmacokinetic modeling, GastroPlus, plasma concentration-time curve, creatine supplementation, ergogenic aids

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review