Abstract
There are a number of forms of creatine available that attempt to improve the solubility
and permeability, with the anticipation this will result in an improved pharmacokinetic
profile and ultimately an enhanced ergogenic response. Previous research has shown
that the different salt forms can improve solubility resulting in slightly altered
pharmacokinetic profiles, however specific data exploring the conversion of esterified
derivatives to creatine is lacking. The purpose of this study was to examine the assertion
that creatine ethyl ester undergoes enzymatic conversion to creatine in human tissues.
The in vitro response of creatine ethyl ester to incubation in human plasma was examined by H-NMR
analysis. Lyophilized human plasma was reconstituted in D2O and phosphate-buffered saline and 1.5 mg of the analyte was added. Following incubation
at 37°C for 4 h and subsequent protein precipitation, the supernatant was analyzed
by NMR, utilizing the diagnostic chemical shift of the methylene signal to determine
the species present in solution, i.e. creatine ethyl ester, creatine, or creatinine. Both creatine and creatinine were
run in parallel as control experiments and each assay was run in triplicate. As expected
both creatine and creatinine remained unchanged. However, conversion of creatine ethyl
ester to creatine by the esterases in human plasma was not observed to any detectable
extent and the only species detected after the incubation period was creatinine. While
not a definitive characterization of the in vivo behavior, these results strongly warrant a complete in vivo pharmacokinetic analysis of creatine ethyl ester since it appears these “pronutrients”
may actually provide large exogenous sources of pharmacologically inactive creatinine
rather than ergogenic creatine.
Key words
creatine - creatine ethyl ester -
in vitro
References
- 1
Bamberger M.
The Magic Potion.
Sports Illustrated.
1998;
88
58-61
- 2
Bird SP.
Creatine supplementation and exercise performance: A brief review.
J Sports Sci Med.
2003;
2
123-132
- 3
Buford TW, Krider RB, Stout JR, Greenwood M, Campbell B, Spano M, Ziegenfuss T, Lopez H,
Landis J, Antonio J.
International Society of Sports Nutrition position stand: creatine supplementation
and exercise.
J Int Soc Sports Nutr.
2007;
4-6
- 4
Calfee R, Fadale P.
Popular ergogenic drugs and supplements in young athletes.
Pediatrics.
2006;
117
577-589
- 5
Chantuin A.
The fate of creatine when administered to man.
J Biochem.
1926;
67
29-41
- 6
Dash AK, Miller DW, Huai-Yan H, Carnazzo J, Stout JR.
Evaluation of creatine transport using Caco-2 monolayers as an in vitro model for
intenstinal absorption.
J Pharm Sci.
2001;
90
1593-1598
- 7
Dash AK, Sawhney A.
A simple LC method with UV detection for the analysis of creatine and creatinine and
its application to several creatine formulations.
, J Pharm Biomed Anal
2002;
29
939-945
- 8
Deldicque L, Décombaz J, Foncea HZ, Vuichoud J, Poortmans JR, Francaux M.
Kinetcs of creatine ingested as a food ingredient.
Eur J Appl Physiol.
2008;
102
133-143
- 9
Department of Health and Human Services
.
http://www.fda.gov/ohrms/dockets/dockets/95s0316/95s-0316-rpt0249-01-vol181.pdf
- 10
Jäger R, Haris RC, Purpura M, Francaux M.
Comparison of new forms of creatine in raising plasma creatine levels.
J Int Soc Sports Nutr.
2007;
4
17
- 11
Ko SY, Lerpiniere J, Christofi AM.
An efficient syntheis of internal guanidines.
Synlett.
1995;
815-816
- 12
Lawrence LJ.
Labeled Creatine Ethyl Ester Hydrochloride..
, US 2006/0067880
- 13
Metz JD, Small E, Levine SR, Gershel JC.
Creatine use among young athletes.
Pediatrics.
2001;
108
421-425
- 14
Osterkamp F, Ziemer B, Koert U, Wiesner M, Raddatz P, Goodman SL.
Synthesis and biological evaluation of integrin antagonists containing trans- and
cis-2,5- disubstituted THF rings.
Chem Eur J.
2000;
6
666-683
- 15
Persky AM, Brazeau GA, Hochhaus G.
Pharmacokinetics of the dietary supplement creatine.
Clin Pharmacokinet.
2003;
42
557-574
- 16
Persky AM, Brazeau GA.
Clinical pharmacology of the dietary supplement creatine monohydrate.
Pharmacol Rev.
2001;
53
161-176
- 17
Persky AM, Müller M, Derendorf H, Grant M, Brazeau GA, Hochhaus G.
Single- and multiple- dose pharmacokinetics of oral creatine.
J Clin Pharmacol.
2003;
43
29-37
- 18
Poortmans JR, Auquier H, Renaut V, Durussel A, Saugy M, Brisson GR.
Effect of short-term creatine supplementation on renal responses in men.
Eur J Appl Physiol.
1997;
76
566-567
- 19
Schedel JM, Tanaka H, Kiyonaga A, Shindo M, Schutz Y.
Acute creatine ingestion in human: Consequences on serum creatine and creatinine concentrations.
Life Sciences.
1999;
65
2463-2470
- 20
Suhs T, König B.
Synthesis of functionalized guanidino amino acids.
Chem Eur J.
2006;
12
8150-8157
- 21
Terjung RL, Clarkson P, Eichner R, Greenhaff PL, Hespel PJ, Israel RJ, Kraemer WJ,
Meyer RA, Spiet LL, Tarnopolsky MA, Wagenmakers AJM, Williams MH.
The physiological and health effects of oral creatine supplementation.
Med Sci Sports Exerc.
2000;
32
706-717
- 22
Vennerstrom JL, Miller DW.
Creatine Ester Pronutrient Compounds and Formulations.
, US 2003/0212136
Correspondence
M. W. Giese
Marian College
Chemistry, 3200 Cold Spring Rd
46222 Indianapolis
United States
Phone: 317-293-6803
Fax: 317-955-6448
Email: matthew.giese@comcast.net
