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Abstract and Figures

Creatine is a nonessential dietary component that, when supplemented in the diet, has shown physiological benefits in athletes, in animal-based models of disease and in patients with various muscle, neurological and neuromuscular disease. The clinical relevance of creatine supplementation is based primarily on its role in ATP generation, and cells may be able to better handle rapidly changing energy demands with supplementation. Although the pharmacological outcome measures of creatine have been investigated, the behaviour of creatine in the blood and muscle is still not fully understood. Creatine is most probably actively absorbed from the gastrointestinal tract in a similar way to amino acids and peptides. The distribution of creatine throughout the body is largely determined by the presence of creatine transporters. These transporters not only serve to distribute creatine but serve as a clearance mechanism because of creatine ‘trapping’ by skeletal muscle. Besides the pseudo-irreversible uptake by skeletal muscle, creatine clearance also depends on renal elimination and degradation to creatinine. Evidence suggests that creatine pharmacokinetics are nonlinear with respect to dose size and frequency. Skeletal muscle, the largest depot of creatine, has a finite capacity to store creatine. As such, when these stores are saturated, both volume of distribution and clearance can decrease, thus leading to complex pharmacokinetic situations. Additionally, other dietary components such as caffeine and carbohydrate can potentially affect pharmacokinetics by their influence on the creatine transporter. Disease and age may also affect the pharmacokinetics, but more information is needed. Overall, there are very limited pharmacokinetic data available for creatine, and further studies are needed to define absorption characteristics, clearance kinetics and the effect of multiple doses. Additionally, the relationship between plasma creatine and muscle creatine needs to be elucidated to optimise administration regimens.
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Clin Pharmacokinet 2003; 42 (6): 557-574
R
EVIEW
A
RTICLE
0312-5963/03/0006-0557/$30.00/0
Adis Data Information BV 2003. All rights reserved.
Pharmacokinetics of the Dietary
Supplement Creatine
Adam M. Persky,
1
Gayle A. Brazeau
2
and G
¨
unther Hochhaus
1
1 Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville,
Florida, USA
2 Department of Pharmacy Practice and Pharmaceutics, State University of New York at
Buffalo, Amherst, New York, USA
Contents
Abstract ....................................................................................557
1. Clinical Relevance .......................................................................558
2. Creatine Metabolism .....................................................................559
3. Absorption ..............................................................................560
4. Distribution ..............................................................................562
4.1 Creatine Transporters.................................................................563
5. Clearance ..............................................................................564
5.1 Skeletal Muscle ......................................................................564
5.2 Renal Elimination ....................................................................566
6. Pharmacokinetic Studies: Single and Multiple Dose ..........................................566
7. Effect of Diet on Pharmacokinetics: Carbohydrate and Caffeine .............................568
8. Special Populations ......................................................................569
9. Conclusion and Dosage Recommendations ................................................570
Creatine is a nonessential dietary component that, when supplemented in the
Abstract
diet, has shown physiological benefits in athletes, in animal-based models of
disease and in patients with various muscle, neurological and neuromuscular
disease. The clinical relevance of creatine supplementation is based primarily on
its role in ATP generation, and cells may be able to better handle rapidly changing
energy demands with supplementation.
Although the pharmacological outcome measures of creatine have been inves-
tigated, the behaviour of creatine in the blood and muscle is still not fully
understood. Creatine is most probably actively absorbed from the gastrointestinal
tract in a similar way to amino acids and peptides. The distribution of creatine
throughout the body is largely determined by the presence of creatine transporters.
These transporters not only serve to distribute creatine but serve as a clearance
mechanism because of creatine ‘trapping’ by skeletal muscle. Besides the
558 Persky et al.
pseudo-irreversible uptake by skeletal muscle, creatine clearance also depends on
renal elimination and degradation to creatinine.
Evidence suggests that creatine pharmacokinetics are nonlinear with respect to
dose size and frequency. Skeletal muscle, the largest depot of creatine, has a finite
capacity to store creatine. As such, when these stores are saturated, both volume of
distribution and clearance can decrease, thus leading to complex pharmacokinetic
situations. Additionally, other dietary components such as caffeine and carbohy-
drate can potentially affect pharmacokinetics by their influence on the creatine
transporter. Disease and age may also affect the pharmacokinetics, but more
information is needed.
Overall, there are very limited pharmacokinetic data available for creatine, and
further studies are needed to define absorption characteristics, clearance kinetics
and the effect of multiple doses. Additionally, the relationship between plasma
creatine and muscle creatine needs to be elucidated to optimise administration
regimens.
Creatine supplementation has become a popular volume of distribution, clearance, bioavailability,
mean residence time, absorption rate and half-life).
ergogenic aid to enhance exercise performance. In
Understanding the pharmacokinetics of creatine can
1998, approximately $US200 million was spent on
provide a foundation for better understanding of
creatine monohydrate.
[1]
In the late 1990s, the bene-
creatine pharmacodynamics. Because of the limited
fits of creatine supplementation were extended from
information on creatine pharmacokinetics in
the exercise performance arena into the clinical set-
humans, this review will be based on available
ting. Creatine supplementation has been, and contin-
human data, relevant animal data and in vitro work.
ues to be, investigated as a possible therapeutic
approach for the treatment of muscular, neurological
1. Clinical Relevance
and neuromuscular diseases (table I). The continued
success of creatine in the treatment of various
There is an increasing amount of research using
diseases is dependent on the understanding of its
creatine in the treatment of various clinically rele-
behaviour with respect to absorption, distribution,
vant diseases and disorders. The clinical pharmacol-
elimination and pharmacodynamic outcomes. The
former three points are essential in the development
of therapeutic regimens to maximise the benefits of
creatine, minimise any possible adverse effects, and
prevent overspending on these supplements. The
majority of research on creatine supplementation
has focused predominantly on pharmacodynamic
outcomes, whereas few studies have investigated the
pharmacokinetics of supraphysiological doses of
creatine. Those studies that have investigated plas-
ma creatine versus time relationships in humans
[2-9]
did not fully report pharmacokinetic parameters (i.e.
Table I. Application of creatine supplementation in human disease
and animal models of disease
Amyotrophic lateral sclerosis
[10,11]
Arthritis
[12]
Congestive heart failure
[13-15]
Disuse atrophy
[16]
Gyrate atrophy
[17-19]
Huntington’s disease
[20-22]
McArdles disease
[23,24]
Miscellaneous neuromuscular diseases
[25-27]
Mitochondrial diseases
[28-30]
Muscular dystrophy
[31-34]
Neuroprotection
[35-42]
Adis Data Information BV 2003. All rights reserved. Clin Pharmacokinet 2003; 42 (6)
Creatine 559
ogy of creatine supplementation has been previously
reviewed.
[43]
The underlying rationale for utilising
creatine supplementation is to increase phosphocre-
atine. The fundamental role of phosphocreatine is
the maintenance of adenine nucleotide homeostasis
in tissues. Part of this role is to produce/regenerate
ATP. ATP can be derived from fatty acid oxidation,
carbohydrate oxidation, glycolysis and phosphocre-
atine. The key for understanding the relationship
between cellular viability and ATP production is the
Creatine
Methionine
S-Adenosylmethionine
Guanidinoacetate
methyltransferase
S-Adenosylhomocysteine
Glycine
Guanidinoacetate
Arginine
Arginine:glycine amidinotransferase
Ornithine
Fig. 1. Biosynthesis of creatine (reproduced from Stockler et al.,
[58]
with permission
)
.
quantity and rate of ATP production. Fat oxidation
yields the largest quantities of ATP, but at the
tine can be obtained through the diet with the con-
slowest rate.
[44]
Conversely, phosphocreatine can
sumption of meat (~5g of creatine in 1kg of meat)
produce ATP very quickly, but has a lower capacity
and is synthesised in the liver, kidney and pancreas.
to generate ATP compared with fat and carbohy-
A total of approximately 2g of creatine is produced
drate metabolism.
[44]
When a cell is energetically
and/or consumed per day, with equal contribution
‘challenged’ by the environment (e.g. exercise, is-
from synthesis and diet (k
input
= 2 g/day). Adequate
chaemia), phosphocreatine is the first system re-
dietary intake of creatine can result from a wide
cruited. However, due to its small capacity, this
range of individual dietary habits.
[57]
Creatine and
system is rapidly depleted of its ATP-generating
phosphocreatine are nonenzymatically degraded to
capacity. In order to increase the ATP-generating
creatinine at a rate of 2 g/day, based on a total body
capacity of this system, creatine supplementation
creatine of a 70kg human with a total creatine pool
has been implemented and shown to increase total
creatine (creatine + phosphocreatine) concentrations
of 120g and a rate constant (k
Crn
) of 0.017 day
–1
.
[56]
in skeletal muscle
[4,45-49]
and in nervous tissue.
[50-52]
Creatinine and creatine are both eliminated from the
Increasing the ATP-generating capacity allows a
body via the kidney (figure 2). Supplementation
cell to better handle energetic challenges, thus
with exogenous creatine has also been shown to
preventing cell damage or death and improve cellu-
reduce endogenous production in humans; however,
lar functioning. The increase in creatine appears to
normal rates return upon termination of supplemen-
aid in the recovery of phosphocreatine after exer-
tation.
[56]
cise,
[47,49,53]
but other studies have found no differ-
The formation of creatinine is almost exclusively
ence in recovery of phosphocreatine after exer-
from creatine, and elevating muscle creatine stores
cise.
[54]
increases the amount of circulating levels of creati-
nine.
[5,59,60]
Increases in plasma creatinine would
2. Creatine Metabolism
suggest a reduced creatinine clearance, thereby rais-
ing some concerns of potential renal impairment
The metabolism of creatine has been pre-
with creatine supplementation. However, kidney
viously reviewed
[55,56]
(figure 1). Creatine (α-
function does not appear to be affected by creatine
methylguanidinoacetic acid) is distributed through-
supplementation,
[61-63]
thus questioning the validity
out the body, with >95% of total creatine found in
of creatinine clearance estimates during creatine
skeletal muscle and the remaining creatine pool
use.
located in the brain, eye, kidney and testes.
[56]
Crea-
Adis Data Information BV 2003. All rights reserved. Clin Pharmacokinet 2003; 42 (6)
560 Persky et al.
The mechanism of creatine absorption in the
gastrointestinal tract is unclear. Current techniques
have identified the mRNA for a creatine transporter
in the gastrointestinal tract.
[64]
Although the creatine
transporter protein has yet to be located on the apical
side of the mucosal layer, the presence of the mRNA
would suggest the possibility of active transport
mechanisms. Furthermore, creatine is structurally
similar to basic amino acids (e.g. arginine and ly-
sine) and may enter the systemic circulation through
the amino acid transporter or peptide transporters
located in the proximal small intestine. Creatine is a
hydrophilic and polar molecule containing carboxyl
and guanidino functional groups possessing nega-
tive and positive charges, respectively (figure 3).
The charge on these functional groups would hinder
passive diffusion of creatine through membranes. A
study in Caco-2 cell layers demonstrated poor api-
Crn
Cr
PCr
1
1
1
2
3
4
7
6
5
Other
tissue
Fig. 2. Determinants of systemic plasma concentrations of creatine
and creatinine. 1 = formation and renal elimination of creatinine
(rate constant k
Crn
); 2 = renal elimination of creatine (k
Cr
); 3 =
release of creatine from non-muscle tissue into the interstitial/vas-
cular space (k
NE
); 4 = uptake by non-muscle tissue of creatine
(k
EN
); 5 = release of creatine from muscle tissue into interstitial
/
vascular space (k
ME
); 6 = uptake of creatine by muscle (k
EM
); 7 =
formation and ingestion of creatine (k
input
). Cr = creatine; Crn =
creatinine; PCr = phosphocreatine
(
reproduced with permission
)
.
cal-to-basolateral movement of creatine,
[65]
further
supporting active processes.
3. Absorption
The absolute oral bioavailability (F) of creatine is
also unknown due to the lack of intravenous data,
Creatine is typically sold as a powder and taken
but there are several possible reasons to conclude
orally as a solution or suspension. In addition, crea-
that bioavailability is less than 100%. Although
tine has been formulated as a capsule and chewable
creatine is not subject to first-pass metabolism, other
tablets. The bioavailability of the capsules and
routes are possible for decreasing systemic creatine
chewable tablets may be limited by dissolution rate
exposure after oral administration. First, the rate of
and solubility (13 g/L) and only recently has a study
formation of the degradation product, creatinine, is
examined the relative bioavailability of various cre-
atine dosage forms.
[57]
This study compared creatine
in solution, suspension, lozenge and meat and found
differences in peak concentration (C
max
), with solu-
tion > suspension = lozenge > meat, and in time to
C
max
(t
max
). Comparisons were made for area under
the concentration-time curve (AUC), an important
determinant for bioequivalence, which indicated
that solution and meat have similar AUC but that
solution has a significantly higher AUC compared
with lozenge or suspension. However, AUC calcula-
tions only extended over the measured timepoints
and were not extrapolated to infinity, which is
necessary to fully demonstrate bioequivalence.
H
3
N
CH
3
N
COO
HN
PO
OO
+
Phosphocreatine
N
NH
O
H
3
C
NH
Creatinine
H
3
N
COO
CH
3
NH
+
Creatine
Fi
g
. 3. Structure of creatine, phosphocreatine and creatinine.
Adis Data Information BV 2003. All rights reserved. Clin Pharmacokinet 2003; 42 (6)
Creatine 561
increased in the presence of acid
[66-68]
and therefore Finally, there is experimental evidence of gut
microflora having the ability to metabolise creatine
accelerated degradation is possible in the lower pH
into creatinine.
[70]
of the stomach. However, creatine degradation to
creatinine occurs at its maximal rate at pH 3–4.
[67]
As previously mentioned, the absorption of crea-
The degradation half-lives for the conversion of
tine may demonstrate nonlinear kinetics based on
creatine to creatinine at pH values 1.4, 3.7 and 6.8 possible transporter uptake. Theoretically, if suffi-
ciently high amounts of creatine are ingested, appar-
are 55, 7.5 and 40.5 days, respectively. At these
ent zero-order absorption may occur with the rate of
rates, less than 0.1g of a 5g dose would be lost in 1
absorption approaching the maximal transport ve-
hour. Therefore, the conversion to creatinine in the
locity (V
max
) of the transporters. On the contrary,
gastrointestinal tract is probably minimal regardless
the transporter affinity (K
m
) for intestinal absorption
of transit time. Secondly, if creatine is absorbed by
can be large and elicit first-order absorption. How-
active mechanisms in the small intestine, these sys-
ever, neither scenario has been demonstrated experi-
tems may be saturable thus leading to nonlinear
mentally.
absorption with respect to administered dose. Third,
there is some evidence that faecal excretion of crea- Creatine t
max
in humans can be <2 hours for
tine is increased with a higher creatine intake.
[69]
doses of <10g
[3-7,9]
(table II). At doses above 10g,
Table II. Reported and approximated pharmacokinetic values for creatine from published data after oral administration. AUC and t
1
/2β
were
estimated with the Kinetica software package (Innaphase, Champs sur Marne, France) from graphs after subtraction of baseline creatine
values. CL/F was calculated as dose/AUC, where AUC is through infinity for the first dose or over one dosage interval for all other doses.
Vd/F was calculated as t
1
/2
× CL/F × 1/ln 2
Study (no. of Dose (g) t
max
(h) C
max
(mg/L) AUC (mg h/L) t
1
/2β
(h) CL/F (L/h) Vd/F (L) Dose no. Comment
subjects)
Green et al.
[7]
(6) 5 0.83 160 340 0.89 14 18 1
5 1.5 70 175 0.68 29 28 1 + CHO
5 0.83 220 570 2.1 8.7 26 13
5 2.2 95 260 0.94 19 26 13 + CHO
Harris et al.
[4]
(3) 5 1 98 260 1.7 19 47 1
Rawson et al.
[9]
(8 5 1.3
a
67
a
183
a
1.2
a
27 47 1 Young
and 7)
5 1.6
a
87
a
282
a
1.4
a
18 36 1 Elderly
Schedel et al.
[5]
(1) 2.5 1 50 140 1.7 18 44 1 Female
5 1.25 110 340 1.3 15 27 1 Female
10 1.25 120 360 0.94 28 38 1 Female
15 3 280 ND ND ND ND 1 Female
20 4 280 ND ND ND ND 1 Female
Steenge et al.
[3]
5 1 120 300 1.2 17 42 1
(12)
5 1.25 95 280 1.2 18 31 1 + CHO
5 1 140 380 2.1 13 39 4
5 1 120 370 2.1 14 42 4 + CHO
Vanakoski et al.
[6]
7 1.53
a
160
a
580
b
2.9
a
14 59 10 Caffeine
(8)
a Reported value.
b Reported value without baseline creatine level.
AUC = area under the concentration-time curve; CL/F = apparent systemic clearance; C
max
= peak concentration; ND = not determined
because of insufficient data; t
max
= time to C
max
; t
1
/2β
= elimination half-life; Vd/F = apparent volume of distribution; + = with; - = without.
Adis Data Information BV 2003. All rights reserved. Clin Pharmacokinet 2003; 42 (6)
562 Persky et al.
3000
2500
2000
1500
1000
500
0
10 10 30 50 70 90 110 130 150 170 190 210 230 250 270 290 310 330 350
160
150
140
130
120
110
100
90
80
n = 16 n = 7 n = 6
Time (min)
Serum creatine (µmol/L)
Serum creatinine (µmol/L)
Creatine
Creatinine
Fig. 4. Plasma levels following a single oral dose (arrow) of creatine 20g. Apparent steady state is attained, suggesting zero-order
absorption at hi
g
h doses
(
reproduced from Schedel et al.,
[5]
with permission from Elsevier Science
)
.
t
max
increases to >3 hours.
[5]
Furthermore, a 20g 4. Distribution
dose can show a steady-state-like plateau (figure
Following administration, creatine can be taken
4).
[5]
The steady-state-like plateau of creatine sug-
up by a variety of cells, including blood cells, the
gests zero-order absorption, probably as a function
brain/nervous tissue, cardiac muscle, spermatozoa
of saturation of gastrointestinal transporters. t
max
and the retina; however, the predominant absorption
tends to increase with the coadministration of carbo-
site is skeletal muscle.
[55]
The polar nature of the
hydrate.
[7]
It is unclear if absorption or elimination is
creatine molecule suggests that if distribution is
responsible for the variability in t
max
seen with dose
based solely on diffusion, the apparent volume of
quantity or with the ingestion of carbohydrate.
distribution should probably not exceed extracellu-
In conclusion, to date, absorption mechanisms
lar water. Plasma protein binding is also expected to
and kinetics have not been studied in detail. How-
be negligible due to the hydrophilicity of the mole-
ever, current evidence for transporters and the phys-
cule.
[71]
As such, low protein binding results in high
icochemical properties of creatine suggest active
free levels of creatine available as substrates for the
processes for the uptake of creatine from the gastro-
creatine transporter. The presence of the creatine
intestinal tract. The kinetics of uptake may be de-
transporter suggests a volume of distribution greater
pendent on the dose, resulting in nonlinearity in the
than the predicted extracellular water, approaching
rate and extent of absorption. Future studies are
that of total body water (~45L), as shown in table II.
needed to identify the cellular location of transport-
Interestingly, studies have shown that skeletal
ers and/or absorption windows in the gastrointesti-
muscle, the main reservoir for creatine, has a finite
nal tract and their role in creatine absorption.
storage capacity.
[4]
Therefore, as creatine accumu-
Adis Data Information BV 2003. All rights reserved. Clin Pharmacokinet 2003; 42 (6)
Creatine 563
lates in the muscle with repeated administration and < rat.
[87]
Human blood levels range from 7–13 mg/L.
eventually saturates the storage capacity, it is possi-
Excluding humans, the creatine transporter in most
ble that the volume of distribution will decrease. The
species is close to saturation based on the K
m
of the
accumulation and subsequent saturation may be a
transporter and resting blood levels.
[72]
The species
result of possible downregulation of creatine trans-
differences in blood and K
m
values for creatine and
porter number or function. The next section will
the creatine transporter, respectively, may hinder the
discuss what is known about regulation of the crea-
usefulness of animal models to elucidate human
tine transporter.
creatine pharmacokinetics. Tissue and species dif-
ferences after supplementation have also been re-
4.1 Creatine Transporters
ported.
[51]
The regulation of the creatine transporter is not
Creatine is transported into tissues against a large
fully understood, but transport activity appears to be
concentration gradient through a sodium- and chlo-
influenced by total creatine content, various hor-
ride-dependent transporter that is similar in structure
mones, and exercise. The CreaT1 protein has several
to the transporters for dopamine, γ-aminobutyric
sites for glycosylation and phosphorylation, which
acid (GABA) and taurine, and has been previously
may be responsible for its regulation. Human
reviewed.
[72,73]
The mRNA for the first creatine
muscle total creatine levels can range from 110–160
transporter gene (CreaT1) has been found in a varie-
mmol/kg dry mass (14–20 g/kg dry mass),
[88]
with
ty of tissues, including kidney, heart, skeletal
60% in the form of phosphocreatine,
[4,45,46,49]
but
muscle, brain, testes, colon and intestine.
[64,74,75]
An-
content is dependent on the skeletal muscle fibre
other creatine transporter gene (CreaT2) has been
type.
[46,89,90]
Differences in muscle creatine content
located, but the expression of this transporter, which
could influence transporter activity, as individuals
shares 97% homology with CreaT1, may be limited
with lower creatine levels at the start of a supple-
to the testes.
[76]
Two creatine transporter isoforms
mentation period respond with larger increases in
(70 and 55 kDa) have been identified in humans and
creatine content in muscle compared with those with
in other species.
[77,78]
The two isoforms differ in
higher initial starting creatine levels.
[4]
This varying
amount of glycosylation and may be responsible for
response to creatine uptake may be a function of the
different cellular targeting, leading to the identifica-
creatine transporter density at the membrane or oth-
tion of the creatine transporter protein in plasma
er regulatory modifications (e.g. phosphorylation) to
membranes, sarcolemma, microsomes and mito-
the transporter.
chondria.
[72]
Various endogenous compounds influence crea-
Creatine appears to be a specific substrate for the
tine uptake into skeletal muscle cells. Studies in cell
creatine transporter, with one of the most efficient
culture show that catecholamines, thyroid hormone,
competitive substrates (i.e. highest affinity) being
insulin-like growth factor 1 (IGF-1) and insulin can
the creatine analogue β-guanidinopropionic
influence the uptake of creatine into skeletal
acid.
[64,74,75]
Other endogenous compounds do not
muscle.
[91]
The increases in creatine uptake in cell
appear to compete efficiently with creatine for the
culture can be 1- to 3-fold higher, depending on the
creatine transporter binding site.
[64,74,75,79-81]
The ki-
compound and concentration.
[91]
Human studies
netics of CreaT1 depend on the species and location
with insulin and compounds that elicit an insulin
of the transporter (red blood cell, macrophage,
response (e.g. high-glycaemic carbohydrates) have
muscle fibre type).
[74,75,82-86]
Blood levels of creatine
vary between species with humans < rabbit < mouse shown similar results to the cell culture experi-
Adis Data Information BV 2003. All rights reserved. Clin Pharmacokinet 2003; 42 (6)
564 Persky et al.
ments.
[2,3,7,48]
For this reason, high-glycaemic carbo- 5. Clearance
hydrates (e.g. glucose, glucose polymers) are typi-
In general, creatine can be removed from the
cally consumed with creatine to elicit an insulin
blood by skeletal muscle (CL
M
) and kidney (CL
R
),
response to enhance uptake. The use of carbohy-
so that (equation 1):
drates not only appears to enhance the rate of uptake
CL CL CL
total M R
=+
but may affect the overall storage capacity of the
The relative contribution of these pathways may
muscle.
[48]
be dependent on both dose and dose frequency.
Increase in creatine uptake with exercise was
Nonlinear pharmacokinetics may be the result of
hypothesised to result from enhanced blood flow,
changes in the contribution of each of the possible
but changes in transport kinetics have not been ruled
clearance mechanisms. For example, with the first
out.
[4]
The hydrophilic nature of creatine means that
dose, creatine clearance can rely on both muscle and
it would generally be thought of as ‘permeability-
kidney, but after a number of doses, when muscle
limited’ with regards to distribution. However, if
creatine stores are saturated, clearance may occur
blood flow limits muscle uptake, skeletal muscle
only via the kidney. Each clearance mechanism will
may serve as a ‘high extraction’ organ with its innate
be discussed in more detail in the following sections.
ability to remove creatine from the blood being far
greater than the blood flow supplying the muscle.
5.1 Skeletal Muscle
This is probably not the case, as data from Robinson
The creatine transporter not only serves to dis-
et al.
[92]
suggest that enhanced muscle blood flow
tribute creatine throughout the body but, once crea-
during recovery or exercise is unlikely to be impor-
tine is intracellular, it appears to be ‘locked’ in the
tant. These investigators suggest that the most likely
muscle, unable to diffuse out or diffusing out at an
reason for the increase in creatine uptake following
extremely slow rate (figure 2; k
EM
>>> k
ME
).
[94]
exercise is an increased activation of the creatine
The pseudo-irreversible uptake of creatine by skele-
transporter, perhaps by a change in phosphorylation
tal muscle and subsequent conversion to phospho-
state. Additionally, it is also possible that exercise
creatine and degradation to creatinine can therefore
will increase the translocation of the creatine trans-
serve as a clearing mechanism similar to the rela-
porter to the muscle membrane, similar to the effect
tionship of haemopoetic growth factors and bone.
[95]
seen with exercise and translocation of the glucose
The majority of creatine conversion to creatinine
transporter GLUT-4.
[93]
occurs in the muscle compartment and appears to be
In summary, distribution of creatine occurs in
a minor pathway of clearance, with CL
Crn
estimated
large part due to the creatine transporter. The crea-
at 0.032 L/h (based on k
Crn
= 0.017 day
–1
[67]
and a
tine transporter is specific for creatine and appears
volume of distribution of 45L or total body water).
to be influenced by hormones, exercise and muscle
Conversely, it has been suggested that creatine turn-
creatine content. The creatine content of muscle has
over in non-muscle compartments occurs at a faster
an upper limit, and could affect pharmacokinetics by
rate than the muscle counterpart.
[94]
reducing the apparent volume of distribution with
Clearance of creatine by muscle would be affect-
repeated administration. This finite storage capacity
ed by the same features that affect the creatine
may be due to changes in transporter number and
transporter: (i) molecules such as insulin, catecho-
function; however, the exact regulatory mechanism
lamines and IGF-1; (ii) exercise; and (iii) muscle
of the creatine transporter is not fully understood.
creatine levels. Furthermore, the amount or percent-
Adis Data Information BV 2003. All rights reserved. Clin Pharmacokinet 2003; 42 (6)
Creatine 565
Table III. Selected administration regimens for creatine supplementation in humans
Study Dose (g) Frequency (per Duration Population
day)
Andrews et al.
[13]
5 4 5 days Congestive heart failure
Bermon et al.
[96]
5 1 52 days Elderly healthy (>60 years)
Hespel et al.
[16]
5 (atrophy period) 4 2 weeks Disuse atrophy
5 (rehabilitation) 3 3 weeks
5 (maintenance) 1 7 weeks
Hultman et al.
[45]
3 1 >30 days Young healthy (<30 years)
Klopstock et al.
[28]
5 4 20 days Mitochondrial disease
Mazzini et al.
[11]
5 4 7 days Amyotrophic lateral sclerosis
3 1 6 months
Rawson and Clarkson
[97]
5 4 5 days Elderly healthy (>60 years)
Rawson et al.
[98]
5 1 30 days Elderly healthy (>60 years)
Tarnopolsky et al.
[25]
10 1 5 days Neuromuscular disease
5 (maintenance) 1 57 days
Vannas-Sulonen et al.
[18]
0.5 3 5 years Gyrate atrophy (adults)
0.25 3 5 years Gyrate atrophy (children)
Volek et al.
[99]
5 5 7 days Young healthy (<30 years)
5 (maintenance) 1 11 weeks
Vorgerd et al.
[23]
150 mg/kg 1 7 days Myophosphorylase deficiency
Walter et al.
[34]
10 1 8 weeks Muscular dystrophy (adults)
5 1 8 weeks Muscular dystrophy (children)
age muscle mass of an individual may also affect V
max
values for intact rodent soleus and extensor
clearance. A larger muscle mass would correlate to
digitorum longus (EDL) muscles of 77 and 100
more transporters and greater potential storage area
nmol/h/g wet weight (10 and 13 µg/h/g wet weight),
for creatine. Therefore, individuals with larger
respectively, have been reported.
[86]
Combined with
muscle mass should demonstrate larger clearance
the respective K
m
values of 73 and 160 µmol/L (9.4
values. Because of the possible relationship between
and 21 mg/L), the resulting values of CL
int
would be
clearance and muscle mass, it may be more appro-
1.06 and 0.63 L/h/kg wet weight for soleus and
priate to scale the dosage of creatine to bodyweight,
EDL, respectively. Human skeletal muscle is com-
ideal bodyweight or lean body mass. Currently, few
posed of mixed fibre types, unlike rodent where the
studies adjust creatine dosage for bodyweight (table
soleus is predominantly slow-twitch and EDL is
III).
predominantly fast-twitch, and therefore the average
There are currently no values or estimates of
value of intrinsic clearance (0.84 L/h/kg wet weight)
CL
M
in humans or animals. The only available data
would be a better estimate for humans. Applying the
to estimate CL
M
are the Michaelis-Menten para-
‘well-stirred’ model with assumptions of: (i) zero
meters for the uptake of creatine, V
max
and K
m
, for
plasma protein binding; (ii) 40% of bodyweight
intact isolated rodent muscle and/or cloned human
being skeletal muscle; and (iii) skeletal muscle
and animal creatine transporter. These enzymatic
blood flow of 60 L/h at rest, the value of CL
M
in
values can be used as a gross estimation of the
humans would be 0.24 L/h/kg body mass, or 17 L/h
intrinsic clearance (CL
int
) by skeletal muscle with
for a 70 kg person. As can be seen in table II, the
the relationship in (equation 2):
[100]
calculated CL
M
of 17 L/h is similar to the estimated
CL V K
mint max
/
=
CL
total
in humans. The proximity of these values
Adis Data Information BV 2003. All rights reserved. Clin Pharmacokinet 2003; 42 (6)
566 Persky et al.
suggests that skeletal muscle is the predominant h.
[9,48,96,104,105]
Supplementation with creatine (>10
contributor to clearance for early doses. g/day) has been shown to increase urinary creatine
levels, and after more than 3 days of loading at 4 × 5
5.2 Renal Elimination
g/day (20 g/day) the rate of excretion was 416–460
mg/h, but steady-state blood levels were not as-
The second pathway of creatine elimination is by
sessed to calculate CL
R
.
[9,48,96,103]
the kidney. Early research estimated that the rate of
To summarise, creatine can be cleared by degra-
renal excretion was close to glomerular filtration
dation, renal filtration and irreversible uptake into
rate (GFR),
[101]
although others have found that cre-
skeletal muscle. The percent contribution of each
atine is reabsorbed in the kidney.
[102]
This is sup-
component is unknown, but the low rate of creatine
ported by the low concentrations of creatine in the
conversion to creatinine and the small reported renal
urine in unsupplemented conditions and the location
clearances suggest that skeletal muscle would re-
of the creatine transporter in the kidney. CL
R
can be
present the largest contribution. The contribution of
calculated by (equation 3):
skeletal muscle may decrease with increasing num-
CL rate of excretion C
Rp
= /
ber of doses because of muscle saturation, allowing
where C
p
is the midpoint plasma concentration.
a higher contribution of renal elimination.
Given that creatine has little protein binding and
assuming no active renal secretion, CL
R
would ap-
6. Pharmacokinetic Studies: Single and
proach GFR (125 mL/min or 7.5 L/h). Poortmans
Multiple Dose
and colleagues
[62,63]
reported normal CL
R
values of
0.3–0.8 L/h, suggesting extensive reabsorption.
The lack of intravenous data has limited the
With supplementation, CL
R
increased to 9–22 L/h,
ability to interpret disposition of creatine in the
indicating that under conditions of supplementation
blood. Some investigators have administered low
CL
R
can range from close to GFR to well above
doses of creatine as an intravenous infusion in
GFR, implying active secretion. However, one of
humans,
[106]
and there are few available intravenous
these studies was based on self-reported estimates of
bolus studies in humans. Fitch and colleagues
[8]
creatine ingestion of 2–30 g/day for 10 months to 5
injected small amounts (<3mg) of radiolabelled cre-
years.
[62]
In a second study by this group, subjects
atine into five patients with various muscular disor-
ingested 5g four times a day for 5 days and plasma
ders. They reported a half-life in plasma of 20–70
levels increased from 9 to 36 mg/L, but the renal
minutes. Creatine concentration followed a mono-
excretion rate reached an unrealistic 682.5 µmol/
exponential decline in three of the five patients, and
min or >5 g/h (or >128 g/24 hours).
[63]
The problem
the remaining two exhibited a bi-exponential de-
with these estimations is that urine was collected for
cline with a distribution phase of less than 40 min-
24 hours and compared with the midpoint blood
utes. It is difficult to interpret these findings, be-
level. These calculations would be a gross estimate,
cause the dose administered was small compared
and smaller windows of urine collection and blood
with the doses that are currently being ingested.
sampling would be required to compute a better
Additionally, patients who showed a bi-exponential
estimate of the renal creatine clearance.
decline were heavier and slightly older than the
Vanderberghe et al.,
[103]
found that women exhib- other three patients in this study. Age might affect
ited a rate of excretion of creatine under unsupple- creatine pharmacokinetics by a reduction in the cre-
mented conditions of 1–1.5 mg/h. Other studies atine transporter. This possibility will be discussed
have found values between 1 and 40 mg/ later in Section 8.
Adis Data Information BV 2003. All rights reserved. Clin Pharmacokinet 2003; 42 (6)
Creatine 567
Several studies have examined the plasma crea-
tine concentration-time profile after a single oral
dose of creatine.
[2,4-7,9]
Most of these did not perform
full pharmacokinetic analysis, but their reported val-
ues, as well as our estimations of the remaining
parameters, are given in table II. Apparent volume
of distribution is close to total body water, and
clearance values are similar to those predicted for
the contribution of skeletal muscle to overall clear-
ance.
1
There is even less information on pharmacokine-
tics after multiple doses. Based on initial work by
Harris et al.,
[4]
creatine administration typically fol-
lows a regimen of a ‘loading’ phase of 4 × 5 g/day
(20 g/day) for 2–6 days and then a maintenance
dosage of 3–5 g/day. This type of loading phase has
been found to increase intramuscular total creatine
levels by at least 17–20%.
[4,15,45,47,49]
Approximately
20% of this increase in total creatine is due to
phosphocreatine.
[4,15,45,46,103]
Clinical studies have
used different administration regimens than those
previously mentioned, and vary in amount and dura-
tion of supplementation (table III).
Green and coworkers
[7]
investigated the effect of
2 days of loading with the 4 × 5 g/day (20 g/day)
1200
900
600
300
0
1200
900
600
300
0
0 60 120 180 240
Plasma creatine (µmol/L)
a
b
Time (mins)
Placebo
Protein-CHO
High CHO
Low CHO
Fig. 5. Plasma creatine concentration following ingestion of crea-
tine 5g followed 30 minutes later by the ingestion of 5g of carbohy-
drate (placebo), 50g of protein + 47g of carbohydrate (Protein-
CHO), 94g of carbohydrate (High CHO) or 50g of carbohydrate
(Low CHO). (a) First oral dose; (b) fourth oral dose. Values are
mean and standard error. Dotted lines are used to facilitate com-
parisons
(
reproduced from Steen
g
e et al.,
[3]
with permission
)
.
regimen on creatine AUC. On day 3, C
max
after a 5g
suggests no accumulation, but this contradicted by
dose showed a ~35% increase compared with day 1,
changes in C
max.
Based on estimated clearance val-
but there was no difference in baseline creatine
ues in table II, it appears that there is a small
levels and no difference in the 6-hour AUC. The
reduction in both clearance and volume of distribu-
large increase in C
max
suggests accumulation, but
tion with repeated doses. This is consistent with
the lack of difference in AUC contradicts accumula-
accumulation of creatine in the skeletal muscle com-
tion. The lack of change in AUC may be a function
partment.
of changes in clearance and/or bioavailability, and
changes in C
max
could be a function of absorption Typically, multiple-dose regimens result in
kinetics. Steenge et al.
[3]
examined AUC from 0 to steady-state drug concentrations. It has never been
220 minutes after a single oral dose and after the experimentally proven that the current administra-
fourth oral dose and found no increases in AUC but tion regimen for creatine results in steady-state
found increases in C
max
and baseline creatine (fig- blood concentrations. However, steady-state blood
ure 5). The lack of change in AUC in both studies concentrations may not be necessary in the case of
1 Since the time of writing this review, Persky et al., published results from a clinical study that supports many of the
hypotheses from this review.
Adis Data Information BV 2003. All rights reserved. Clin Pharmacokinet 2003; 42 (6)
568 Persky et al.
creatine supplementation. Skeletal muscle has a lim- nonlinear tissue binding was proposed for intrave-
nous bolus administration in rabbits.
[109]
However,
ited capacity to store creatine
[4,46]
and the saturation
this is not the most likely model, since the hydro-
of these stores can be accomplished quickly with a
philic nature of creatine would suggest little tissue
typical loading phase, or more slowly by taking 3 g/
binding. Mathematically the nonlinear tissue bind-
day over 30 days.
[45]
Even when using a loading
ing model may be similar to a two-compartment
phase, maximal accumulation of intramuscular crea-
body model. A two-compartment model may be
tine is believed to occur after about 2 days, and
used to describe intravenous bolus data and may be a
amounts of 20 g/day after this time may be unneces-
better model based on distribution into muscle. For
sary.
[107]
Further evidence suggesting that 20 g/day
oral administration, a one-compartment body model
may be unnecessary is reflected in the progressive
may work depending on the length of the distribu-
increase in urinary creatine with continuous high
tion phase. The input parameters can vary among
doses.
[4,96,103,108]
By day 3 of a 5-day loading period
apparent zero-order input, first-order input or
ingesting 4 × 5 g/day, urinary loss of creatine can be
Michaelis-Menten kinetics, and elimination can be a
up to 60% based on 24-hour urine collection.
[4]
combination of first-order and Michaelis-Menten
Additionally, creatine levels in humans can remain
kinetics.
elevated for up to 1 month post-supplementation,
[45]
in part due to lack of passive movement of creatine
7. Effect of Diet on Pharmacokinetics:
out of the cell and the slow turnover of creatine to
Carbohydrate and Caffeine
creatinine. Given a half-life of 40 days and an upper
limit of 160 mmol/kg dry mass (20 g/kg dry mass),
As discussed in section 4, data from cell culture
then about 2.5–3 g/day will be lost and therefore
suggests that insulin enhances creatine uptake into
ingesting 2–3 g/day may be sufficient to maintain
muscle. Based on this information, studies have
saturated muscle stores. A similar dosage (2 g/day)
investigated the effect of insulin and carbohydrate
has previously been used to maintain skeletal
on the AUC after oral administration of creatine.
muscle levels.
[45]
Steenge et al.,
[2]
enterally infused creatine (100
Fitch et al.
[94]
proposed a schematic model and
mmol/L, 2.5 mL/min or ~1.97 g/h) along with insu-
estimated rate constants after creatine administra-
lin at various rates and followed plasma creatine.
tion in patients with muscular dystrophies, neuro-
Steady-state plasma creatine reached ~ 95 mg/L
muscular disease or polymyositis. This is one of the
with an insulin infusion rate of 105 mU/m
2
/min, and
few proposed mathematical models to describe crea-
~135 mg/L with an insulin infusion of 5 mU/m
2
/min
tine pharmacokinetics in humans. A model using (table IV). These data suggest an apparent clearance
Table IV. Pharmacokinetic values in healthy adults after nasogastric infusion of creatine at a rate of 1.97 g/h
[2]
Insulin infusion t
max
(h) C
ss
(mg/L) CL/F
a
(L/h) AUC
b
(mg h/L) tCr (mg/kg dry mass)
(mU/m
2
/min)
5 1.83 135 15 390 328
30 1.83 120 16 342 380
55 1.83 110 18 314 603
105 1 95 21 304 1101
a Estimated from infusion rate/C
ss
.
b AUC from 0220 minutes without baseline creatine (9.8 mg/L).
AUC = area under the concentration-time curve; CL/F = apparent systemic clearance; C
ss
= steady-state plasma creatine; tCr = change in
muscle total creatine; t
max
= time to C
max
.
Adis Data Information BV 2003. All rights reserved. Clin Pharmacokinet 2003; 42 (6)
Creatine 569
(CL/F) of 15–20 L/h depending on infusion rate, orally. C
max
without caffeine ingestion was 160 mg/
L with a t
max
of 92 minutes and a terminal half-life
with the slower insulin rate eliciting a smaller clear-
of 172 minutes. The concomitant administration of
ance. Additionally, higher infusion rates caused
caffeine had no statistically significant effect on
greater change in muscle total creatine in a possible
creatine pharmacokinetics. The lack of change in
maximal-effect (E
max
) relationship (table IV). The
pharmacokinetics is supported by data suggesting
time to steady-state in this study was approximately
that caffeine ingestion does not increase creatine
120 minutes after the start of creatine infusion, thus
loading into muscle.
[111]
The lack of effect could be
suggesting a half-life of ~25 minutes (5 half-lives).
due to the fact the pharmacokinetic analysis was
This finding would coincide with earlier work re-
performed after three days of loading, which would
porting that patients without primary muscle disease
increase muscle creatine and thus reduce skeletal
had a creatine half-life of ~20 minutes after small
muscle clearance and target total clearance predom-
doses (<3mg ) administered by intravenous bolus.
[8]
inantly to the kidney. With a reduced ability of
Green et al.,
[7]
found a near 3-fold reduction in
skeletal muscle to take up creatine, any stimulatory
plasma creatine AUC if a 5g dose of creatine was
effect of caffeine would be reduced. Additionally,
ingested with a simple sugar solution (table II). C
max
this study was a crossover design with a 1-week
decreased 2-fold and t
max
was slightly prolonged.
washout between treatments. This would further
The effect of carbohydrate has been attributed to
taint the analysis, because elevated muscle total
enhanced removal of creatine from blood caused by
creatine levels can last up to 28 days
[45]
and the
the stimulatory effect of insulin on creatine uptake
accumulation of muscle creatine would reduce
by skeletal muscle. An alternative explanation of the
clearance and volume of distribution.
decrease in AUC could be a decrease in bioavaila-
Dietary intake of carbohydrate and caffeine can
bility. Rate of change in skeletal muscle creatine
potentially influence creatine pharmacokinetics by
could support the former reasoning for a decrease in
affecting skeletal muscle clearance. However, the
AUC, as suggested by a previous study.
[2]
Others
effects of carbohydrate and caffeine may only influ-
have shown that the ingestion of carbohydrate and/
ence pharmacokinetics during early doses (first day)
or protein increases whole body creatine retention
when the contribution of skeletal muscle clearance
by decreasing plasma AUC (figure 5) and decreas-
may be the greatest, as demonstrated by Steenge et
ing urine output.
[3]
These stimulatory effects of insu-
al.
[3]
The increase in clearance with carbohydrate
lin on creatine disposal appear to diminish within 24
appears to be a function of the insulin response. The
hours of beginning creatine supplementation.
[3]
Al-
evidence for an effect of caffeine is not substantiat-
though the addition of carbohydrate can decrease
ed, and further research is needed.
gastric emptying time,
[110]
there is little evidence to
suggest carbohydrate would decrease the bioavaila-
8. Special Populations
bility of creatine.
Based on work on the stimulatory effects of β-
Most studies on creatine have focused on young,
agonists on creatine uptake in cell culture,
[91]
healthy populations. Emerging research is showing
Vanakoski et al. investigated the pharmacokinetics
possible usefulness for creatine supplementation in
of creatine with and without caffeine ingestion.
[6]
special populations. The evidence of the ergogenic
Subjects were supplemented for 3 days with creatine
effects in the elderly are equivocal, with some stud-
100 mg/kg 3 times daily (~20 g/day). After 3 days, a
ies showing an exercise performance benefit
[112,113]
single dose of 100 mg/kg (6–7g) was administered whereas others have shown no benefit.
[97,98]
This
Adis Data Information BV 2003. All rights reserved. Clin Pharmacokinet 2003; 42 (6)
570 Persky et al.
lack of an effect may be attributed, at least in part, to decreases in creatine ‘trapping’ by skeletal muscle
in specific patient populations.
[94]
Further studies in
a difference in pharmacokinetics, resulting in a lack
the elderly and patient populations are needed to
of increase in phosphocreatine. Rawson et al.
[9]
examine the impact of changes in creatine transport-
compared blood levels of creatine after a 5g dose in
er activity and total creatine content on pharmaco-
young and elderly (>60 years) healthy men. They
kinetics and pharmacodynamic outcomes.
found no statistically significant difference in termi-
nal half-life, AUC, C
max
or t
max
between groups
9. Conclusion and
(table II), but did find in elderly men that intramus-
Dosage Recommendations
cular phosphocreatine levels did not increase with
supplementation. Both populations also had similar
Creatine pharmacokinetics are far from being
renal excretion rates of creatine. However, despite
elucidated. Current data suggest that clearance is
the lack of difference in AUC, table II shows ap-
dependent on skeletal muscle and kidney function.
proximately a 35% difference in calculated CL/F
The contribution of these systems may be dependent
between the two age groups. Since both groups had
on dose and dose frequency. Part of the difficulty in
similar renal excretion rates, the difference in clear-
characterising the pharmacokinetics of creatine
ance may be attributable to skeletal muscle differ-
arises from differences in study design (dose, single
ences.
versus multiple doses, oral administration or infu-
Patients with muscular dystrophy can have
sion, effect of diet). Creatine kinetics may in fact be
hypercreatinaemia and creatinuria, along with lower
nonlinear as a result of transporter-based mechan-
muscle levels of creatine and phosphocreatine.
[94]
isms in the gut, skeletal muscle and kidney, and
Patients and animals with failing hearts
[77]
and popu-
therefore dose-dependency has to be fully under-
lations with myopathies
[78]
have shown lower
stood. Not only does the behaviour of creatine in the
CreaT1 content and lower creatine and phosphocre-
blood need to be understood, but more importantly
atine muscle levels. Inborn errors in creatine meta-
the relationship between blood concentrations and
bolism have been reported, as in the case of gyrate
muscle concentrations needs to be defined. With an
atrophy that leads to tubular aggregates and type II
understanding of the relationship between plasma
fibre atrophy, both of which are relieved by creatine
creatine and muscle creatine and vice versa, admin-
supplementation.
[19]
It has been suggested that
istration regimens can be tailored to reach therapeu-
diseases that cause defects in creatine or phospho-
tic muscle levels quickly and maintain these levels,
creatine levels may be caused by ineffective ‘trap-
possibly allowing ‘drug holidays’ to maintain both
ping’ of creatine in muscle, or by lack of uptake.
[94]
endogenous production and creatine transporter
As discussed in section 6, Fitch et al.,
[8]
examined
levels.
the pharmacokinetics of an intravenous bolus of
Given the available data, it is difficult to recom-
creatine in five patients, three patients with primary
mend an administration regimen because the plasma
muscle disease and two patients without primary
concentrations needed to obtain a maximal uptake
muscle disease. Patients with primary muscle dis-
velocity by skeletal muscle are unknown. However,
ease demonstrated an average half-life of 50 min-
current regimens of a loading phase followed by a
utes, and the patients without primary muscle dis-
maintenance phase appear to be effective in reach-
ease had an average half-life of 24 minutes. This
ing therapeutic muscle levels. A short loading phase
further supports other work by this group showing
of 2–3 days taking 0.071 g/kg bodyweight (equiva-
differences in creatine uptake by skeletal muscle and lent to 5g for a 70kg person) four times a day is
Adis Data Information BV 2003. All rights reserved. Clin Pharmacokinet 2003; 42 (6)
Creatine 571
strength in amyotrophic lateral sclerosis: preliminary results. J
suggested. Creatine should be taken with a high-
Neurol Sci 2001; 191 (1-2): 139-44
carbohydrate meal or beverage, but high-fructose
12. Willer B, Stucki G, Hoppeler H, et al. Effects of creatine
supplementation on muscle weakness in patients with rheuma-
components (e.g. fruit juice) should be avoided be-
toid arthritis. Rheumatology (Oxford) 2000; 39 (3): 293-8
cause fructose does not elicit a significant insulin
13. Andrews R, Greenhaff P, Curtis S, et al. The effect of dietary
response. After the loading phase, creatine can be
creatine supplementation on skeletal muscle metabolism in
congestive heart failure. Eur Heart J 1998; 19 (4): 617-22
taken once daily at a dosage of 0.029 g/kg body-
14. Field ML. Creatine supplementation in congestive heart failure.
weight to maintain muscle levels.
[45]
This regimen
Cardiovasc Res 1996; 31 (1): 174-6
15. Gordon A, Hultman E, Kaijser L, et al. Creatine supplementa-
should cause rapid increases in muscle creatine
tion in chronic heart failure increases skeletal muscle creatine
without overuse of the supplement.
phosphate and muscle performance. Cardiovasc Res 1995; 30
(3): 413-8
16. Hespel P, Eijnde BO, Van Leemputte M, et al. Oral creatine
Acknowledgements
supplementation facilitates the rehabilitation of disuse atrophy
and alters the expression of muscle myogenic factors in
The authors would like to thank Mrs. Patricia Kahn for her
humans. J Physiol 2001; 536 (Pt 2): 625-33
help in preparation of the manuscript. Preparation of this
17. Heinanen K, Nanto-Salonen K, Komu M, et al. Creatine cor-
manuscript was supported, in part, by The Experimental and
rects muscle
31
P spectrum in gyrate atrophy with hyper-
Applied Science (EAS) Research Grant on Nutrition and
ornithinaemia. Eur J Clin Invest 1999; 29 (12): 1060-5
Human Performance from the American College of Sport
18. Vannas-Sulonen K, Sipila I, Vannas A, et al. Gyrate atrophy of
Medicine Foundation.There are no conflicts of interest rele-
the choroid and retina: a five-year follow-up of creatine sup-
plementation. Ophthalmology 1985; 92 (12): 1719-27
vant to the content of this review.
19. Sipila I, Rapola J, Simell O, et al. Supplementary creatine as a
treatment for gyrate atrophy of the choroid and retina. N Engl J
Med 1981; 304 (15): 867-70
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... On the other hand, when pH is <2.5, the amide functional group on the creatine molecule is protonated and prevents the intramolecular cyclization (see Figure 5) [25]. Since stomach acid is generally less than 2.5, less than 1% of CrM is degraded to creatinine during digestion and 99% of creatine is taken up by tissue or excreted in urine after ingestion [12,25,58,59]. As mentioned above, the degradation of creatine can be limited or prevented when creatine is in very low or very high pH environments [25]. ...
... On the other hand, when pH is <2.5, the amide functional group on the creatine molecule is protonated and prevents the intramolecular cyclization (see Figure 5) [25]. Since stomach acid is generally less than 2.5, less than 1% of CrM is degraded to creatinine during digestion and 99% of creatine is taken up by tissue or excreted in urine after ingestion [12,25,58,59]. ...
... For example, when mixing CrM in solution, some CrM residue remains at the bottom of the glass requiring consumers to add more fluid, swirl, and quickly ingest to ensure they consumed all the creatine. While this has no effect on creatine bioavailability as CrM is nearly 100% bioavailable [12,25,58,59], there has been interest in finding ways to improve the solubility of creatine. The solubility of creatine in water increases linearly with increasing temperature. ...
Article
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In 2011, we published a paper providing an overview about the bioavailability, efficacy, and regulatory status of creatine monohydrate (CrM), as well as other “novel forms” of creatine that were being marketed at the time. This paper concluded that no other purported form of creatine had been shown to be a more effective source of creatine than CrM, and that CrM was recognized by international regulatory authorities as safe for use in dietary supplements. Moreover, that most purported “forms” of creatine that were being marketed at the time were either less bioavailable, less effective, more expensive, and/or not sufficiently studied in terms of safety and/or efficacy. We also provided examples of several “forms” of creatine that were being marketed that were not bioavailable sources of creatine or less effective than CrM in comparative effectiveness trials. We had hoped that this paper would encourage supplement manufacturers to use CrM in dietary supplements given the overwhelming efficacy and safety profile. Alternatively, encourage them to conduct research to show their purported “form” of creatine was a bioavailable, effective, and safe source of creatine before making unsubstantiated claims of greater efficacy and/or safety than CrM. Unfortunately, unsupported misrepresentations about the effectiveness and safety of various “forms” of creatine have continued. The purpose of this critical review is to: (1) provide an overview of the physiochemical properties, bioavailability, and safety of CrM; (2) describe the data needed to substantiate claims that a “novel form” of creatine is a bioavailable, effective, and safe source of creatine; (3) examine whether other marketed sources of creatine are more effective sources of creatine than CrM; (4) provide an update about the regulatory status of CrM and other purported sources of creatine sold as dietary supplements; and (5) provide guidance regarding the type of research needed to validate that a purported “new form” of creatine is a bioavailable, effective and safe source of creatine for dietary supplements. Based on this analysis, we categorized forms of creatine that are being sold as dietary supplements as either having strong, some, or no evidence of bioavailability and safety. As will be seen, CrM continues to be the only source of creatine that has substantial evidence to support bioavailability, efficacy, and safety. Additionally, CrM is the source of creatine recommended explicitly by professional societies and organizations and approved for use in global markets as a dietary ingredient or food additive.
... Creatine is a naturally occurring compound that is found predominantly in skeletal muscle [1][2][3][4][5][6]. There is a plethora of evidence that creatine supplementation is safe and effective [2]. ...
... There is a plethora of evidence that creatine supplementation is safe and effective [2]. Powdered or solid forms of creatine are more stable than aqueous solutions containing creatine [1,[7][8][9][10]. However, it is generally accepted that creatine consumed as a drink has better bioavailability [8,10,11]. ...
... Highly acidic environments can negatively affect the breakdown of creatine [2,7,13]. It has been suggested that creatine is absorbed in the gastrointestinal tract [1,6,10,14,15]. The acidic environment of the stomach could potentially lead to degradation of creatine leading to lower absorption and ultimately less uptake by muscles. There are few studies that have examined the bioavailability and absorption of creatine. ...
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The purpose of this study was to determine the relative pharmacokinetics of creatine monohydrate delivered as a formula or as a pure powder (all mixed in solution). A single 5 g bolus of creatine monohydrate was ingested as CreaBev 1, CreaBev 2, or creatine monohydrate. Participants we assigned a test product and monitored in a supervised laboratory setting for ingestion and all blood draws starting 30 min post-ingestion to the 6-h mark. Standard pharmacokinetic analysis was undertaken to determine relative maximum concentration (Cmax), time to maximum concentration (Tmax), and area under the curve (AUC) for the products. Cmax data indicate that CreaBev 1 10.55±4.10, CreaBev 2 15.45±5.48, and creatine monohydrate 12.77±4.0 nmol/h/μL. The Tmax analysis demonstrated CreaBev 1 1.20±1.01, CreaBev 2 1.23±0.65, and creatine monohydrate 0.91±0.2 h. The AUC data indicate that CreaBev 1 22.90±9.17, CreaBev 2 33.92±9.52, and creatine monohydrate 29.58±11.93 nmol/h/μL. When examining the data for pharmacokinetics, the AUC and Cmax pharmacokinetics were greatest for CreaBev 2 (p<0.021 and 0.020). Within the confines of this study, CreaBev 2 produced the highest blood concentrations of creatine as compared to creatine monohydrate and CreaBev 1.
... Exogenous creatine is digested, absorbed and metabolized in the gut and liver, where it is synthesized into endogenous creatine and then transported to other tissues by the creatine transport proteins (Persky et al. 2003). Creatine can be used to produce creatinine directly through a non-enzymatic reaction, or with the help of creatine kinase, which catalyses creatine into creatine phosphate (ck), which in turn produces creatinine (Nabuurs et al. 2013). ...
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High carbohydrate diets can affect the growth and metabolism of fish; e.g. decrease the concentration of liver betaine and cause disturbances in the creatine pathway, and damage the liver. Previous studies have shown that dietary betaine can effectively alleviate these negative effects. The aim of this study was to explore the effects of creatine on growth performance, liver health status, metabolites and gut microbiota in M. amblycephala . The results showed that supplementing creatine and betaine together reduced the feed conversion ratio significantly ( P < 0.05, compared to CD and HCD) and improved liver health (compared to HCD). Compared with the BET group, dietary creatine significantly increased the abundances of Firmicutes, Bacteroidota, ZOR0006 and Bacteroides , and decreased the abundances of Proteobacteria, Fusobacteriota, Vibrio , Crenobacter , and Shewanella in the CRE1 group. Dietary creatine increased the content of taurine, arginine, ornithine, γ-aminobutyric acid (g-ABA) and creatine (CRE1 vs. BET group), and the expression of creatine kinase ( ck ), sulfinoalanine decarboxylase ( csad ), guanidinoacetate N-methyltransferase ( gamt ), glycine amidinotransferas ( gatm ), agmatinase ( agmat ), diamine oxidase1 ( aoc1 ), and glutamate decarboxylase ( gad ) in the CRE1 group. Overall, these results suggested that dietary supplementation of creatine (0.5% − 2%) did not affect the growth performance, but it altered the gut microbial composition at the phylum and genus levels; it also increased the serum content of taurine by enhancing the activities of creatine metabolism and the CSA pathway, and increased the serum content of g-ABA by enhancing the activities of arginine metabolism, putrescine synthesis, and synthesis of g-ABA.
... Consequently, creatine is abundant in organs with high energy turnover, with ∼95% of the human body's creatine stores found in the skeletal muscle and the remaining 5% in the brain, liver, kidney, and testes (Rackayova et al., 2017;Wyss and Kaddurah-Daouk, 2000). The amount of total creatine stored in the human body is ∼120 g for an average sized individual, and ∼1.7% of total body creatine is lost per day (Brosnan et al., 2011;Persky et al., 2003). To compensate for this daily loss, an average person needs ∼2 g of creatine per day. ...
Article
Aims: There is evidence that both aging and increased adiposity may impact creatine levels in the brain, and brain cre-atine levels are important for cognition. The aim of this study was to assess correlation between dietary creatine intake and cognition in in elderly women with overweight. Methods: Twenty seven overweight women over 60 years of age who were part of a larger study participated in an Eriksen Flanker Task (EFT) to asssess cognitive performance. Additionally, diet was assessed over 5 days via daily diary nutritional recalls and the estimate of the daily amount of cre-atine was calculated. Results: In the EFT when incongruente stimulus were presented there was a significant diferences between those with low and high intake of creatine (−35.3 ± 5.84; p < 0.001). Similarly, reaction time to answer incon-gruent stimulus (r = −0.383; p = 0.004) and the percent of correct answers (r = 0.743; p < 0.001) showed weak to strong correlations with self-reported daily creatine intake. Conclusions: In conclusion, our results suggest that in elderly women with overweight that dietary intake of creatine may influence cognitive ability. Clinical Implications: Our findings support the idea that intake of dietary creatine may be an important factor for cognition in older adults.
... Indeed, plasma creatine rises after ingestion, followed by a reduction in plasma levels, indirectly suggesting increased uptake into the target tissue. However, data from the "gold standard" instruments for measuring the effects of creatine supplementation on target tissues, magnetic resonance spectroscopy (MRS), muscle biopsy, or stable isotope tracer studies are scanty (Harris et al., 2002;Jäger et al., 2007;Kreider et al., 2017) Pharmacokinetics of creatine absorption, half-life, and transport show that the time elapsed between plasma creatine's rise and fall can be up to 60 min (Deldicque et al., 2008;Harris et al., 2002;Persky et al., 2003), in addition, it appears that higher doses of orally consumed creatine result in lower bioavailability (Alraddadi et al., 2018). Also, the bioavailability of creatine appears to vary depending on the type of supplement (lower in creatine monohydrate vs. creatine pyruvate; Jäger et al., 2007). ...
Article
The purpose of this study was to test whether believed versus actual acute creatine ingestion impacted resistance exercise performance. Fifteen men (21.9 ± 2.7 years old) completed four bouts of three sets each of squat and bench press to volitional fatigue at a 10RM load with 1-min between-sets rest interval. Thirty minutes prior to each exercise bout, they received the following treatments in a randomized order: 1) nothing (CON); 2) 0.3 g·kg−1 dextrose placebo (PLC); 3) 0.3 g·kg−1 dextrose, identified as creatine (Cr-False); 4) 0.3 g·kg 20 −1 creatine, identified as creatine (CrTrue). Between-treatments comparisons included the total repetitions completed and the rate of perceived exertion. Results revealed (p < 0.05) higher repetitions performed for all treatments versus CON for both squat and bench press. In the squat, more repetitions were performed with Cr-True (p < 0.001) and CrFalse (p < 0.001) than with either CON or PLC. Bayes Factor analyses revealed strong (PLC to Cr-True BF = 19.1) and very strong (PLC to CrFalse BF = 45.3) posterior probability favouring positive effects for both "creatine" conditions over PLC for the squat. In conclusion, in acute measures, belief versus ingestion of creatine yields similar exercise performance. ARTICLE HISTORY
... Phosphocreatine can be rapidly catabolized via creatine kinase (CK) and acts as a metabolic intermediary of energy transfer by facilitating the rapid re-synthesis of adenosine triphosphate (ATP). The average amount of total creatine stored in the body is ∼120 g (for a 70 kg human) and the rate of creatine degradation to creatinine is ∼1.7% of the total body creatine pool per day (Brosnan et al., 2011;Persky et al., 2003). To compensate for this daily turnover, the average person requires ∼2 g of creatine per day, with about half of this daily requirement (1 g) synthesized endogenously and the remainder coming from dietary sources (Alraddadi et al., 2018;Candow et al., 2021;Ostojic and Forbes, 2022;Rackayova et al., 2017). ...
Article
Aims: The purpose was to examine the relationship between habitual dietary creatine intake obtained in food and visuo-spatial short-term memory (VSSM). Methods: Forty-two participants (32 females, 10 males; > 60 yrs of age) completed a 5-day dietary recall to estimate creatine intake and performed a cognitive assessment which included a visuospatial short-term memory test (forward and reverse corsi block test) and a mini-mental state examination (MMSE). Pearson correlation coefficients were determined. Further, cohorts were derived based on the median creatine intake. Results: There was a significant correlation between the forward Corsi (r = 0.703, P < 0.001), reverse Corsi (r = 0.715, P < 0.001), and the memory sub-component of the MMSE (r = 0.406, P = 0.004). A median creatine intake of 0.382 g/day was found. Participants consuming greater than the median had a significantly higher Corsi (P = 0.005) and reverse Corsi (P < 0.001) scores compared to participants ingesting less than the median. Conclusions: Dietary creatine intake is positively associated with measures of memory in older adults. Clinical Implications: Older adults should consider food sources containing creatine (i.e. red meat, seafood) due to the positive association with visuospatial short-term memory.
... Creatine is primarily distributed in skeletal muscle as either free creatine or phosphocreatine [1,4], where it functions as part of the phosphagen energy system to provide energy and facilitate ATP resynthesis via creatine kinase, in particular during very high intensity exercise [2,5]. Creatine absorption is mediated by sodium and chloride-dependent transporters where it is first absorbed in small intestines, then distributed throughout the body, where skeletal muscle serves as a primary reserve [6,7]. Exogenous creatine supplementation has been demonstrated to enhance intramuscular stores by 20-40% and elicit ergogenic effects [1][2][3]8]. ...
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Background Numerous studies have demonstrated the efficacy of creatine supplementation for improvements in exercise performance. Few studies, however, have examined the effects of phosphocreatine supplementation on exercise performance. Furthermore, while polyphenols have antioxidant and anti-inflammatory properties, little is known regarding the influence of polyphenol supplementation on muscular strength, power, and endurance. Thus, the purpose of the present study was to compare the effects of 28 days of supplementation with phosphocreatine disodium salts plus blueberry extract (PCDSB), creatine monohydrate (CM), and placebo on measures of muscular strength, power, and endurance. Methods Thirty-three men were randomly assigned to consume either PCDSB, CM, or placebo for 28 days. Peak torque (PT), average power (AP), and percent decline for peak torque (PT%) and average power (AP%) were assessed from a fatigue test consisting of 50 maximal, unilateral, isokinetic leg extensions at 180°·s − 1 before and after the 28 days of supplementation. Individual responses were assessed to examine the proportion of subjects that exceeded a minimal important difference (MID). Results The results demonstrated significant ( p < 0.05) improvements in PT for the PCDSB and CM groups from pre- (99.90 ± 22.47 N·m and 99.95 ± 22.50 N·m, respectively) to post-supplementation (119.22 ± 29.87 N·m and 111.97 ± 24.50 N·m, respectively), but no significant ( p = 0.112) change for the placebo group. The PCDSB and CM groups also exhibited significant improvements in AP from pre- (140.18 ± 32.08 W and 143.42 ± 33.84 W, respectively) to post-supplementation (170.12 ± 42.68 W and 159.78 ± 31.20 W, respectively), but no significant ( p = 0.279) change for the placebo group. A significantly ( p < 0.05) greater proportion of subjects in the PCDSB group exceeded the MID for PT compared to the placebo group, but there were no significant ( p > 0.05) differences in the proportion of subjects exceeding the MID between the CM and placebo groups or between the CM and PCDSB groups. Conclusions These findings indicated that for the group mean responses, 28 days of supplementation with both PCDSB and CM resulted in increases in PT and AP. The PCDSB, however, may have an advantage over CM when compared to the placebo group for the proportion of individuals that respond favorably to supplementation with meaningful increases in muscular strength.
Article
A controlled creatine-release system has been developed from whey protein-based gels. Their functionalization was carried out by aeration and sodium ions induced “cold gelation” processes. The effect of protein concentration in the aerated whey protein gels at pH 7.0 and 8.0 was analyzed. Physicochemical properties of the aerated gels were evaluated. It was possible to obtain the ions induced whey protein aerated gel with well distributed creatine and different microstructure as well as rheological properties. Different protein concentrations and pH enabled obtaining gels with different rheological properties, texture, air fraction, diameter of air bubbles, microstructure and surface roughness. An increase in the protein concentration enhanced the hardness of the samples, regardless of their pH. The mechanical strength of gels prepared at pH 8 were higher than those obtained at pH 7, as was manifested by the smaller storage modulus of the latter. The former gel exhibited a microstructure between particulate and fine-stranded. A stronger gel matrix produced smaller air bubbles. Aerated gels produced at pH 7.0 had higher roughness than those obtained at pH 8.0. Optimal conditions for inclusion of air bubbles into the gel matrix were: 9% protein concentration at pH 8.0 and this aerated gel was selected for digestion in the artificial stomach. There is a small conversion of creatine to creatinine in the artificial stomach digestion process (9.6% after 6 h). The diffusion of creatine crystals from the aerated gel matrix was the mechanism responsible for the release process. Aerated whey protein gels can be used as matrices for time extended releasing of creatine in the stomach.
Article
A creatina é uma substância produzida naturalmente pelo corpo e encontrada em alimentos de origem animal. É considerada um recurso ergogênico nutricional efetivo para aumento do desempenho e ganho de massa muscular. O presente estudo teve como objetivo descrever os principais mecanismos de ação da creatina, apresentando as doses recomendadas de suplementação, tempo de uso, possíveis efeitos colaterais e para quais tipos de exercícios a suplementação é recomendada. Trata-se de uma revisão narrativa da literatura que foi realizado a partir de publicações científicas em português e inglês oriundas das bases de dados PubMed®, SciElo® e Google Acadêmico®. Os estudos selecionados apontaram que a suplementação de creatina entre 3 a 5 gramas por dia pode proporcionar um aumento no volume de água nas células musculares, aumento de síntese proteica, aumento na expressão gênica de IGF-1 e o aumento de fatores miogênicos regulatórios, além de atuar em uma das vias metabólicas de fornecimento e reposição de energia, possibilitando aumento do rendimento no treino (principalmente naqueles de alta intensidade e curta duração) e aumento do ganho de massa muscular. A suplementação de creatina demonstra-se segura para indivíduos saudáveis, sendo válido ressaltar a importância do acompanhamento profissional para adequação das dosagens de acordo com as necessidades.
Article
Background In breast cancer survivors, chemotherapy-induced muscle loss has been shown to be attenuated with structured resistance exercise. Creatine supplementation can increase bioenergetics in skeletal muscle, which helps to improve overall strength and endurance and reduce muscular fatigue. Therefore, we hypothesize that adding creatinine supplementation to exercise training will accelerate improvements in strength, endurance, and bioenergetics in breast cancer survivors. Objective The primary objective is to determine the effects of combining creatine supplementation with exercise on modulating strength and physical function in breast cancer survivors by comparing these effects to those of exercise alone. The secondary objectives are to determine if creatine supplementation and exercise can increase the intramuscular storage of creatine and improve body composition by comparing this intervention to exercise alone. Methods We aim to test our hypothesis by conducting an open-label randomized controlled trial of 30 breast cancer survivors who have completed chemotherapy within 6 months of enrollment. Eligible participants will be equally randomized (1:1) to either a creatine and exercise group or an exercise-only group for this 12-week intervention. Individuals who are randomized to receive creatine will be initially dosed at 20 g per day for 7 days to boost the availability of creatine systemically. Thereafter, the dose will be reduced to 5 g per day for maintenance throughout the duration of the 12-week protocol. All participants will engage in 3 center-based exercise sessions, which will involve completing 3 sets of 8 to 12 repetitions on chest press, leg press, seated row, shoulder press, leg extension, and leg curl machines. The primary outcomes will include changes in strength, body composition, and physical function in breast cancer survivors. The secondary outcomes will be intramuscular concentrations of creatine and adenosine triphosphate in the vastus lateralis, midthigh cross-sectional area, and quality of life. Results As of October 2021, a total of 9 patients have been enrolled into the study. No unexpected adverse events have been reported. Conclusions Creatine is being studied as a potential agent for improving strength, endurance, and bioenergetics in breast cancer survivors following chemotherapy. The findings from our trial may have future implications for supporting breast cancer survivors in reversing the muscle loss experienced during chemotherapy and improving their physical function and quality of life. Trial Registration ClinicalTrials.gov NCT04207359; https://clinicaltrials.gov/ct2/show/NCT04207359 International Registered Report Identifier (IRRID) PRR1-10.2196/26827
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Proton magnetic resonance spectroscopy (MRS) was employed to determine the concentrations of N-acetylaspartate (NAA), total creatine (tCr), choline-containing compounds (Cho), myo-inositol (Ins), glucose (Glc), and lactate (Lac) in rat brain before and after 10 days of oral supplementation of 2.6 g Cr-monohydrate per kg body weight per day. Measurements were performed both in vitro (n = 16) and in vivo (n = 6), The neuroprotective potential of oral Cr was assessed by dynamically monitoring brain Glc and Lac in response to transient global ischemia (12 min). In comparison to controls the in vitro concentrations of Cr (13.1 +/- 9.3%) and Ins (12.7 +/- 14.0%) were significantly increased in Cr-fed rats. Under in vivo conditions, the data revealed trends for elevated tCr (4.7%) and Ins (10.6%) which were enhanced in the concentration ratios of tCr:Cho (10.2%) and Ins:Cho (17.8%). Together with an increased Glc level (27.3%), the observation of a statistically significant decrease of brain Lac (-38.5 +/- 19.3%) in Cr-fed rats may reflect a shift of the energy metabolism from non-oxidative toward oxidative glycolysis. One hour after global ischemia most of the metabolic differences between Cr-fed rats and controls were retained. The increased Glc level (44.4 +/- 33.3%) reached statistical significance, but the accumulation of Lac and its time course during ischemia and early reperfusion showed no differences between Cr-fed rats and controls. Copyright (C) 1999 John Wiley & Sons, Ltd.
Article
The purpose of this study was to examine the effects of creatine supplementation on exercise performance and maximal isometric muscular strength in 20 ALS patients. Dynamometric measurement of 12 muscular groups of upper and lower limbs were obtained by using a device developed in our institute which consists of a force transducer and a mechanical structure to counteract movements. A high-intensity, intermittent protocol was also chosen to test fatigue in elbow flexors and knee extensors muscles. All examinations were performed by 2 registered physical therapists at entry and 2 days later to assess the learning effect. All patients completed the protocols after creatine supplementation of 20 g per day for 7 days and after creatine supplementation of 3 g per day for 3 months. ALS- FRS and Norris scale were computed at each control. In the short period, diarrhea was the most common side effect, while in the long term water retention was observed in 10% of patients. A total of 20% of subjects experienced an increase in fasciculations. The maximal peak of strength significantly increased in 25% of patients and fatigue significantly decreased in 40% of patients after creatine supplementation in the short term (7 days). In the other patients we did not observe any changes. No effects were evident in the long term (3 months); in particular, muscular strength showed a linear, progressive decline. No significant correlations were found with clinical and functional variables. We think that, as demonstrated by the research in normal subjects, some patients respond to creatine supplementation, while others can be considered nonresponders. However, further studies in a larger population of patients are needed to verify this data and likely to identify the clinical characteristics of the two groups.
Article
Creatine metabolism was studied in relation to creatine intake and creatinine excretion. Young men were fed 0.23 g creatine/day for 9 days and then 10 g/day for 10 days consecutively. Thereafter, the diet fed was creatine free. From day 81 through 90, isonitrogenous amounts (4 g N/day) of either an equimolar mixture of the creatine precursors arginine and glycine or of alanine were added to the diet. As reported in a previous paper, creatinine excretion increased during creatine feeding, continued to remain elevated immediately afterwards and then decreased gradually during the period of feeding the creatine free diet, whereas two subjects not fed creatine showed no significant changes in creatinine output throughout the experiment. The present paper describes studies in which di 15N creatine was injected into the same subjects on two occasions during the creatine free period, near the beginning of this period and 43 days later. By isotope dilution, the creatine pool sizes were calculated and the rate of conversion of this pool to creatinine was computed. The pool of body creatine diminished during the creatine free period in parallel with the daily output of creatinine, that is, the fractional rate of conversion of creatine to creatinine was very similar for all subjects (0.0169±0.0006 day-1, n = 13). In contrast to the marked constancy of the rate of conversion of creatine to creatinine, apparent fractional creatine synthesis rates were much more variable between subjects (0.011 to 0.016 day-1). Administration of the creatine precursors arginine and glycine significantly increased apparent creatine synthesis, whereas administration of alanine depressed synthesis. From these data on di 15N creatine metabolism, it can be concluded that the size of the body pool of creatine can be influenced by dietary creatine, administration of precursor amino acids can increase the rate of synthesis of creatine, creatinine output is a constant fraction of the body creatine pool and can change independently of lean body mass.
Article
The cellular role of creatine (Cr) and Cr phosphate (CrP) has been studied extensively in neural, cardiac and skeletal muscle. Several studies have demonstrated that alterations in the cellular total Cr (Cr + CrP) concentration in these tissues can produce marked functional and/or structural change. The primary aim of this review was to critically evaluate the literature that has examined the regulation of cellular total Cr content. In particular, the review focuses on the regulation of the activity and gene expression of the Cr transporter (CreaT), which is primarily responsible for cellular Cr uptake. Two CreaT genes (CreaT1 and CreaT2) have been identified and their chromosomal location and DNA sequencing have been completed. From these data, putative structures of the CreaT proteins have been formulated. Transcription products of the CreaT2 gene are expressed exclusively in the testes, whereas CreaT1 transcripts are found in a variety of tissues. Recent research has measured the expression of the CreaT1 protein in several tissues including neural, cardiac and skeletal muscle. There is very little information available about the factors regulating CreaT gene expression. There is some evidence that suggests the intracellular Cr concentration may be involved in the regulatory process but there is much more to learn before this process is understood. The activity of the CreaT protein is controlled by many factors. These include substrate concentration, transmembrane Na^+ gradients, cellular location, and various hormones. It is also likely that transporter activity is influenced by its phosphorylation state and by its interaction with other plasma membrane proteins. The extent of CreaT protein glycosylation may vary within cells, the functional significance of which remains unclear.
Article
GA is an autosomal recessive disorder with characteristic chorioretinal degeneration; atrophy and tubular aggregates in type II muscle fibers; 10-20 fold increase in ornithine concentration in body fluids; and deficient activity of ornithine-δ-aminotransferase. Based on the inhibition by high ornithine concentration of the rate-limiting enzyme of creatine synthesis, the low excretion of the reaction product (guanidinoacetic acid), and low serum and urinary concentrations of creatine and creatinine in the patients, creatine and creatine phosphate deficiency has been suggested to be involved in the pathogenesis of GA. We supplemented 13 patients (age 6-31 years) with creatine, 0.5 g × 3 daily for 36-72 months. Deterioration of visual function tests and fundus photographs was seen during the treatment, apparently with similar velocity as in untreated cases. Deterioration varied considerably among individuals, being fastest in the youngest patients. Muscle abnormalities decreased or disappeared within months of the initiation of the therapy; changes reappeared in two who discontinued supplementation. Differences in creatine responses in the two organs may depend on too small creatine dosage, impermeability of blood-eye barrier for creatine, or on different mechanisms of the atrophy in muscle and eye.
Article
Creatine is a nutraceutical that has gained popularity in both well-trained and casual athletes for its performance-enhancing or ergogenic properties. The major disadvantages of creatine monohydrate formulations are poor solubility and oral bioavailability. In the present study, creatine transport was examined using Caco-2 monolayers as an in vitro model for intestinal absorption. Confluent monolayers of Caco-2 cells (passage 25–35) were used for the permeability studies. Monolayers were placed in side-by-side diffusion chambers. 14C-Creatine (0.1–0.5 μCi/mL) was added to either the apical or basolateral side, and the transport of the creatine across the Caco-2 monolayer was measured over a 90-min period. The apical to basolateral transport of 14C-creatine was small, ranging from 0.2–3% of the original amount appearing on the receiver side in a 90-min period. Interestingly, the basolateral to apical permeability of radiolabeled creatine was substantially greater than that observed in the apical to basolateral direction. Studies with drug efflux transport inhibitors indicate that neither the P-glycoprotein nor multidrug resistance-associated protein is involved in the enhanced basolateral to apical transport of creatine. © 2001 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 90:1593–1598, 2001
Article
Fatigue in patients with mitochondrial cytopathies is associated with decreased basal and postactivity muscle phosphocreatine (PCr). Creatine monohydrate supplementation has been shown to increase muscle PCr and high-intensity power output in healthy subjects. We studied the effects of creatine monohydrate administration (5 g PO b.i.d. × 14 days → 2 g PO b.i.d. × 7 days) in 7 mitochondrial cytopathy patients using a randomized, crossover design. Measurements included: activities of daily living (visual analog scale); ischemic isometric handgrip strength (1 min); basal and postischemic exercise lactate; evoked and voluntary contraction strength of the dorsiflexors; nonischemic, isometric, dorsiflexion torque (NIDFT, 2 min); and aerobic cycle ergometry with pre- and post-lactate measurements. Creatine treatment resulted in significantly (P < 0.05) increased handgrip strength, NIDFT, and postexercise lactate, with no changes in the other measured variables. We concluded that creatine monohydrate increased the strength of high-intensity anaerobic and aerobic type activities in patients with mitochondrial cytopathies but had no apparent effects upon lower intensity aerobic activities. © 1997 John Wiley & Sons, Inc. Muscle Nerve20: 1502–1509, 1997