THE FATE OF CREATINE WHEN ADMINISTERED TO MAN.

BY ALFRED CHANUTIN.
WITH THE ASSISTANCE OF LOREN P. GUY.
(From the Laboratory of Physiological Chemistry, University of Virginia,
University.)
(Received for publication, October 22, 1925.)

The fate of creatine in the organism has been the subject of

many investigations. A recent, review of the literature on this
subject discloses conflicting ideas concerning creatine-creatinine
metabolism. The apparent inconsistencies may be ascribed to
several factors, the most outstanding being the varying quantities
of creatine administered, usually quite small, together with the
fact that administration of the substance was not continued
over a sufficiently long period. In most cases the difficulty and
expense of isolating pure creatine limited the amount which could
be used for experimentation.
It is possible t.o omit much of the literature since one may
refer to the excellent review on this subject by Hunter (1). In
his classic paper Folin (2) concluded that creatine and creatinine
were independent of one another in metabolism, and that the
former was utilized as a food. However, the results of later
investigations, particularly those of Rose and Dimmitt (3) and
Benedict and Osterberg (4), have shown that ingestion of creatine
may lead to an increased output of creatinine in the urine. This
evidence coupled with the fact that the creatinine found in mus-
cular tissue is apparently derived from the “crcatine complex”
by the action of enzymes, leads one to believe that urinary creati-
nine must depend upon creatine as its precursor.
The possibility of creatine acting as an anabolite has been
shown by Benedict and Osterberg (-1). Dogs that were fed on a
basal diet to which creatine was added not only gained weight
but showed a marked positive nitrogen balance. The evidence
obtained in these experiments seems to indicate that creat,ine
may serve as a food, which would confirm the idea advanced by
Folin (2) in 1906.
29

This is an Open Access article under the CC BY license.

30 Creatine

In this investigation, we carried out feeding experiments with

creatine on man. The results obtained show definitely that creat-
ine and creatinine are not independent of one another in the body.
Furthermore, these experiments demonstrate that a major portion
of the creatine retained by the tissues may be converted to creat-
inine. Proof is given that creatine may spare protein.

EXPERIMENTAL PROCEDURE.

The writers served as the subjects for the present experiments,

subsisting upon a creatine-free diet for 6 and 8 weeks respectively.
The diet, consisting of shredded wheat, bananas, bread, butter,
strawberry preserves, sugar, and milk, represented an intake of
approximately 3400 calories. The diet was adhered to strictly
with respect to its composition. During the experiment, daily
exercise was part of the regular routine. The type of exercise
indulged in was not strenuous and varied from day to day.
It was found that the nausea induced by the bitter taste of
the creatine could best be avoided by dissolving it in hot weak
tea. The creatine was taken about 2 hours after the noon meal.
By recrystallizing commercial creatine twice, the resulting product
was found to be pure upon analysis.
The urines collected at the end of 24 hours were diluted to the
same volume each day with a few exceptions. Total nitrogen
was estimated by the macro Kjeldahl-Gunning method and
creatinine by the Folin method. Creatine was determined by
the autoclave method of Folin. Creatinine zinc chloride was
used as a standard for the creatine and creatinine determina-
tions. Ammonia nitrogen was estimated by the procedure of
Van Slyke and Cullen.
In order to be certain that the body was in nitrogen equilib-
rium the experimental diet was begun 2 weeks before the first
sample of urine was collected. After a satisfactory control
period during which the urinary constituents studied were fairly
constant, the administration of creatine was begun.
The detailed results of the experiments are recorded in Tables
I and II. The experimental periods lasted ~9 and 44 days during
which time 250 and 340 gm. of creatine, respectively, were in-
gested. The analyses for July 12 cannot be considered because
 A. Chanutin 31
of a mistake made in taking unknown quantities of creatine on
the previous day. These data have been omitted from the
averages obtained for this period.

Results.
During the first few days of creatine feeding its retention by
the body is striking. A gradual decrease in retention may be
noted, however, as the experiment proceeds. On the other hand}
the extra creatinine eliminated rises slowly towards a maximum
level. It is interesting to note that the smallest creatine and
extra creatinine output during the entire experiment is obtained
after the 1st day of creatine feeding. If creatinine is to be con-
sidered as the end-product of creatine metabolism we must as-
sume that creatine may be stored without any appreciable break-
down.
Apparently the ability of the tissues to store creatine should
reach its maximum after the daily ingestion of 10 gm, of creatine
over a period lasting more than a week. At this point Subject
A. C. (Table I) doubled the daily dose of creatine fed. The
figures for the extra creatinine eliminated and the creatine re-
tained both show marked increases. In fact the output of
extra creatinine on the 2nd day of this period shows an in-
crease of about 160 per cent over the control period. We
believe this figure represents the largest percentage creatinine
output due to creatine feeding recorded in the literature. The
unexpected increased retention of creatine indicates that the
creatine reservoir may be larger than has been hitherto thought
possible. As the period progresses the amount of creatine re-
tained becomes smaller.
At the end of an 8 day period during which time 160 gm. of
creatine were taken, the daily dose was dropped back to 10 gm.
Although this period lasted but 2 days evidence regarding creatine
storage in the body is given. The excretion of creatine was
greater than the intake on the 1st day.
Subject L. P. G. continued to consume 10 gm. of creatine daily
over a period of 34 days. In Table II it is seen that the creatine
and creatinine excretion rose slowly until a fairly even level was
reached at about the end of the first period. Although the
THE JOURNAL OF BIOLOGICAL CHEMISTRY, VOL. LXVII, No.1
 TABLE I.
Experiment 1. Fate of Ingested Creatine. CI:i
Subject A. C. l:>.?

The figures for creatine are expressed as creatinine.

.i, ""d""d
<li
.S .S "...,
"''''
.~ ol
.,; ~.S
<li <li "
~ '" ".S'" .- '"
1:l S .
Date. "
'0:

-a'"
"
"
';3
:;;
...'" .
'"
""d 'e""
+>
"
:;;
ol
-~"
~ ~:g
~
bJ)"'+>
0 <li
:i '" ~~ ~.S ~
"'"
S .S ...;
:;; """'"
;; ;; .8 1< e ~~ ",ol"
C~O'..I ""
.~

~"
P1 ...
b b
0'" Q'"
1:l "k" ~o~
Eo< Z
Eo< Po< j:il Po< ~'"
-- -- -- -- -- --- --
1925 CC. gm. gm. gm. gm. gm. gm. gm. per cent kg.

June 20 70.4 (1
" 29 72.0 C6
~.....
July 1 840 7.80 0.327 1.49 1.49 Preliminary period of 7 days.
" 2 850 7.77 0.271 1.52 1.52 No creatine given. &
" 3 1,020 7.82 0.339 1.54 1.54
" 4 730 7.41 0.315 1.55 1.55
" 5 590 7.53 0.347 1.46 1.46
" 6 685 7.66 0.241 1.49 1.49 72.0
" 7 470 7.42
-- --
0.336 1. 53
-- --
1.53
7.62 0.311 1. 51 1. 51 Average daily output.

July 8 690 9.04 0.378 4.44 1.73 2.71 5.91 0.22

" 9 595 8.60 0.436 5.26 1.96 3.30 5.32 0.45
" 10 1,090 9.57 0.554 6.12 2.14 3.98 4.64 0.63 First period of creatine administration.
" 11 970 9.70 0.571 6.53 1.90 4.63 3.99 0.39 10 gm. of creatine (8.62 gm, creatinine)
" 12* 740 8.32 0.549 2.96 1. 73 1. 23 ingested daily.
July 13 715 8.82 0.420 5.84 2.22 3.62 5.00 0.71
" 14 610 9.13 0.431 6.15 2.17 3.98 4.64 0.66
" 15 735 9.02 0.532 6.16 2.26 3.90 4.72 0.75
" 16 710 8.96 0.473 7.14 2.32 4.82 3.80 0.81
" 17 650 9.46
-- --
0.448 8.11 2.32 5.79
-- - - - - - - -
2.83 0.81
--
9.14 0.471 6.19 2.10 4.08 4.54 0.60 13 Average daily output.

July 18 1,200 12.56 0.445 16.38 3.59 12.79 4.45 2.08

" 19 1,240 12.56 0.445 15.54 4.05 11.49 5.75 2.54 Second period of creatine administration.
" 20 780 12.12 0.420 16.12 3.88 12.24 500 2.37 74.0 20 gm. of creatine (17.24 gm. creatinine)
" 21 990 12.37 0.414 17.24 3.66 13.58 3.66 2.15 ingested daily. ~
" 22 860 11.80 0.381 15.87 3.46 12.41 4.83 1.95
oP'"
" 23 930 12.37 0.398 16.00 2.74 13.26 3 98 1. 23
" 24 960 12.88 0.386 16.00 2.70 13.30 3.94 1.19 !l'
" 25 1,275 12.31
--
0.487 18.45
-- -- -- --
12.37 0.422 16.45 3.44
3.42 15.03
13.01
2.21
--- --
4.23
1 91
1. 93 45 Average daily output.
~.....
~

July 26 940 9.99 0.429 11.69 2.32 9.32 -0.70 0.81 Third period of creatine administration.
" 27 670 9.48 0.429 11.17 3.02 8.15 0.47 1. 51 10 gm. creatine (8.62 gm, creatinine)
-- -- -- -- -- --- -- ingested daily.
9.73 0.429 11.43 2.67 8.73 -0.12 1.16 Average daily output.
July 28 490 7.14 0.420 4.62 2.20 2.42 0.69 75.2 Fourth period. No creatine ingested.
" 29 620 8.03 0.408 2.80 2.12 0.68 0.61
-7.58
- -0.414
- -- --
3.71 2.16
--
1. 55 0.65 Average daily output.
* Figures for day not averaged. ~
~
 TABLE II.
Experiment 2. Fate of Ingested Creatine. C/.:)
Subject L. P. G. I+>-
The figures for creatine are expressed as creatinine.
"d"d
~ :§ ""
0:""
'OJ11
'S .,; 'iil .,.,.~

.~
Date.
~
'5 .S 1 l
11 .S0:
:g
e.§ a;
.... -0:
ow ....
~<I)~
'0 1.., z
"d
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.S ~1S ~'''''Q)

.
8 "'oem.., ~
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~ Z ~
;:l
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-----\---,---,---,---
e o
1<0:
ril ~
--------,---'---1---------------------
/925 cc. am, 1 qm, qm, 1 gm. gm. gm. gm. Iper cent I kg.

June20 68.5 Q
" 29 68.5 >-oj
(p

~......
July 1 670 8.69 0.476 1. 66 1.66
" 2 770 7.69 0.256 1.49 1.49 g
" 3 750 8.40 0.268 1. 77 1. 77
" 4 620 8.42 0.336 1.65 1. 65 Preliminary period of 7 days.
" 5 510 7.91 0.282 1.60 1.60
" 6 520 7.20 0.370 1.54 1.54 69.5 No creatine given.
" 7 530 7.80 0.402 1. 60 1. 60
8.0110.3411 1.611 1.61 Average daily output.

July 8 575 7.91 0.260 3.64 1.82 1.82 6.80 0.21

" 9 550 8.37 0.380 4.32 1.85 2.47 6.15 0.24
" 10 670 8.22 0.424 5.63 2.22 3.41 5.21 0.61
" 11 640 9.18 0.409 5.40 1. 98 3.42 5.20 0.37
" 12* 1,810 10.41 0.437 8.42 2.22
July 13 520 8.93 0.526 6.10 2.38 3.72 4.90 0.77 First period of creatine administration.
" 14 640 1O.~4 0.632 6.50 2.24 4.26 4.36 0.63 10 gm. creatine (8.62 gm. creatinine)
" 15 1,100 11.05 0.646 7.94 2.65 5.29 3.33 1.04 ingested daily.
" 16 725 9.48 0.504 8.42 2.47 5.95 2.67 0.86
" 17 685 9.60 0.454 9.42 2.52 6.90 1.72 0.91
-- -- -- -- -- --- --
9.29 0.423 6.37 2.24 4.14 4.48 0.62 14 Average daily output.

July 18 810 10.50 0.330 9.61 2.72 6.89 1.73 1.11

" 19 940 10.95 0.314 9.05 2.84 6.21 2.41 1.23 Second period of creatine administration.
" 20 1,085 11.00 0.336 9.44 2.86 6.58 2.02 1.25 70.7 10 gm, creatine (8.62 gm. creatinine)
" 21 930 10.90 0.252 9.62 2.54 7.08 1.54 0.93 ingested daily.
" 22 830 10.54 0.151 9.62 2.88 6.74 1.88 1.27
" 23 845 10.40 0.263 9.90 2.24 7.66 0.96 0.63
" 24 830 10.28 0.400 9.56 2.28 7.28 1.34 0.67 ?>
" 25
" 26
840
1,120
10.69
10.58
0.336 10.20 2.66 7.54 1.08 1.05
0.292 12.78 4.04 8.74 -0.12 2.43 Q
" 27 730 9.70 0.375 11.23 3.22 8.01 0.61 1. 61 ~
-- -- -- -- -- --- -- g.
.....
10.55 0.305 10.10 2.85 7.27 1.35 1.22 90 Average daily output.
~

July 28 630 9.46 0.325 9.22 2.72 6.50 2.12 1.11 71.0
" 29 860 10.66 0.263 10.63 2.52 8.11 0.51 0.91
" 30 930 10.79 0.379 10.33 2.78 7.55 1.07 1.17 Third period of creatine administration.
" 31 1,720 10.92 0.405 10.00 2.84 7.16 1.45 1.23 10 gm. creatine (8.62 gm. creatinine)
Aug. 1 2,720 11.59 0.403 15.40 2.81 12.59 -3.97 1. 20 ingested daily.
" 2 2,290 10.75 0.386 9.10 2.74 6.36 2.26 1.13
" 3 1,500 10.92 0.241 9.96 2.54 7.42 1.20 0.93 71.5
" 4 1,080 10.88 0.336 8.32 2.63 5.69 2.93 1.02
" 5 870 9.49 0.329 10.92 2.36 8.56 0.04 0.75
" 6 860 10.86 0.325 10.53 2.46 8.07 0.55 0.85 C/.j
-- -- -- -- -- --- -- i;.rI
10.63 0.339 1044 2.64 7.80 0.816 1.03 126 Average daily output.
 CN
OJ

TABLE II-Concluded.
oj .§ 1"0"0
<1 "''''-:d
.S
'8 -ti ~ -S.S
~ ~
oj ~ S .
<1
'8 ~
'"
.S '"
<1 .~
--<1 '"
Date. "§ :;; 0 ~.... :§ o ~ .....
<1
"0 ~ ~(l):Z
'0
:i "~ '"
S
oj
<1 '"
.S
~
0"0
. .g.S ill
,,""' ~
'"
S
0
....
.a :g ~
,,$ ","0 ....

'" ""0 k"" ~~~~

.!?P
~"
"'0" ci3 '"
Q'"
....
~ .... ....
E-< Z E-< ~ Q :£
1925 CC.
---
gm.
--
gm.
---
gm.
- - --- - - -
gm. gm. gm.
""
- - --- - -
gm. per cent kg.

Aug. 7 830 10.22 0.375 10.00 2.46 7.54 1.08 0.85 Fourth period of creatine administration c:
I-j
" 8 690 9.86 0.386 8.86 2.34 6.52 2.10 0.73 10 gm. creatine (8.62 gm. creatinine:
" 9 690 9.88 0.389 9.33 2.38 6.95 1. 67 0.77 ingested daily. ~.......
" 10 710 10.60 0.347 11.40 2.80 8.60 0.02 1.19 72.0 g
" 11 540 9.74 0.342 10.72 2.72 8.00 0.62 1.11
-- -- -- -- -- --- --
10.06 0.368 10.06 2.54 7.52 1.09 0.93 85 Average daily output.

Aug. 12 500 9.46 0.386 3.15 2.34 0.81 0.73 Fifth period. No creatine ingested.
" 13 680 8.30 0.364 2.50 2.30 0.20 0.69 72.3
--- - - - - - - --- --
8.88 0.375 2.82 2.32 0.50 0.71 Average daily output.

* Figures for day not averaged.

 A. Chanutin 37
figures for creatinine elimination show slight daily variations
throughout the remainder of the experiment, the averages ob-
tained for the various periods correspond closely. On further
analysis of the data it will be seen that the amount of extra
creatinine eliminated is almost the same as that of creatine re-
tained (in terms of creatinine). During the first period 14 per
cent of the creatine retained was recovered as extra creatinine.
The second, third, and fourth periods show a conversion of 90,
126, and 85 per cent. In Subject A. C. 45 per cent of the retained
creatine is converted to creatinine during the second period.
These data would lead us to conclude that a considerable portion
of the creatine retained by the body may be transformed to its
anhydride during the metabolic cycle under the conditions of
these experiments.
The work of Fowler and Hawk (5) showed that creatine ap-
pears in the urine of normal adults after copious water drinking.
Large quantities of water were drunk by Subject L. P. G. to
note what effect it would have on creatine excretion. On August
1 this subject secreted 2720 cc. of urine which was accompanied
by an increase over the preceding day of more than 5 gm. of
creatine. An almost corresponding diuresis on the following day
failed to produce this result again. No effect on creatinine
excretion was noted.
In Tables III and IV the results are summarized in terms of
nitrogen elimination. The figures for the nitrogen balance are
significant. In estimating the nitrogen derived from ingested
creatine, it is necessary to include the extra creatinine. Hence
the addition of the average for the basal total nitrogen plus the
nitrogen of total creatine and extra creatinine should give the
theoretical total nitrogen elimination. The results show that
the figures obtained for total nitrogen are much lower than would
be expected. The feeding of creatine seems to act as a protein
sparer. Although the creatine retained is for the most part
converted to creatinine (Subject L. P. G.), the evidence still
points to a storing of nitrogen. Benedict and Osterberg (4)
suggest that "creatine may cause nitrogen storage in the body
far beyond that contained in creatine itself."
During the experimental period both subjects increased steadily
in weight (Tables I and II). An increase of about 3 kilos in
38 Creatine
TABLE III.
Results Summarized in Terms of Nitrogen Output.
Subject A.C.
The figures are for the average daily output.
~'§
'"0
'"
:0;..
.8
:i
.., ~
:i "
~ ·S" . J.i
ec .8'"
Period.
"'"
·Z
"
2:Z
o. ~Z
"'- :sZ'"
~ '"0 :i ~ Z.S Z~
eo '" ~ ~.~.-d ~.8
:i
~ .-i% :s"'"
2J
~ ~i~ '"
:Ii
0
~ fZ ~ ~ f:;'~1=l H
'"
- - - - - - - -t5-
<'-< p.. ~ Q Q
--- ------
om. am. am. am. a-m; um. um. am,
Preliminary 7.62 0.56 0.56
(7 days).
I (10 days). 9.14 2.29 0.78 1.51 0.22 1.73 9.35 3.71
II ( 8 " ). 12.37 6.10 1.27 4.83 0.72 5.55 13.17 7.42
III ( 2 " ) . 9.73 4.24 0.99 3.24 0.43 3.67 11.29 3.71
IV ( 2 " ) . 7.58 1.37 0.80 0.58 0.24 0.82 8.44

TABLE IV.
Results Summarized in Terms of Nitrogen Output.
Subject L. P. G.
The figures are for the average daily output.

~'§
'"0
.8'"
't'<l"
:i .8 :i :~
Period.
'"
'a"
't<l
~ 'a"'" -a,Z
·S" .
~Z
"'-
j
:i :+l z1l z
:i 1 '"0
'"
S
H
:s"e'"
'c"
e !=l'a .
0· ..... .-0
:;;i$
z~
~~
·•... 00
'"
.8
~ ""'''
<il <il ~
~ ~
]z
p.. Q
e~~
~ 0'" Q 0
"'-
eO. H

--- --- --- - - - - --- - -

um, um. am, um. am, m. om. um. u
Preliminary 8.01 0.60 0.60
(7 days).
I (10 days). 9.29 2.36 0.83 1.53 0.23 1.76 9.77 3.71
II (10 " ) . 10.55 3.75 1.05 2.69 0.45 3.14 11.15 3.71
III (10 " ) . 10.63 3.88 0.98 2.89 0.38 3.27 11.28 3.71
IV ( 5 " ) . 10.06 3.73 0.94 2.79 0.35 3.14 11.15 3.71
V ( 2 " ).
I 8.88 1.05 0.86 0.19 0.26 0.45 8.46

body weight during a short experimental period is rather unusual.

This addition of weight is noted during the ingestion of the basal
diet, but we are inclined to believe that much of the subsequent
 A. Chanutin 39

increase is related in some way to creatine ingestion. These

results are suggestive and might stimulate further research under
more carefully controlled conditions.
DISCUSSION.

A discussion of the creatine-creatinine metabolism must of

necessity be of somewhat hypothetical nature because of the num-
ber of unknown factors to be dealt with. In order to study this
problem these experiments were made under fairly constant con-
ditions by flooding the organism with a large excess of creatine.
The present research has shown that when creatine is given to
normal adults in large doses per as, a definite transformation of
creatine to creatinine is possible. No definite percentage trans-
formation can be postulated since the reaction apparently de-
pends entirely upon the equilibrium established in the "active
tissue." No marked increase in extra creatinine is noted until
the body has retained much of the creatine administered. Ac-
cordingly, it is not surprising that small doses, which undoubtedly
can be easily retained in a creatine reservoir, would not be traced
by analysis of the urine. Mter small doses, creatine may pos-
sibly be stored and metabolized slowly, just as fat or glycogen
which has been deposited in its respective depots.
The significance of creatine in the tissues is unknown, although
it is present in relatively large amounts. Its behavior in disease,
muscular exercise, protein feeding, and fasting would lead one to
assume that there is a close relationship with protein metabolism.
These experiments suggest that creatine, in some manner, may
under certain conditions, playa role in determining the nitrogen
balance of the organism. It is unlikely that much, if any, crea-
tine is converted to protein since extra creatinine continues to be
excreted after creatine ingestion is stopped. The relationship
of creatine storage to protein metabolism cannot be postulated
without more definite evidence.
If creatine can be stored in the tissues we can calculate roughly
the quantity retained. Of the 340 gm. of creatine taken by
Subject L. P. G., it is found that 38 gm. are held by the body
at the end of the experiment. Subject A. C. retained 58 gm. of
creatine after taking 270 gm. The apparent discrepancy in
results is due to the time in which the body was allowed to react
40 Creatine
to the respective quantities of creatine taken. Since the subjects
each weighed about 70 kilos, the creatine content of the muscles
may be calculated roughly at about 115 gm, This would mean
that there was increased storage in the muscles amounting to about
33 and 50 per cent. This retention does not seem improbable
in the light of the experiments of Folin and Denis (6) and Myers
and Fine (7), who demonstrated that muscles could hold, tem-
porarily, at least, even larger quantities of added creatine than
have been noted in these experiments.
The inability to discover the fate of small quantities of creatine
is responsible for the theory that creatine is destroyed in the
alimentary tract through bacterial action. Folin (2) was unable
to find any trace of creatine in the feces after feeding. The
experiments of Rose and Dimmitt (3) indicate that creatine is
not decomposed in the alimentary tract since there is no appreci-
able increase in urinary urea or ammonia. The figures obtained
lor the conversion of retained creatine to creatinine in these
experiments would lead us to assume that creatine is completely
absorbed from the alimentary tract, carried to the tissues,
and either stored there or rejected at once and eliminated through
the kidneys.
It is a generally accepted fact that there is an active mass
of tissue where creatine is built up and stored as an unstable
complex form which apparently has an important role in the
normal functioning of the protoplasmic mass. The organism
under normal conditions apparently has its full quota of creatine.
However, it seems that the tissues can completely store a small
amount of ingested creatine during a limited period of feeding.
Large amounts are only partially retained-a retention which
depends entirely upon the period of administration. Metabolic
studies would lead one to suggest that stored creatine may act
as an anabolite in protein metabolism. We believe that an anal-
ogy may be drawn between creatine and glucose metabolism.
Small quantities of both these substances are completely retained
by the body after being fed. Upon increasing the dosage, both
substances will appear in the urine in amounts depending entirely
on the quantities ingested. Glucose is stored as the polysac-
charide glycogen and it is probable that creatine may be built
up in a similar manner to a polycreatine compound. Whereas
 A. Chanutin 41

glucose is broken down to CO2 and H 20, the end-product of

creatine metabolism is creatinine in all likelihood or some creati-
nine precursor. Undoubtedly both these reactions take place
through the action of enzymes. Creatine may thus be stored
as a reserve food material and utilized very slowly until the
normal level is reached.

SUMMARY AND CONCLUSIONS.

1. The absorption of creatine from the alimentary tract ap-

pears to be complete. There is no evidence of its bacterial de-
struction in the alimentary tract.
2. The creatinine content of the urine in man increases after
ingestion of large doses of creatine. Data are presented to prove
that extra creatinine excretion is derived directly from the creatine
fed.
3. Evidence is presented to indicate that creatine has an in-
direct action on nitrogen metabolism.

BIBLIOGRAPHY.

1. Hunter, A., Physiol. Rev., 1922, ii, 586.

2. Folin, 0., in Hammarsten, 0., Festschrift, Upsala, 1906, pt. 3,1.
3. Rose, W. C., and Dimmitt, F. W., J. Biol. Chem., 1916, xxvi, 345.
4. Benedict, S. R., and Osterberg, E., J. Biol. Chem., 1923, lvi, 229.
5. Fowler, C. C., and Hawk, P. B., J. Exp. Med., 1910, xii, 388.
6. Folin, 0., and Denis, W., J. Biol. Chem., 1914, xvii, 493.
7. Myers, V. C., and Fine, M. S., J. Biol. Chem., 1913-14, xvi, 169.