Articles in PresS. J Appl Physiol (December 13, 2002). 10.1152/japplphysiol.00911.2002
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The effect of a divided caffeine dose on endurance
cycling performance, post-exercise urinary caffeine
concentration, and plasma paraxanthine.
Kylie J. Conway, Rhonda Orr*, and Stephen R. Stannard
School of Exercise and Sport Science, The University of Sydney,
*PO Box 170
Lidcombe, 1825
NSW, Australia
[email protected]
Key words: caffeine, paraxanthine, urine, cycling, performance, doping
Copyright (c) 2002 by the American Physiological Society.
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Lidcombe, Australia.
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Abstract
This study compared the effects of a single and divided dose of caffeine on endurance
performance, post-exercise urinary caffeine and plasma paraxanthine concentrations.
Nine male cyclists and triathletes, cycled for 90-min at 68%VO2max, followed by a
self-paced time-trial (work equivalent to 80%VO2max workload over 30-min) with
three randomised, balanced, and double-blind interventions: 1) placebo 60-min prior
to, and 45-min into exercise (PP); 2) single caffeine dose (6 mg.kg-1) 60-min prior to
exercise and placebo 45-min into exercise (CP); and 3) divided caffeine dose (3
unchanged with caffeine ingestion (p = 0.08), but tended to be faster in the caffeine
trials (CP: 24.2-min and CC: 23.4-min) compared with placebo (PP: 28.3-min). Postexercise urinary caffeine concentration was significantly lower in CC (3.8 µg.ml-1)
compared to CP (6.8 µg.ml-1). Plasma paraxanthine increased in a dose-dependent
fashion and did not peak during exercise. In conclusion, dividing a caffeine dose
provides no ergogenic effect over a bolus dose, but reduces post-exercise urinary
concentration.
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mg.kg-1) 60-min prior to, and 45-min into exercise (CC). Time-trial performance was
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Introduction
Caffeine is one of the most widely consumed drugs in the world and is known to be
ingested by sportspeople to augment performance. Ample laboratory-based (6; 8; 13;
14; 15; 16; 19; 21; 25) and some field- based evidence (3; 23) demonstrate the
beneficial effects of caffeine on endurance exercise performance. However, few
reports document the incidence of its use as an ergogenic aid in the athletic population
and its ideal pattern of delivery.
by endurance cyclists during their event, particularly towards the latter stages (24).
Sport or ‘energy’ drinks and carbohydrate gels that contain caffeine (or caffeine
analogues such as guarana) have recently become widely available. Such products
are designed for consumption both before and during endurance exercise.
The majority of laboratory studies demonstrating the ergogenic effect of caffeine
ingestion on performance administer caffeine as a single dose one hour prior to
exercise (3; 6; 12; 13; 14; 15; 23; 25). This is largely to ensure a peak plasma
concentration during exercise. However, it is unknown if this is the optimal timing of
caffeine administration to maximise its ergogenic effect. Few studies have measured
the plasma concentration of caffeine during exercise or examined its variability in
exercising subjects.
To date, five studies have investigated the effects of repeated caffeine administration
during exercise (7; 19; 21; 26; 29); not all observing a performance enhancing effect.
Of these, only two have employed a self-paced time trial- a protocol more reliable
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There is some evidence that caffeine-containing cola drinks are commonly consumed
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(20) and representative of competition- as an endurance performance measure (7; 21).
Thus, there is limited available information on the effects of the timing of caffeine
ingestion during simulated competition.
As a central nervous system stimulant, caffeine is classed as a prohibited substance by
the International Olympic Committee and other sporting bodies. However, because it
is present in many commonly ingested foodstuffs, 12 µg/ml is the permissible postexercise urinary threshold, under which no doping offence is recorded. Performance
this threshold (14; 25), so it is uncommon for a positive result to be registered (9).
There is substantial inter-subject variability in the metabolism and elimination of
caffeine (4; 21; 25), particularly during exercise (11). Thus, urinary caffeine
concentration as a marker of caffeine consumption may not accurately reflect dose or
plasma levels.
Both Cox et al. (7) and Kovacs et al. (21) measured post-exercise urinary caffeine
concentrations following caffeine ingestion during exercise. The former study
showed no effect of splitting the dose on urine concentrations, but the latter observed
lower concentrations (2.5 µg/ml) following a split dose than previous studies (5.8
µg/ml, 6.1 µg/ml, (28) and 4.8 µg/ml (25)) with a bolus dose. It is possible that
splitting the caffeine dose delays the appearance in the urine, but still provides a
similar ergogenic effect to a bolus dose.
Paraxanthine, the primary metabolite of caffeine, accounts for more than 80% of
caffeine degradation (22). It is pharmacologically active as an adenosine receptor
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enhancing effects have been observed with post-exercise urinary levels well below
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antagonist and thus potentially ergogenic (2; 17; 18; 27), presenting difficulties in
determining whether caffeine alone is responsible for the effects on exercise
performance. Little is known about paraxanthine kinetics during exercise.
The purpose of this study was three-fold: to compare the ergogenic effects of caffeine
administration before exercise with administration before and during simulated
endurance cycling performance; to test the hypothesis that dividing the dose would
reduce the post-exercise urinary concentration; and to observe the plasma kinetics of
Methods
Subjects.
Nine healthy and well-trained cyclists and triathletes agreed to participate in the
study. The subjects, age 25.5 ± 5 years, weight 76.4 ± 6.9 kg, VO2max 5.5 ± 0.3 (l.min1
) (mean ± SD), were non-smokers. Each subject was fully informed about the
experimental procedures and possible risks before giving informed, written consent.
The protocol was approved by the Human Ethics Committee of The University of
Sydney.
Pre-experimental Protocol
Subjects reported to the laboratory prior to the start of the experiment for an
incremental test to measure their sub-maximal and maximal oxygen uptake (VO2max)
on an electronically-braked cycling ergometer (Lode Excalibur Sport - Netherlands).
All subsequent exercise tests were done on the same ergometer. The sub-maximal
test required each subject to cycle in a step-wise fashion for eight minutes at four sub-
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paraxanthine during exercise following the single and divided dose.
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maximal workloads (100 W, 175 W, 250W and 325 W) at a constant, self-selected
cadence. The VO2max test followed, beginning five minutes after the last sub-maximal
workload, and required a linear increase in power from 0 W at 1 W per second until
volitional fatigue. A relationship between oxygen consumption in the last minute of
each sub-maximal workload and power was developed and used to calculate a
workload equivalent to both 70% and 80% of VO2max.
Experimental Protocol
trial. Subjects were tested on three occasions where gelatine capsules containing
either lactose (placebo) or caffeine were administered one hour before exercise and 45
minutes into exercise. The treatments administered in a double blind manner were:
placebo – placebo (PP); single dose: caffeine (6 mg.kg-1) – placebo (CP); and caffeine
(3 mg.kg-1) – caffeine (3 mg.kg-1) (CC). The subjects were assigned randomly to one
of three test sequences (PP-CP-CC, CP-CC-PP or CC-PP-CP), each containing three
subjects. Following the test, subjects were asked whether they could determine which
treatment they had received. The tests were administered on the same day of the
week, with an interval of seven days between tests.
Subjects arrived at the laboratory after an overnight (12 hour) fast. They were
encouraged to drink adequate water on the previous evening and on arising to ensure
full hydration. Subjects were asked to refrain from ingesting products containing
caffeine for 48 hours prior to presentation and refrain from heavy exercise 24 hours
prior to testing. To minimize variation in pre-exercise muscle glycogen status,
subjects were required to repeat the same training and food selection for subsequent
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The study was a randomised, double-blind, placebo-controlled, balanced factorial
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tests. Food and training diaries were collected for the 48 hours prior to presentation.
Written and verbal reminders were given to ensure compliance.
At the start of each test, a catheter was inserted in the dorsal aspect of the hand. The
catheter was kept patent by flushing with saline every 15 minutes. A resting blood
sample (-60 minutes) was obtained. The test dose (caffeine or placebo) was
administered and the subject remained seated for one hour. Further samples were
collected after 30 minutes of rest (-30 minutes), and just prior to the beginning of
Exercise consisted of a five minute warm-up at a workload of half that calculated to
elicit an oxygen uptake of 70%VO2max. Subjects then cycled for 90 minutes at the
70%VO2max workload. During this first 90 minutes, the ergometer was set in
hyperbolic mode so that the work rates were independent of cadence. At 90 minutes
the ergometer automatically changed to linear mode (workload was proportional to
cadence in a relationship defined by the linear factor) and 30 minute self-paced timetrial was performed. The linear factor was calculated according to the formula:
W = L * (rpm)2
where L is the linear factor and was determined in a way where W represented the
work rate eliciting 80%VO2max and rpm as the average pedalling rate in the final
stages of the VO2max test.
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exercise (0 minuets).
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The time-trial required the subject to complete a target amount of work (i.e. that
eliciting 80%VO2max for 30 min) as quickly as possible. Subjects were aware of the
endpoint and were verbally encouraged to complete the time-trial as quickly as
possible.
During all tests, the ambient temperature was 22 ˚C and the relative humidity varied
between 50-60%. A constant fan-speed was provided at all times during exercise and
the same self-selected, hydration protocol was used during each test.
Further samples were obtained at 30, 45, 60, and 90 minutes of exercise, and at the
completion of performance. Blood was drawn into a 5 ml syringe and divided
between a lithium heparinized tube (2 ml) and a fluoridated tube (2 ml). The tubes
were immediately inverted, placed on ice and later centrifuged (Beckman, model T
J-6 Centrifuge), the serum aliquoted into plastic tubes and frozen at - 20oC.
Analyses
Serum caffeine and paraxanthine levels were determined by using fully automated
HPLC (Waters 510, Milford, MA, USA). Samples were deproteinized by mixing 100
µl of 0.8 M perchloric acid with 100 µl of serum. Following vortex mixing, the
proteins were removed by centrifugation at 14 000 g (room temperature) for 3 to 4
min. A 125 µl aliquot of the supernatant was neutralised with 10.7 µl of 4 M sodium
hydroxide. Samples were centrifuged for 5 minutes at 2000 g, then transferred to
plastic 200 µg tubes, respun for five minutes at 2000 g to remove air bubbles then
placed in the auto-sampler. The method involved a dilution factor of 2.17. The
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Blood Sampling
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deproteinized sample (100 µl) was injected by auto-injector and eluted isocratically
with the elution buffer [potassium phosphate (3.47 g) – methanol (300 ml)] for 20
minutes. The mobile phase was filtered through a 0.45 µm filter and degassed under
vacuum before use. Eluted peaks were detected by ultraviolet absorbance at 274 nm
and peak areas were used for quantitation using a four-point standard curve. The
elution time for caffeine was 7.7 minutes and for paraxanthine 3.3 minutes. The
temperature was ambient (range 21 - 24oC) and the flow-rate was constant at 1.2
ml.min-1. Standards were run in duplicate at the beginning of and half way through
Urine samples were collected at the beginning and end of the test. Immediately after
collection, urine samples were stored at –20oC for later analysis of caffeine using the
HPLC system. Urine volume throughout the duration of the test was also recorded.
Statistical analyses
Dependant variables were analyzed by a repeated measures analysis of variance.
Polynomial functions of time were chosen in the contrasts to characterize outcome
variables measured at several distinct time points. Different treatment groups were
then compared using the appropriate interaction terms in an analysis of variance table.
All statistical analyses were performed using specialised statistical software (SPSS
Version 8.2). Statistical significance was accepted at P ≤ 0.05. All data are expressed
as means ± SE unless otherwise stated.
Results
Eight of nine subjects completed all aspects of the trial. One subject was excluded
from analysis because he was unable to complete the time-trial when given the single
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each assay.
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dose (CP) of caffeine. The subject experienced nausea and nervousness, which have
both been commonly associated with caffeine ingestion. None of the subjects
reported habitual consumption of large amounts of caffeine (< 250 mg caffeine/day).
During the three trials, mean body weight loss during the entire experiment, corrected
for urine output, was 1.26 ± 0.6 kg, indicating no significant differences in hydration
status between trials. The mean fluid ingested during the exercise protocol was 1444
± 309 ml.
Repeated measures ANOVA revealed no main effect of sequence of ingestion on
performance time (P = 0.080). However, there was a clear trend for the time-trial to
be completed significantly faster after the ingestion of caffeine (average CP and CC
23.8 ± 2.8 min) compared with placebo (28.3 ± 3.1 min) (Figure 1).
Figure 1.
Plasma Caffeine Levels
Before each trial subjects showed zero levels of caffeine, confirming their compliance
to abstaining from caffeine containing products prior to testing. During the
experiment, the plasma caffeine levels increased in a dose-related manner following
the ingestion of the caffeine capsules and no caffeine was present when placebo was
ingested (Figure 2A). Plasma caffeine levels were significantly elevated at -30
minutes (P = 0.000) and reached a peak within 90 minutes following CP
administration. With CC there was an initial peak between 0 and 30 minutes followed
by a slow decline until the second caffeine dose when plasma caffeine levels
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Time trial performance
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increased again and continued to rise until the end of the time trial. Plasma caffeine
concentration was significantly greater in the CP compared to the CC trial until
approximately 60 minutes into exercise (P = 0.001), after which the caffeine
concentrations were similar (P = 0.483). Maximum caffeine concentrations were 7.3
and 6.7 µg.ml-1 for CP and CC respectively.
Figure 2.
The presence of paraxanthine in the plasma was significantly higher in the CP trial
compared to CC (P < 0.05). Paraxanthine concentration continued to increase
following caffeine ingestion but showed a different relationship to the previously
described plasma caffeine levels. The increase in paraxanthine levels occurred at a
slower rate to caffeine and no peak concentration was obtained (Figure 2B).
Urinary Caffeine Content
There were no significant differences among trials in the volume of urine produced,
but it was less after exercise than before. Urine production during the 1 hour preexercise period was 228 ± 21 ml, 247 ± 27 ml, 233 ± 31 ml for PP, CP, CC
respectively. No caffeine was detected in urine following PP. Mean post-exercise
caffeine levels for CP and CC were 6.89 ± 0.73 µg.ml-1 (3.70 – 9.06 µg.ml-1) and 3.82
± 0.34 µg.ml-1 (2.35 – 6.16 µg.ml-1) respectively (P = 0.002) (Figure 3). Betweensubject variations in post-exercise urinary caffeine levels were large.
Figure 3.
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Paraxanthine
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When the initial dose of caffeine (3 vs 6 mg.kg-1) was considered, there was a
significant correlation between initial caffeine intake and post-exercise urinary
caffeine concentration (r = 0.735, P = 0.001) (Figure 4). A similar relationship was
observed between plasma and urinary caffeine concentrations. No relationship was
present between urine and plasma caffeine levels at the end (120 minutes), whereas
there was a significant relationship between plasma caffeine levels at 45 minutes and
urinary caffeine levels at the completion of exercise (r = 0.774, P < 0.001).
Discussion
There is ample evidence in the literature that caffeine, ingested prior to exercise,
improves endurance exercise performance (6; 7; 8; 13; 14; 15; 16; 19; 25). Although
the present study does not mirror these previous findings, there was a strong trend (P
= 0.080) towards an ergogenic effect of caffeine. The mean effect size of the caffeine
treatments (0.56) indicates a worthwhile ergogenic effect of caffeine ingestion
compared to placebo. However, low subject numbers and the exclusion of data from
one subject due to the possible adverse effects of caffeine, reduced the statistical
power (1-ß = 0.442). Lack of a significant effect of caffeine on time-trial
performance in the present study was thus likely due to a type-II error.
To our knowledge, only one previous study (7) has reported the effect of caffeine
given as a single dose compared with the same amount given as a divided dose.
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Figure 4.
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Others (19; 21; 29) have administered caffeine at intervals throughout exercise but
most were not primarily concerned with examining a divided dose of caffeine on
performance and therefore did not include a single dose for comparison. These
studies also used concomitant carbohydrate supplementation making comparison
between the findings of the present study with these investigations difficult. The
results of the present study, like those of Cox et al. (7), indicate that dividing a
caffeine dose for ingestion during exercise provides no ergogenic effect on endurance
cycling performance over a bolus dose given prior to exercise. It is possible that the
Therefore, ingestion of more caffeine prior to, or during exercise will have no further
ergogenic effect.
Caffeine was rapidly absorbed into the blood and peak concentration occurred within
90 minutes following ingestion. Similar findings have been previously reported
observing peak plasma concentration to occur around 75 minutes after caffeine
ingestion (2; 4; 5). The mean peak plasma concentration of 7.5 µg.ml-1 was also in
agreement with earlier studies (2; 4; 5).
Despite a relationship between plasma caffeine levels and initial caffeine dose, we
were surprised that there was no noticeable difference in endurance performance
between single and split dosing. Type II error is the unlikely cause, because of the
small difference between the two caffeine trials, and others (7) have had similar
findings.
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maximal ergogenic effect of caffeine occurs with doses ≤ 3 mg.kg-1 (7; 15).
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Paraxanthine exhibits similar pharmacologic and ergogenic properties to caffeine
[Hetzler, 1990 #116; (2). Its effects on skeletal muscle have been demonstrated in
vivo to reduce plasma potassium concentrations (27) and in vitro to increase calcium
concentration transiently to subcontracture levels in resting skeletal muscle (17).
Paraxanthine concentrations were significantly higher throughout the test following
the single dose compared with the divided caffeine dose; maximum levels were 1.4
and 1.1 µg.ml-1 respectively. However, with both treatments, paraxanthine continued
plasma caffeine levels were decreasing paraxanthine was still rising. These results are
consistent with the findings of earlier studies. Caffeine doses of 2 and 4 mg.kg-1 gave
peak paraxanthine concentrations of 1.4 µg.ml-1 at 300 min and 1.6 µg.ml-1 at 540 min
respectively (2). In six spinal-cord injured subjects, paraxanthine concentration
increased gradually throughout 180 min without plateauing, following administration
of 6 mg.kg-1 caffeine (27). Similarly, a constant elevation of paraxanthine after
caffeine ingestion (4 mg.kg-1) to a peak concentration of 1.15 µg.ml-1 was measured at
180 min with no indication of a plateau (18).
The relative contributions of caffeine and paraxanthine to performance enhancement
remain unclear. It is has been suggested that paraxanthine formation may be
quantitatively more important in having pharmacological effects than previously
believed (22). Nonetheless, no conclusions can be made to determine the impact of
paraxanthine during exercise in this study.
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to increase throughout exercise such that no peak was obtained. Therefore when
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The amount of caffeine excreted is consistent with values reported in other studies
using caffeine dosages up to 9 mg.kg-1, which observed significant improvements in
endurance performance with caffeine doses that produce urinary levels well below the
IOC threshold of 12 µg.ml-1 (14; 15; 21; 28). We believe this is the first study to
report a lower post-exercise urinary caffeine concentration of divided dose caffeine
administration as opposed to single dose administration. The mean caffeine level
present in the urine was almost twofold greater in the single dose trial compared with
caffeine levels were due to spreading the dose throughout the duration of exercise.
Since total caffeine intake was identical in both trials, the timing of administration
must have influenced urine concentration. This is reflected by the significant positive
correlation between initial caffeine dose and the final urine concentration (Figure 4),
suggesting the second dose of caffeine did not influence the urinary caffeine levels at
the time of collection. A comparison of previous observations support these findings.
Split administration of a 4.5 mg.kg-1 dose (21) achieved markedly lower urinary
caffeine concentrations (2.5 µg.ml-1) than a similar (5 mg.kg-1) single dose (4.8 µg.ml-1
(25) and 5.8 and 6.1 µg.ml-1 (28))
Two important implications can be drawn from the urine results. Firstly, larger
ergogenic doses of caffeine may not exceed the IOC limit if the dose were divided
throughout exercise. Secondly, the timing of caffeine intake and urinary sampling has
a large influence on the subsequent caffeine concentration in the urine. Therefore, the
caffeine levels present in the urine are not always an accurate indication of total
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divided dose trial. These results support those of Kovacs et al. (21) that lower urinary
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caffeine intake. It is possible that an individual could manipulate the urinary caffeine
concentration at the completion of competition, by altering the timing of caffeine
ingestion.
Our results suggest that urine is not the best method for doping analysis of caffeine.
Current urine analysis is based solely on the 1 to 3% excreted as unmetabolised
caffeine and does not account for the metabolites cleared by the kidney.
Paraxanthine, like caffeine is a potent competitive adenosine antagonist which can
concentrations continue to rise after completion of exercise (2). Although
paraxanthine concentration can be measured in the urine, its excretion is highly
variable (1) and, like caffeine, could be influenced by event duration, individual
metabolism and environmental conditions. Other more accurate methods, such as
analysis of caffeine metabolite ratios in the urine, have been suggested (10).
In conclusion, caffeine ingestion did not significantly alter endurance cycling
performance compared to a placebo, though it tended to have an ergogenic effect.
Furthermore, there was no significant effect of timing of caffeine delivery on
performance, however, dividing the caffeine dose resulted in substantially lower postexercise urinary caffeine levels. This latter effect may present a potential loophole to
accurately determining an athlete’s caffeine intake via urine analysis.
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contribute to the ergogenic effects of caffeine (2; 17; 27). Furthermore, paraxanthine
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Acknowledgements
The authors thank Patricia Ruell from the School of Exercise and Sport Science for
her assistance in the analysis of urinary caffeine, plasma caffeine and plasma
paraxanthine concentrations.
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(n = 8, values are mean ± SE).
Figure 2. Plasma caffeine and paraxanthine concentrations during rest and exercise (mean ±
#
S.E.). *Significantly lower compared with CP (P < 0.05). Significantly different from previous
value (P < 0.05).
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Figure 1. Performance times to complete target amount of work for PP, CP and CC trials
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*Significantly lower compared with CP (P < 0.05).
Figure 4. Relationship between initial caffeine dose and final urinary caffeine concentration (r
= 0.735, P = 0.001).
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Figure 3. The mean (± SE) post exercise urinary caffeine concentration in CP and CC trials.