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B. D. Maes, G. Mys, B. J. Geypens, P. Evenepoel, Y. F. Ghoos and P. J.

Rutgeerts
Am J Physiol Gastrointest Liver Physiol 275:169-175, 1998.

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on the following topics:
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Gastric emptying flow curves separated from carbon-labeled
octanoic acid breath test results
B. D. MAES,1 G. MYS,2 B. J. GEYPENS,1 P. EVENEPOEL,1
Y. F. GHOOS,1 AND P. J. RUTGEERTS1
1Department of Medicine, Division of Gastroenterology and Gastrointestinal Research Center,

University Hospital Gasthuisberg, and 2Department of Mathematics,


Catholic University, Leuven B-3000, Belgium

Maes, B. D., G. Mys, B. J. Geypens, P. Evenepoel, and radioscintigraphic measurements taken simulta-
Y. F. Ghoos, and P. J. Rutgeerts. Gastric emptying flow neously in normal subjects and dyspeptic patients
curves separated from carbon-labeled octanoic acid breath allowed for highly accurate description of the gastric
test results. Am. J. Physiol. 275 (Gastrointest. Liver Physiol. emptying rate of a solid test meal (7, 16). With the use
38): G169–G175, 1998.—Recently, we developed the
of a regression model, we were able to calculate the
[13/14C]octanoic acid breath test to measure gastric emptying
of solids. Although the method has been validated exten- half-emptying time and lag phase, correcting for the
sively, absorption, metabolism, and excretion of the label in postgastric processing of octanoic acid.
the breath need to be corrected for. In this study a mathemati- The aim of this study was to develop a separation
cal model was developed that allows for 1) separation of the model in which the postgastric processing of octanoic
acid could be mathematically separated from the CO2

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global CO2 excretion after ingestion of the labeled test meal
into the emptying rate of the labeled test meal from mouth to excretion curve after ingestion of a standard solid test
pylorus and the postgastric processing of absorption, metabo- meal to obtain real-time gastric emptying curves. This
lism, and excretion of the label, and 2) numerical calculation approach of breath test curve analysis has two poten-
of the half-emptying time and lag phase of the emptied meal. tial benefits: 1) physiologically meaningful gastric emp-
The model was applied to the gastric emptying results
tying parameters can be calculated from breath test
obtained by simultaneous scintigraphic and breath test mea-
surements. An excellent correlation was found between the curves without correcting for postgastric processing of
gastric half-emptying time (r 5 0.98) and lag phase (r 5 0.85) the label on a linear regression-estimated basis be-
determined scintigraphically and via breath test. There was tween radioscintigraphy and breath tests, and 2) it
also a good agreement between the two methods [mean allows for the evaluation of gastric emptying rates,
values and confidence limits for differences: t½ 5 10 min (220 instead of amounts of emptied food, as a function of
to 41) and tlag 5 23 min (239 to 34)]. Moreover, the separated time (flow curves). The classic multicompartmental
gastric emptying curves, lacking the influence of postgastric analysis, however, was not used due to the specific
processing of the label, showed real patterns of gastric conditions encountered in breath test technology. The
outflow, which changes from moment to moment. multiple-chamber model is difficult to apply in clinical
breath test technology; mathematical models practice, because the dynamic exchange of CO2 with the
rapid and slow bicarbonate pool and the loss of label via
excretion in urine and feces and incorporation into bone
is difficult to estimate in humans, certainly in each
RECENTLY, WE DEVELOPED the [13/14C]octanoic acid breath individual. Solution of the breath curve would require
test to measure gastric emptying of solids (7, 16). The the fitting of at least four exponential functions. This
rationale of a breath test is based on the firm retention can rarely be done convincingly with biological data,
of 13/14C-labeled octanoic acid in the solid phase of a test even if sampling takes place over long periods of time.
meal during mixing and grinding in the stomach, Also, it is not possible to obtain a steady state of
followed by rapid absorption from the chyme entering exchange between the different compartments (espe-
into the duodenum, an immediate and maximal oxida- cially the slowly exchanging ones) during the 4-h period
tion in the liver to labeled CO2, and a fast exhalation in of breath sampling. Moreover, when dose is not in the
breath. In vitro experiments showed that octanoic acid subsequently measured compartment the rate con-
is firmly retained in a standard solid test meal in a stants for intercompartmental exchange cannot be
gastric environment (7). It has been known for a long explicitly calculated from the multiexponential curve
time that octanoic acid, an eight-carbon fatty acid for tracer in breath.
found in dietary fats, is rapidly absorbed from the
intestine and carried to the liver via the portal venous RATIONALE FOR THE SEPARATION MODEL
system, where it is rapidly and completely oxidized (1,
2, 4–6, 10–13, 17–20, 22, 25). Therefore gastric empty- To elaborate the mathematical model, three func-
ing of the meal, and not the postgastric processing of tions were introduced to describe three different pro-
the label, could be considered the rate-limiting step in cesses.
the rate of labeled CO2 excretion in breath after inges- 1) The emptying rate of a labeled solid meal from
tion of a labeled solid test meal. mouth to pylorus is given by M(t).
Mathematical analysis of CO2 excretion curves made 2) The rate of postgastric processing (absorption,
it possible to exclude the influence of endogenous CO2 metabolism, and excretion in breath) of the label is
production on the breath test results, and breath test given by D(t).
0193-1857/98 $5.00 Copyright r 1998 the American Physiological Society G169
G170 A SEPARATION MODEL FOR BREATH TEST ANALYSIS

3) The global process of CO2 excretion after inges- that had already been metabolized during the first time
tion of a labeled solid test meal is given by T(t). interval (simplified: the first passage in the liver). The
The aim of this study is to determine M(t) given T(t) addition of all layers describes the total process T(t),
and D(t), which can both be measured, and to describe i.e., a 13/14CO2 excretion curve after ingestion of a solid
the relation between the three functions. Therefore the test meal. Mathematically it is expressed as
following assumptions were made. 1) The meal is
ingested at once, at time 0. This is not true, but the time T2 5 M1D1
of ingestion was always restricted to 10 min, and time 0 T3 5 M1D2 1 M2D1
was taken as the time of completion of the ingestion of
the meal. 2) T(t), D(t), and M(t) are piecewise continu- T4 5 M1D3 1 M2D2 1 M3D1
ous functions, not identical to zero and positive for each
time $ 0. 3) The rate of metabolism of the label [D(t)] is T5 5 M1D4 1 M2D3 1 M3D2 1 M4D1
proportional to the rate of gastric emptying of the label or, in general, as
[M(t)]. This implies that the kinetics of metabolism of
n 21
the label are independent of the rate at which the label
is emptied [no saturation of D(t) as a function of M(t)], Tn 5 oD
i 51
n 2 i Mi (1)
or, stated differently, that D(t) is invariant of M(t).
We first demonstrate that, in theory, under the By decreasing the length of the time intervals to zero,
assumptions made above, the separation model is a the formula becomes a continuous function
mathematically correct alternative to the multicompart-

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e D(t 2 t )M(t ) dt
t
mental model to separate a function (i.e., gastric empty- T(t) 5 0 0 0 (2)
ing rate) from a global process when rate constants for 0

intercompartmental exchange cannot be explicitly cal- The relationship between the different rates as de-
culated. We then demonstrate the practical elaboration scribed in equation 2 is mathematically known as a
of deriving the gastric emptying rate from labeled convolution product. A number of properties can easily
octanoic acid breath test curves and the proportionality be derived mathematically. However, these properties
of D(t) to M(t). are not of interest in this study, since it is not possible
DESIGN OF THE SEPARATION MODEL in general to find the inverse relation between T and M,
except for special classes of functions such as ex. Such
To simplify the rationale of the model, T(t), D(t), and functions are used in Fourier and in Laplace trans-
M(t) are not considered to be continuous but are divided forms, but these functions do not have the form ob-
into discrete time intervals. The rate of 13/14CO2 excre- served in our data. Therefore, we have used the discrete
tion during a certain time interval is the result of the formalism (Eq. 1) to derive a discrete calculation in
accumulated effect of parts that have left the stomach practice
in the past intervals (Fig. 1). For example, the rate of
label recovered in breath during time interval 3, called T2
M1 5
T3 , is the result of the part of the label that left the D1
stomach in the first time interval but was metabolized
during the second time interval (simplified: during the T3 2 D2M1
M2 5
second passage in the liver), plus the part of the label D1
that left the stomach in the second time interval but
T4 2 D3M1 2 D2M2
M3 5
D1
or, in general
i21

Ti 1 1 2 oD
j51
i 1 1 2 j Mj

Mi 5 (3)
D1
If T(t) and D(t) are known, M(t) can be separated from
the total process T(t) by decreasing the length of the
time intervals.
ELABORATION OF THE MODEL

Methods
Fig. 1.13/14CO
2 excretion curve for gastric emptying of solids. Rate of Subjects and materials. As functions of T(t), the
13/14CO excretion during a certain time interval is the result of the
14CO
2 excretion data obtained in the validation study
2
cumulative effect of parts that have left the stomach in the past
intervals. Each layer shows how one excretion package of the label comparing the [14C]octanoic acid breath test and the
that has left the stomach is excreted in breath as a function of time. radioscintigraphic technique were used (7). Briefly, in
A SEPARATION MODEL FOR BREATH TEST ANALYSIS G171

this study a standard solid test meal (250 kcal) consist- under the curve of 14CO2 in breath obtained during the
ing of one egg (labeled with 74 kBq of [14C]octanoic acid first hour after injection of each bolus of [14C]octanoic
and 110 MBq of 99mTc-labeled albumin colloid), two acid [using the formula for D(t)].
slices of bread, and 5 g of margarine was ingested by 16 The study protocol was approved by the ethics com-
healthy volunteers and 20 dyspeptic patients. Immedi- mittee of the University of Leuven. Informed consent
ately after ingestion of the meal, each subject was was obtained from all subjects.
seated between the two heads of a dual-headed gamma Measuring techniques and mathematics. 14CO2 in
camera equipped with parallel-hole low-energy collima- breath was collected by blowing through a pipette into
tors and interfaced to a computer. Scanning scinti- vials containing 2 ml of 1 M hyamine hydroxide and 2
graphic information was obtained every 10 min for up ml of ethanol together with one drop of thymolphtha-
to 1 h and every 15 min for another period of 1 h. lein solution. This amount of hyamine is neutralized by
Radioactivity remaining in the stomach at each scan- 2 mM of CO2. The end point of neutralization is
ning period was expressed as a percentage of the indicated by decoloration of the indicator. After decolor-
activity initially present. The gastric emptying rate so ation, 10 ml of scintillation cocktail (Hionic Fluor,
obtained was fitted by the modified power exponential Packard Instruments) were added and radioactivity
formula of Siegel et al. (24). The half-emptying time was determined by liquid scintillation spectrometry
(t1/2 s ) and lag phase (tlag s ) were calculated according to (Packard Tri-Carb liquid scintillation spectrometer,
that formula. Breath sampling for 14CO2 followed the model 3375; Packard Instruments, Downers Grove, IL).
same time schedule as the scintigraphic imaging tech- CO2 production was assumed to be 300 mmol per
nique but continued for another 2 h of sampling, during square meter of body surface per hour. Body surface

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which breath was collected and measured in 15-min area was calculated by the weight-height formula of
intervals. The results were expressed as the percentage Haycock et al. (9). The results were expressed as the
of 14C recovery per hour and were further analyzed by percentage of 14C recovery per hour as a function of
nonlinear regression analysis to calculate t1/2 and tlag. time.
The gastric emptying parameters of both techniques
were compared by correlation and linear regression Application of the Model
analysis in this study. The function T(t) can be adequately described in both
To obtain the function D(t), 20 healthy subjects (10 healthy volunteers and subjects with abnormal gastric
women and 10 men, mean age 23 yr, range 18–28 yr) emptying rates (1) by two classes of function: atbe2ct or
were examined. None of the subjects had a history of mkbe2kt(1 2 e2kt )b 2 1, where t is time and a, b, c, m, k,
gastrointestinal disease or surgery and none were and b are regression-estimated constants.
taking medication. After an overnight fast, a flexible The mean 14CO2 excretion curve obtained in 20
tube was positioned in the second part of the duodenum healthy volunteers after intraduodenal administration
under radioscopic control. The dynamics of 14CO2 ap- of 74 kBq of [14C]octanoic acid served as the function
pearance in breath were measured after intraduodenal D(t). As far as the function D(t) is concerned, no class of
administration of 74 kBq of [14C]octanoic acid sodium functions exists. Accurate fitting of this curve is done by
salt (DuPont NEN, Boston, MA), dissolved in 20 ml of a combination of exponential and polynomial functions
water. Breath samples were taken before and every 3 b
min during the first 30 min, every 5 min for the next 30 I. Ascending slope: c(1 2 e2at )
min, and every 15 min thereafter for up to 4 h. The (f 1 g)
14CO excretion curves were evaluated by 1) the 14CO
2 2
II. Descending slope: e2dt
peak excretion time, 2) the 14CO2 peak excretion, and 3) III. Binding of I and II: h 1 it 1 jt 2 1 kt 3 1 lt 4
the half-emptying time of the curve [using the formula
for D(t)]. where t is time and a, b, c, d, f, g, h, i, j, k, and l are
To validate the invariance of D(t) from M(t), six regression-estimated constants.
healthy volunteers (3 women, 3 men; age 18–24 yr) Using these equations for T(t) and D(t), in Eq. 3 the
were studied. None of the subjects had a history of curve M(t) is obtained. Two gastric emptying param-
gastrointestinal disease or surgery and none were eters were calculated numerically from the individual
taking medication. After an overnight fast, a flexible curves M(t): 1) the gastric half-emptying time is calcu-
tube was positioned in the second part of the duodenum lated by solving the equation
under radioscopic control, and 129.5 kBq of [14C]octa-
e e
t1/2b `
noic acid sodium salt (supra) dissolved in 50 ml of water M(t ) dt 5 1⁄2 M(t ) dt
0 0
were injected into the second part of the duodenum in a
bolus at three different times: 74 kBq at time 0, 18.5 and 2) the lag phase (tlag b ), as defined by Siegel et al.
kBq (1/4 of the initial dose) 1 h later, and 37 kBq (1/2 of (24), which corresponds to the time of peak excretion in
the initial dose) at 2 h. Breath samples were taken the function M(t).
every 5 min for 4 h. The kinetics of metabolism of each Statistics. The gastric half-emptying times and lag
bolus of [14C]octanoic acid were evaluated by three phases of the separated functions of M(t) were calcu-
parameters: 1) the time until peak excretion of 14CO2 in lated numerically after integration into M(t) as a
breath, 2) the maximal increase of 14CO2 excretion after function of time and were compared with the scinti-
injection of each bolus, and 3) the increase in area graphically determined half-emptying times and lag
G172 A SEPARATION MODEL FOR BREATH TEST ANALYSIS

tion of three different boluses of [14C]octanoic acid. At


each bolus injection of [14C]octanoic acid, peak excre-
tion in breath was reached at 10 6 0.83 min, with a
peak of 33.05 6 2.49% dose/h after the first bolus,
24.18 6 1.54% dose/h after the second bolus, and 28.61 6
2.03% dose/h after the third bolus. The increase in
14CO excretion 10 min after injection of the bolus was
2
33.05% (0.447% per injected kBq of activity) at 10 min,
8.18% (0.442%/kBq) at 70 min, and 16.59% (0.448%/
kBq) at 130 min. The area under the curve during the
first hour was 22.99 6 1.20% (0.31% per injected kBq of
activity) for the first injected bolus of 74 kBq, 7.17 6
0.47% (0.39%/kBq) for the second bolus of 18.5 kBq, and
10.64 6 05.4% (0.29%/kBq) for the third bolus of 37
kBq. The differences between the three boluses for the
three parameters (parameters 2 and 3 calculated per
Fig. 2. Dynamics of 14CO2 appearance in breath after intraduodenal kBq of activity) were statistically not significant.
administration of 74 kBq of [14C]octanoic acid in the second part of
the duodenum in 20 healthy volunteers (means 6 SE). Application of the Model

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phases of the validation study (7), using correlation Figure 4 depicts the relationship between the three
analysis [SAS: PROC CORR (21)]. The two tests were functions T(t), M(t), and D(t) in two subjects after
further compared using the Bland and Altman proce- ingestion of a [14C]octanoic acid-labeled standard solid
dure (3). The three parameters for evaluation of the test meal. The first subject had a normal gastric
kinetics of metabolism of [14C]octanoic acid after intra- emptying rate with a scintigraphically determined
duodenal administration were compared for the three half-emptying time of 59 min (Fig. 4A): the rate of
boluses using the Mann-Whitney-Wilcoxon test (21). gastric emptying accelerates very quickly before reach-
ing a peak, followed by a gradual decline in the velocity
RESULTS of gastric emptying. The second subject had a delayed
gastric emptying rate with a scintigraphically deter-
Postgastric Processing of [14C]Octanoic Acid mined half-emptying time of 89 min (Fig. 4B); the
Figure 2 represents 14CO2 excretion as a function of acceleration and deceleration in the gastric emptying
time in 20 healthy subjects, after intraduodenal admin- rate is less pronounced and less steep. By analyzing the
istration of 74 kBq of [14C]octanoic acid (means 6 SE). gastric emptying data in this way, it was clear that
14CO appeared in the breath almost immediately, with
2
gastric emptying velocity changes from minute to
a peak excretion of 33.73 6 1.69% dose/h after 10.69 6 minute and never has a constant value.
0.77 min, followed by an exponential decrease of 14CO2 The separated gastric emptying function M(t) al-
activity in the breath. The half-excretion time of the lowed not only for evaluation of the real pattern of
curves was 67.5 6 1.37 min. emptying but also for the calculation of a half-emptying
time. The relationship between the gastric half-
Invariance of D(t) from M(t) emptying times determined scintigraphically and via
breath test in 16 healthy volunteers and 20 dyspeptic
In Fig. 3, the 14CO2 excretion as a function of time is
patients after ingestion of a dually labeled solid test
given in six subjects, after intraduodenal administra-
meal of 250 kcal is given in Fig. 5A. The correlation
coefficient between the two parameters was 0.98. Fig-
ure 5B gives the relationship between the lag phases
obtained by both techniques, defined as the point of
maximal gastric emptying rate according to the method
of Siegel et al. (24). The correlation coefficient was 0.85.
The Bland and Altman plots of gastric half-emptying
times and lag phases determined scintigraphically and
via breath test, given in Fig. 6, showed, first, an off-set
between both methods not significantly different from
zero, and second, no proportional differences between
the two methods [mean and confidence limits for differ-
ences between the methods: t1/2, 10 min (220 to 41) and
tlag, 23 min (239 to 34)].

DISCUSSION
Fig. 3. 14CO2 appearance in breath after intraduodenal administration
of 74, 18.5, and 37 kBq of [14C]octanoic acid in the second part of the duo- This study aimed to develop a mathematical model to
denum at 0, 1, and 2 h, respectively, in 6 healthy volunteers (means 6 SE). separate one physiological function from breath test
A SEPARATION MODEL FOR BREATH TEST ANALYSIS G173

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Fig. 4. 14CO2 excretion [T(t)], postgastric process-
ing [D(t)], and gastric emptying [M(t)] after inges-
tion of a [14C]octanoic acid-labeled standard test
meal in a subject with normal gastric emptying
(t1/2 s 5 59 min; A) and a subject with delayed
gastric emptying (t1/2 s 5 89 min; B) (% dose per
hour as a function of time). Scintigraphic data are
shown at bottom (% retention as a function of
time).

results. All breath tests are based on the administra- By applying this mathematical model to the
tion of a substrate with a functional group containing a [13/14C]octanoic acid breath test to measure gastric
carbon atom with either the radioactive (14C) or the emptying of solids, we were able to demonstrate that
stable (13C) isotope of carbon. The functional group is postgastric processing of [13/14C]octanoic acid until
enzymatically cleaved during passage through the gas- 13/14CO exhalation occurs very rapidly, with minimal
2
trointestinal tract, during its absorption, or in subse- intersubject variability. This is due to very rapid absorp-
quent metabolic processes. After cleavage of the target tion from the small intestine, quick transport to the
bond, the cleaved portion undergoes further metabo- liver [no mucosal esterification, no incorporation in
lism to 14CO2 or 13CO2, which mixes with the bicarbon- chylomicrons (10, 18–19)], and a ready and almost
ate pool of blood and is finally expired in the breath. In complete oxidation to 13/14CO2 in the liver [no require-
this way, 14/13CO2 excretion is a reflection of the total ment for carnitine to cross the double mitochondrial
amount or kinetic properties of the enzyme studied, membrane (4, 22)]. Therefore, gastric emptying of the
given that this enzyme relates to the rate-limiting step meal can be considered the rate-limiting step in 13/14CO2
in the whole process. excretion after ingestion of a [13/14C]octanoic acid-
G174 A SEPARATION MODEL FOR BREATH TEST ANALYSIS

Fig. 5. Scintigraphically determined gas-


tric half-emptying time (t1/2 s ) (A) and lag
phase (tlag s ) (B) vs. gastric half-emptying
time and lag phase determined via breath
test (t1/2 b and tlag b ), using the separation
model.

labeled solid meal. Also, an average function can be major differences in flow pattern.’’ A gastric emptying
used to describe the ‘‘postgastric processing’’ of octanoic flow curve can be obtained from radioscintigraphic data
acid. Metabolism of octanoic acid remains unaltered by taking the first derivative of the measured curve.
not only in healthy volunteers but also in other circum- However, mathematical derivation is less stable than

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stances, as has been shown for insulin-dependent diabe- mathematical integration. This leads to inaccuracies
tes mellitus (14) or after administration of octreotide for calculation of kinetic parameters such as the lag
(15). phase, as defined by Siegel (24), since it is mathemati-
The assumption of invariance of postgastric process- cally easier to determine the peak of a flow curve than
ing of [13/14C]octanoic acid from the rate of emptying to determine the point of inflection of a cumulative
from the stomach was fulfilled in this study. Hence all curve. This could be the explanation for a less good
other assumptions made were also fulfilled and the correlation of the lag phases of both techniques in this
separation model could be applied by ‘‘subtracting’’ the study.
shape of the postgastric processing curve on each On the other hand, the separation model has it
moment from the global 13/14CO2 excretion curves after limits. By using fitting curves for the actual measured
ingestion of a labeled meal, in a continuous way and data of 13/14CO2 excretion, the transpyloric flow is
according to the amount of label that has left the smoothed to a general flow curve and does not display
stomach at that moment. the gushes of chyme leaving the stomach in a pulsatile
The results obtained with the separation model are way.
excellent. The model allows gastric half-emptying time The separation model presented has a theoretical
and lag phase to be calculated very accurately and it advantage compared with the classical multiple cham-
also provides a method to evaluate patterns of gastric ber model (8), in that it makes fewer assumptions. It
emptying velocity or flow, which changes from minute makes no assumptions about laws governing the flow
to minute. In 1990, Schulze-Delrieu (23) pointed out stream of the label. Moreover, the multiple chamber
that radioscintigraphic gastric emptying results, ex- model is difficult to apply in clinical practice, as dis-
pressed as a percentage of the initial amount still cussed in the introduction. The use of the curve D(t),
remaining in the stomach, represent cumulative data representing the postgastric processing of the label, in
(i.e., mathematical integration of a velocity curve, or separating M(t) out of T(t) and D(t) is an appropriate
‘‘distance’’ rather than ‘‘velocity’’) and that ‘‘gastric solution to these problems because D(t) is shown to be
emptying rates determined in this way do not allow any proportional to M(t).
conclusions regarding the rate or pattern of actual In conclusion, an accurate mathematical model was
gastric outflow and identical emptying rates may hide developed to separate gastric emptying flow curves

Fig. 6. Bland and Altman plots of t1/2 s


and t1/2 b (A) and tlag s and tlag b (B).
Individual differences between test re-
sults are plotted against averages of
individual test results of both tests
(solid and dashed lines, mean differ-
ence 6 2 standard deviations).
A SEPARATION MODEL FOR BREATH TEST ANALYSIS G175

from 13/14CO2 excretion curves obtained after ingestion Kaunitz, K. Lang, and W. Fekl. Berlin: Z. Ernährungswiss, 1974,
of a [13/14C]octanoic acid-labeled solid test meal, thereby vol. 17, p. 9–16.
11. Kritchevsky, D., and S. A. Tepper. Influence of medium-chain
also excluding the influence of endogenous CO2 produc- triglycerides on cholesterol metabolism in rats. J. Nutr. 86:
tion on breath test results. The model also has attrac- 67–72, 1965.
tive prospects for other (breath) tests to separate a 12. Leveille, G. A., R. S. Pardini, and J. A. Tillotson. Influence of
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