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Institute for Biological Chemistry and Nutrition, University of Hohenheim, Stuttgart, Germany and the * Center for Studies of Sensory Impairment, Aging and Metabolism (CeSSIAM), Guatemala City, Guatemala
1To whom correspondence should be addressed.
 |
ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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KEY WORDS: • glutamine • alanine • humans • pharmacokinetics • oral administration
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). Together with alanine
(Ala), it accounts for ~80% of the amino acids released from
skeletal muscle (Felig 1975
). Glutamine plays a major
role in various metabolic pathways and is essential to normal immune
responses (Calder 1994
and 1995
, Newsholme et al. 1988
). There is a growing body of evidence that Gln, but not
glutamate, is easily transported across the cell membrane, hence
serving as the glutamate precursor in glutathione synthesis (Cao et al. 1998
, Hong et al. 1992
, Welbourne et al. 1993
).
Hypercatabolic and hypermetabolic situations are accompanied by marked
depressions in muscle intracellular Gln and Ala (Jepson et al. 1988
, MacLennan et al. 1988
). It has thus been
postulated that Gln supplements might be beneficial in the treatment of
stressed and malnourished patients (Fürst 1998
).
The constraints in administering free Gln, at least parenterally, are
its limited solubility of ~ 3 g/100 mL (Stehle and Fürst 1995
), which leads to the need for large fluid
volumes to administer the requisite amounts of Gln, and its instability
in aqueous solutions (Fürst et al. 1990a
). This
problem can be overcome by the use of synthetic, stable, highly soluble
(568 g/L) Gln-containing dipeptides (Stehle and Fürst 1995
). They are rapidly cleared from the circulation without
accumulation in tissues and with inconsequential losses in urine
(Albers et al. 1988
and 1989
). Enteral (oral)
utilization of Gln or Gln-containing dipeptides is a controversial
issue at present. On the one hand, there are numerous negative reports
related to nitrogen utilization, protein synthesis and plasma Gln
concentrations (Jebb et al. 1994
, Long et al. 1995
). On the other hand, beneficial effects have been claimed
after administration of high doses of free Gln to victims of multiple
trauma (Houdijk et al. 1998
).
A proper evaluation of the efficacy of Gln requires knowledge of its
pharmacokinetics from the various alternative dosing forms and
protocols. About 50% of orally administered Gln is extracted by the
splanchnic bed in healthy humans (Hankard et al. 1996
,
Matthews et al. 1993
, Ziegler et al. 1990
). Moreover, the increase in circulating concentrations of
free Gln after varying oral loads is dose related (Ziegler et al. 1990
).
In this work, we present the pharmacokinetic response to bolus and
intermittent oral doses of the Gln dipeptide,
L-alanyl-glutamine (Ala-Gln), in healthy adults, living in
sanitary environments in Guatemala City, as the standard for the
pharmacokinetic response. A fixed amount of 20 g of
L-Ala-Gln, containing ~13 g Gln, was administered both as
a bolus and intermittently. This is approximately half the amount of
Gln that was recently estimated to be needed as an exogenous supplement
in disease (Silk 1999
). Bolus dosing is a model for a
conventional regimen of episodic oral doses, and intermittent dosing
was chosen to mimic an enteral-drip delivery. In Guatemala and many
other developing countries, gastritis is an endemic problem; thus the
use of antacids and acid-secretion blockers is rising. Moreover,
the spreading endemicity of Helicobacter pylori
(Castro and Coelho 1998
) may produce premature gastric
atrophy in large segments of developing societies. For both reasons, it
was of interest to determine whether induced hypochlorhydria influenced
the response to the Ala-Gln dipeptide. Because amino acids are
electronically charged molecules when dissociated in solution, the
intraluminal transit, which is dependent on pH, may be influenced by
the pH change induced by the antacid. This, in turn, may have an effect
on pharmacokinetic variables such as maximum peak height or time of
appearance of the maximum peak height. Most of the recent studies in
humans have been done in patients suffering from severe illness. Our
interest, however, was to evaluate the pharmacokinetic characteristics
in subcritical acute disease, and specifically in tropical febrile
disease. Therefore, we assessed the pharmacokinetics of the dipeptide
in patients with classical Dengue fever.
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SUBJECTS AND METHODS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Solutions of Ala-Gln (Degussa, Coubevoie, France) were prepared
<24 h before administration, at 20 g/20 mL purified water for bolus
and 4 g/20 mL purified water for intermittent administration, and
stored at 4°C until used. The dipeptide is highly soluble in water
(568 g/L H2O at 20°C) (Fürst and Stehle 1994
).
Healthy subjects and patients.
Eight normal volunteers, aged 22–36 y, were recruited in Guatemala
City among the staff and students affiliated with CeSSIAM (Table 1
). They were healthy, and without known metabolic or gastrointestinal
diseases. All were free of gastroenteritis episodes within 3 wk of the
study. None were taking antibiotics, antacids or gastric
acid-suppressive medications.
|
,
suffering from classical Dengue fever, were recruited in the public
hospital in Tiquisate, Escuintla Province, on the tropical, coastal
plain of Guatemala where the vectors, Aedes aegypti and
Aedes albopictus mosquitoes, are endemic. Patients with
a maximum duration of 5 d of the disease were eligible. Dengue
fever was diagnosed on the basis of clinical symptoms, including high
fever (>40°C), severe frontal headache, pain behind the eyes, muscle
and joint pain, nausea and vomiting. The absence of a malarial
parasitemia on a thick blood smear strongly suggested a diagnosis of
Dengue. Dengue infection was confirmed by one or both of virus
isolation using a CC-36 cell culture line of Aedes
albopictus cells and serological testing by detecting
immunoglobulin M using a capture ELISA. These determinations were made
in the laboratories of the Division on Malaria and Vector Diseases of
the Ministry of Health of the government of Guatemala within 24 h
after blood drawing. The clinical information obtained from each
patient was sent with the blood specimen as part of the surveillance
system in Guatemala. All subjects gave their informed consent after receiving an explanation of the nature, purpose, inconveniences and discomforts. The survey was approved by the Human Subjects Committee of CeSSIAM.
Experimental design.
The individual regimen of Ala-Gln administration consisted of three
protocols (A, B and C). Protocol A was designed to determine how oral
bolus or intermittent doses of Ala-Gln, administered on two
different study days to eight healthy subjects, would influence plasma
Gln and Ala concentrations compared with their baseline concentrations.
The baseline concentrations were obtained on a third study day from
seven of the eight healthy volunteers (one subject did not appear on
the study day when baseline concentrations were determined). After an
overnight fast, a basal 2-mL blood sample was drawn at 0800 h for
measurement of baseline plasma concentrations of Gln and Ala.
Additional, identical blood samples of 2 mL each were drawn every 30
min during the study period of 3 or 5 h, yielding a total of 7 and
11 samples per subject per day, respectively, after the bolus or
intermittent doses. Blood samples were drawn using an indwelling
scalp-vein needle and cannula system, which remained in the vein
until the end of the absorption study. The system was kept open between
blood collections with sterile heparin solution. The blood samples were
transferred from a syringe into EDTA-containing vacutainer tubes
(Becton Dickinson, Franklin Lakes, NJ), immediately placed on ice and
subsequently centrifuged at 2800 x g for 7 min to
obtain plasma. The plasma was separated into screw-cap plastic
vials and stored at -40°C. Sampling and timing of the experiments
are depicted in the figures, illustrating Gln and Ala concentration
changes after bolus and intermittent administration of Ala-Gln
(Fig. 1B, C
). Hematocrit was determined every hour. For packed cell volume
(hematocrit), a heparinized capillary was filled with whole blood and
centrifuged in a hematocrit microcentrifuge for 5 min at 4192 x g. Hematocrit was measured using an International
Microcapillary Reader (International Equipment Company, Boston, MA) and
recorded as a percentage of packed red blood cells.
|
), before
Ala-Gln administration would influence the absorption of the
dipeptide (Maton 1993
) and thus alter the
pharmacokinetics. Volunteers were asked to take a pretreatment dose of
20 mg of Omeprazole three times, at 24, 12 and 2 h before the
scheduled dipeptide intake. Four of the healthy volunteers from
protocol A underwent two additional applications (bolus and
intermittent) using the Omeprazole regimen. The sampling and sample
handling were as described in protocol A. Protocol C was designed to assess how an oral bolus dose of Ala-Gln influences plasma Gln and Ala concentrations in eight Dengue patients. A further objective was to compare the response to the bolus dose in patients with that in healthy volunteers. The patients were admitted to a hospital in the coastal area of Guatemala during the febrile phase of the disease, and the study was carried out in the morning in fasting subjects. Sampling and sample handling were identical as described in protocol A.
Analytical methods.
Free plasma Gln and Ala were determined using an automated on-line
reversed-phase HPLC system with precolumn derivatization
(o-phthaldialdehyde/3-mercaptopropionic acid)
(Fürst et al. 1990b
). The samples were
precipitated with 5-sulfosalicylic acid (300 g/L), incubated at 4°C
for 1 h and centrifuged; the supernatant was collected in
screw-cap cryovials (Greiner, Kremsmünster, Austria) before
placement on dry ice. The samples were stored at -40°C until
transport to the University of Hohenheim, Stuttgart, Germany, and
stored at -80°C until analyzed.
Pharmacokinetic evaluation.
For each subject, pharmacokinetic variables, such as areas under the
concentration-time curve
(AUC),3 terminal
half-life time (t1/2), total clearance
(Cl) and volume of distribution (Vd) were calculated
from the individual plasma concentration vs. time profiles according to
a noncompartmental model, using the computer program TopFit
(Heinzel et al. 1993
). Areas under the concentration vs.
time curves were calculated according to the linear trapezoid method.
Statistical analysis.
All results are expressed as means ± SEM. The SPSS program (SPSS, Chicago, IL) was used for statistical analyses. To compare the distinct response variables (AUC, peak rise, time of peak increment and total clearance) for main effects of bolus or intermittent dosing and the influence of pretreatment with Omeprazole, paired t test was used. To test for differences in pharmacokinetic responses between healthy subjects and Dengue patients, independent t test was perfomed. Results were considered significant if the P-value was < 0.05.
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RESULTS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The baseline concentrations of Gln and Ala are illustrated in Figure 1A
. Plasma Gln concentrations were borderline low
(Fürst et al. 1990b
), whereas Ala concentrations
were normal (Divino Filho et al. 1997
) and remained
essentially unchanged throughout the study. The pharmacokinetic
responses to bolus intake are shown in Figure 1B
as the
increment of Gln and Ala concentrations over the individual baseline
levels. The peak rise was calculated as the maximum increase of Gln or
Ala plasma concentrations above the basal, individual concentration,
measured at the beginning of each study day. The peak increment in Gln
concentration in response to the 20-g bolus dose of dipeptide was 794
± 107 µmol/L (Table 2
), representing a 1.4-fold increase above the baseline concentration.
The peak increment occurred from 30 to 120 min postdose, with a mean of
49 ± 8 min. Plasma values of Gln and Ala were normal 180 min
after dipeptide administration. The average peak rise in Ala
concentration was 981 ± 147 µmol/L, representing a
2.7-fold increase above baseline concentration. The peak rise occurred
between 30 to 150 min postdose, with a mean of 64 ± 13 min.
Plasma Ala concentrations returned to baseline values at the completion
of the study. In Figure 1C
, the composite curves of the
individual changes in plasma concentrations of Gln and Ala in response
to the intermittent administration are shown. The average peak rise in
Gln concentration was 398 ± 61 µmol/L (Table 2)
,
representing a 0.8-fold increase. The peak increment occurred from 30
to 210 min postdose, with a mean of 146 ± 28 min. The average
peak rise in Ala concentration in response to the dose was 462 ± 85 µmol/L (Table 2)
, which is a 1.4-fold increase above
baseline values. The maximum peak rise occurred between 30 to 150 min
postdose, with a mean of 101 ± 14 min. The results of the
pharmacokinetic calculations are shown in Table 3
. There was a wide variation in the AUC for both Gln and Ala. After the
intermittent administration of Ala-Gln, a steady-state plasma
concentration of Gln and Ala was reached within 120 min after the first
dose. The average AUC
in the steady-state phase was multiplied
by five as a correction for the intermittent dosing. All subjects had
normal hematocrits (Lee et al. 1989
). Packed cell volume
remained stable throughout each study period, indicating that no
dehydration or fluid shifts arose during the study.
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) was not significantly different from
that following the intermittent dosing (AUC · 5) (Table 3)
. The
average peak rise for individual Gln concentrations for the former was
significantly greater than that for the latter (P = 0.003). The time from baseline to attainment of the peak increment, as
mentioned above, was 49 ± 8 min for the bolus and 146 ± 28
min for the intermittent dose (P = 0.009).
For Ala, the accompanying amino acid in the dipeptide, the
within-individual differences between the bolus and intermittent
administration followed an identical pattern to that seen with Gln with
respect to peak rise and time course (data not shown). Areas under the
curve (AUC0) were significantly larger
after the bolus dose than in the steady-state phase after
intermittent dosing (AUC · 5) (P < 0.01, using
paired t test).
Protocol B: influence of Omeprazole-induced gastric acid inhibition on the pharmacokinetics of Ala-Gln.
The integrated response curves for Gln and Ala were not significantly
different after the bolus dose, when subjects received the acid blocker
regimen before ingestion of the dipeptide (Fig. 2
). Furthermore, no significant differences for peak increment across
these two situations of gastric acid secretion were observed when
Ala-Gln was administered as intermittent loads. Comparing the
responses to bolus and intermittent administration of Ala-Gln after
Omeprazole intake, AUC0180, peak height and
time course were not significantly different (data not shown). There
were no differences in Cl, t1/2 and
Vd with or without gastric blocker intake.
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Figure 3
depicts the changes in concentrations of the two index amino acids
derived from the dipeptide; the individual, averaged AUC for the same
analytes are shown in Table 3
. The peak increment of Gln was 942
± 177 µmol/L in Dengue patients compared with 794
± 107 µmol/L in the group of healthy subjects (Fig. 1A
). The time to peak increment of 71 ± 10 min in the
Dengue patients tended to be longer than the 49 ± 8 min observed
in controls (P = 0.09). Pharmacokinetic variables were
not different in healthy controls and Dengue patients (data not shown).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). The majority
of enterally or orally administered Gln is absorbed and subsequently
extracted by the splanchnic bed. We observed a significant increase in
free plasma Gln. This is in good agreement with previous studies in
which the effect of an enteral Gln load was evaluated (Hankard et al. 1995
, Welbourne 1995
, Ziegler et al. 1990
), although there are also studies in which little or
no increase of plasma Gln concentrations was observed (Darmaun et al. 1994
, Long et al. 1995
).
The evaluation of AUC is the usual method to appraise in vivo kinetics.
Because the major interest in the present evaluation was to study the
increment of Gln over time, we disregarded the extracellular Gln pool.
Hence, plasma baseline concentrations of Gln and Ala (t
= 0) on each study day were subtracted from the observed
concentrations throughout the study
(t1,
t2,...,
t11). This means that the average
baseline concentrations (Fig. 1A
) in the fasting state were
not used for this correction to avoid probable effects of fasting
(Darmaun 1995
) and to allow adjustment for individual,
day-to-day variations in plasma baseline levels. Differences in
extracellular Gln might be due to varying amounts, routes of
administration and the timing of the Gln load.
It is interesting to address the question of how comparable are the
differences in circulating Gln concentrations in the two Guatemalan
populations, healthy and infected, with those reported in a previous
study in the U.S. in healthy volunteers who received oral Gln at two
dosage levels (0.1 and 0.3 g/kg) (Ziegler et al. 1990
).
Those authors assessed whole-blood concentration vs. time profiles
of 240 min. The body weight of the healthy population in this study and
in the North American investigation was the same (75 kg); the mean
dosage of Gln in Guatemala was 0.18 g/kg, which falls between the
dosages used in the North American study. To compare the two sets of
data, we assumed a bioavailability factor (F) for Gln and
Ala derived from Ala-Gln dipeptide of 1.0. Indeed, this assumption
is justified, considering the prompt in vivo hydrolysis of Ala-Gln
(Albers et al. 1988
and 1989
), indicating that after
oral administration, the appearance of Gln from the dipeptide might be
practically identical with that of free Gln. This deduction allows the
calculation of Vd per kg body weight, which is 761 vs. 512
mL/kg with 0.1 g/kg and 1254 mL/kg with 0.3 g/kg dosage in the North
American study. Nevertheless, by extrapolating the dosage of the North
American study to 0.18 g/kg as given in this study, the resultant
Vd is comparable (809 mL/kg). Similarly, Vd
derived from the Dengue patients was 1199 mL/kg compared with 1031
mL/kg in the North American study when adjusted to the 0.24 g/kg given
to the patients. After the dose of 0.18 g/kg, we observed an average
maximal plasma concentration of 1342 µmol/L, whereas in
the North American study with a dosage of 0.3 g/kg, a mean
whole-blood concentration of 1328 µmol/L was reported.
Because the transmembrane gradient is 1.1, we may assume that there was
an equal volume of distribution, and thus the concentrations obtained
in plasma or in whole blood are directly comparable.
In our study, Gln t1/2 was 28 min,
which is more rapid than the half-life time reported in the North
American study of 117 min. This finding is interesting in the face of
the classical studies from the late 1960s (Adibi and Phillips 1968
, Matthews et al. 1968
), demonstrating a
specific dipeptide carrier in the intestine. These early reports
emphasized that the transport of amino acids is more rapid from
dipeptides than from free amino acids. Indeed, this notion has been
confirmed repeatedly during the years (Abumrad and Miller 1983
, Ganapathy and Leibach 1986
, Gardner 1975
, Gardner et al. 1983
), and the present
finding may indicate the importance of the favorable physiologic
handling of the Gln dipeptide.
Various tissues, such as muscle, are the major store of intracellular
Gln; the concentration is ~20 mmol/L intracellular water
(Bergström et al. 1974
), with an
intra-/extracellular transmembrane gradient of 30. Consequently, a
change in intracellular concentration after supplemental oral
Gln-dipeptide might considerably influence and complicate
pharmacokinetic calculations. We assume that the healthy adults in our
study were not Gln depleted, and thus the oral Gln administered would
not be taken up by the muscle. This line of reasoning implies that
changes occurring in the extracellular compartment may reflect
postabsorptive Gln handling fairly well. Indeed, we employed a
noncompartmental pharmacokinetic model to avoid all possible influences
of a large intracellular Gln pool.
As shown in Figure 1A
, baseline plasma concentrations of Ala
were lower than those of Gln. Because the constituent amino acids of
the dipeptide were given in equimolar amounts, it is interesting to
note that increments in Ala concentrations are higher than those of Gln
in both relative (fold-increase) and absolute terms. After intravenous
administration of Ala-Gln to healthy adults (Albers et al. 1988
), this pattern was not observed. Reduced splanchnic
extraction of Ala compared with Gln might serve as an explanation.
Alternatively, we may hypothesize that Gln and Ala have different
metabolic handling as far as uptake, initial clearance, and secondary
clearance are concerned. Indeed, these factors may define the course of
plasma Gln and Ala after the dipeptide administration, although the
principal response of the two amino acids is similar.
Despite the within-subject, repeated-measure design, the sample size of only four subjects completing all five components of the Ala-Gln pharmacokinetic study was insufficient to resolve whether lower gastric acidity is a modulating factor. The data, however, showed no significant difference between AUC with and without gastric acid blockade.
Relating the amount of administered Ala-Gln to weight, Dengue fever patients had a significantly higher intake (0.18–0.26 g/kg) than healthy volunteers (0.13–0.20 g/kg). This can be explained by the significantly lower body weight of Dengue patients. Despite the greater uptake, no greater peak increments of the constituent amino acids or greater AUC were observed in Dengue patients. Because Dengue fever is a systemic disease, without specific localization in the gut, it is not surprising that neither digestion of the dipeptide nor uptake of the constituent amino acids was different from that in healthy adults.
Both bolus and intermittent oral administration of the dipeptide Ala-Gln led to similar time vs. concentration responses in healthy adults; only the maximum increment was higher with the bolus dosing. In this study, neither the intake of a gastric acid blocker nor acute febrile Dengue infection affected the pharmacokinetic responses of the constituent amino acids in plasma compared with healthy adults.
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FOOTNOTES |
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Manuscript received April 8, 1999. Initial review completed June 18, 1999. Revision accepted October 18, 1999.
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]) denotes the
timing of administration of oral Ala-Gln doses.
