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Rubbens2016
1. ÔØ Å ÒÙ× Ö ÔØ
Ethanol concentrations in the human gastrointestinal tract after intake of
alcoholic beverages
Jari Rubbens, Joachim Brouwers, Kris Wolfs, Erwin Adams, Jan Tack,
Patrick Augustijns
PII: S0928-0987(16)30039-2
DOI: doi: 10.1016/j.ejps.2016.02.009
Reference: PHASCI 3486
To appear in:
Received date: 8 December 2015
Revised date: 19 January 2016
Accepted date: 14 February 2016
Please cite this article as: Rubbens, Jari, Brouwers, Joachim, Wolfs, Kris, Adams, Erwin,
Tack, Jan, Augustijns, Patrick, Ethanol concentrations in the human gastrointestinal
tract after intake of alcoholic beverages, (2016), doi: 10.1016/j.ejps.2016.02.009
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Ethanol concentrations in the human gastrointestinal tract
after intake of alcoholic beverages.
Jari Rubbensa
, Joachim Brouwersa
, Kris Wolfsb
, Erwin Adamsb
, Jan Tackc
, Patrick Augustijnsa,*
a
KU Leuven, Drug Delivery & Disposition, Gasthuisberg O&N2, Herestraat 49 Box 921, 3000 Leuven,
Belgium, jari.rubbens@kuleuven.be; joachim.brouwers@kuleuven.be; patrick.augustijns@kuleuven.be
b
KU Leuven, Pharmaceutical Analysis, Gasthuisberg O&N2, Herestraat 49 Box 923, 3000 Leuven, Belgium,
kris.wolfs@kuleuven.be; erwin.adams@kuleuven.be
c
KU Leuven, Translational Research Center for Gastrointestinal Disorders (TARGID), Gasthuisberg O&N1,
Herestraat 49 Box 701, 3000 Leuven, Belgium; jan.tack@med.kuleuven.be
*Corresponding author at: KU Leuven, Drug Delivery & Disposition, Campus Gasthuisberg O&N 2, Box 921,
Herestraat 49, 3000 Leuven, Belgium.
E-mail address: patrick.augustijns@pharm.kuleuven.be (P. Augustijns).
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ABSTRACT
Introduction: The goal of this study was to monitor gastric and duodenal ethanol concentrations
arising from the consumption of commonly used alcoholic beverages.
Materials and methods: In a cross-over study, five fasting volunteers were asked to drink two
standard consumptions of commercially available alcoholic beverages, including beer (Stella Artois®,
500 mL, 5.2% ethanol), wine (Blanc du Blanc®, 200 mL, 11% ethanol) and whisky (Gallantry Whisky®,
80 mL, 40% ethanol). The volunteers finished drinking beer within 10 minutes and wine or whisky
within 5 minutes. Ethanol concentrations in gastric and duodenal fluids, aspirated as a function of
time, were analyzed by headspace gas chromatography.
Results: In all three conditions, the average gastric profile shows a maximum ethanol concentration
(Cmax) at 7 minutes, while the mean duodenal profiles have a Tmax at 20, 7 and 12 minutes for beer,
wine and whisky, respectively. The median gastric ethanol Cmax (min – max) for the beer, wine and
whisky conditions amounts to 4.1 % (3.1 – 4.1), 4.1 % (2.6– 7.3) and 11.4 % (6.3 – 21.1), respectively.
The mean duodenal profiles follow the same pattern as their corresponding gastric profiles, albeit
with lower percentages of ethanol. Median duodenal ethanol Cmax (min – max) for beer, wine and
whisky are 1.97% (0.89- 4.3), 2.39 % (2.02 – 5.63) and 5.94 % (3.55 – 17.71), respectively.
Intraluminal ethanol concentrations appear to decline relatively rapidly in fasting conditions: both
stomach and duodenum contained less than 0.05% of ethanol after 120 minutes.
Conclusions: This in vivo study is the first to present intraluminal ethanol concentrations in man after
the intake of alcoholic beverages. Relatively low and fast declining gastric ethanol concentrations
were observed, contrasting with the current Food and Drug Administration guidelines for the in vitro
testing of formulations with respect to ethanol resistance. The presented gastric and duodenal
ethanol concentrations and their variation may serve as reference data to design relevant models for
predicting (i) ethanol resistance of drug formulations and (ii) ethanol effects on drug solubility and
permeability.
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1. Introduction
In clinical trials and bio-equivalence studies, drugs are typically administered orally with 240 mL of
water. (FDA, 2002) This does not necessarily reflect what happens in daily practice. Patients take
their medication with soft drinks, hot drinks or even alcoholic beverages. The resulting intraluminal
alterations in fluid volume, pH, temperature, osmolality and solubilizing capacity can influence the
local behavior of the administered formulation and may cause significant variability in drug
absorption and systemic exposure.
As the consumption of alcoholic beverages is widespread and socially accepted, patients may co-
ingest their medication with ethanol. Many drugs interact with ethanol at a pharmacodynamic
and/or pharmacokinetic level, potentially leading to serious adverse effects. (Lennernäs, 2009)
Ethanol is also known to disrupt the extended release mechanism of formulations resulting in dose
dumping and possible safety concerns. (Jedinger et al., 2014) In 2005, the US Food and Drug
Administration (FDA) requested Perdue Pharma to suspend their extended release pain treatment
drug Palladone®, an extended-release capsule of the opioid analgesic hydromorphone, after the
observation of severe ethanol-induced dose-dumping in healthy volunteers. (FDA, 2005) Compared
with water, ingestion of a single dose of Palladone® with 240 mL of an ethanol solution at 4, 20 and
40%, resulted in an increased mean Cmax of hydromorphone by 1.06-, 1.89-, and 5.53-fold,
respectively. One volunteer even had a 16-fold increase in Cmax when the formulation was co-
ingested with a 40% ethanol solution. (Walden et al., 2007) This type of ethanol induced dose
dumping poses serious safety concern for drugs with a small therapeutic window or known
pharmacodynamic interaction with ethanol. Ever since, the FDA established guidelines to test the
robustness of certain drug formulations towards ethanol in vitro. These tests are required for all
(generic) extended release formulations containing opioid drugs and are preferred for other
modified-release formulations with risk of alcohol-induced dose dumping. (FDA, 2013) (FDA, 2015)
Drug release from the dosage form should be tested during two hours in a medium of 0.1N HCl with
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concentrations of 0, 5, 20 and 40% ethanol in order to simulate the consumption of common
alcoholic beverages like beer (5%), mixed drinks (20%) and liquor (40%). (FDA, 2014)(Anand et al.,
2011) The European Medicines Agency (EMA) recommends in vitro ethanol resistance testing for all
modified-release products and other formulations with scientific grounds for an ethanol effect on
release characteristics. The EMA does not provide authoritative methodological requirements in
terms of minimum testing time or dissolution medium. The dissolution medium should contain
ethanol at levels that are likely to be reached in the proximal gastrointestinal tract: concentrations of
5%, 10% and 20% ethanol are suggested. (EMA, 2009) Based on literature, Lennernas et al.
concluded that the FDA test is physiologically relevant. (Lennernäs, 2009) However, it is important to
note that the relevance of the in vitro test imposed by the FDA has never been judged by in vivo
studies.
Besides the impairment of formulation behavior, high concentrations of ethanol in the stomach and
duodenum may also act as a co-solvent and increase the solubilizing capacity for lipophilic
compounds, resulting in more effective drug absorption. Fagerberg et al. measured the solubilities of
9 lipophilic compounds in fasted state simulated gastric fluids (FaSSGF) with 20% ethanol. (Fagerberg
et al., 2015) A large ethanol-induced increase in solubility was observed for the neutral compounds
and for two out of three weak acids. The solubility of ionized weak bases was unaffected. The same
group also investigated the apparent solubility of 22 poorly soluble compounds in Fasted State
Simulated Intestinal Fluids (FaSSIF) in the presence of 0, 5 and 20% ethanol. The effects of 5%
ethanol were negligible. 13 out of 22 compounds displayed a more than 3-fold increased solubility in
FaSSIF with 20% ethanol, although this effect may be temporarily due to ethanol dilution and
absorption in the intestine. (Fagerberg et al., 2012)(Lennernäs, 2009) A large increase in solubility
may also affect the release mechanism of a drug from its dosage form; diffusion-mediated release
will become more important than erosion-mediated release. (Roberts et al., 2007)
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Ethanol can also enhance drug absorption directly through modulation of the intestinal permeability
by causing mucosal injury, disruption of membrane integrity and even mucosal leakage. (Draper et
al., 1983)(Tarnawski et al., 1985)(Lavo, 1992) Volpe et al. found that ethanol concentrations up to 5%
significantly increased the permeability of oxycodone, oxymorphone and atenolol across Caco-2 cell
monolayers. (Volpe et al., 2008)
The demand for tools to evaluate ethanol impact on formulation performance and drug absorption
on the one hand and the ignorance of relevant in vivo ethanol concentrations on the other hand,
proves the need for further fundamental research in humans. Existing studies on the gastrointestinal
fate of ethanol typically administer an artificial ethanol solution or instill a solution directly into the
stomach through a gastric tube (Johnoson et al., 1991)(Levitt et al., 1997)(Klockhoff et al.,
2002)(Franke et al., 2004)(Halsted et al., 1973), which may affect the disposition of intraluminal
ethanol in a non-relevant manner. The present study therefore aims to assess intraluminal ethanol
concentrations in the stomach and duodenum of healthy volunteers after the consumption of
common alcoholic beverages.
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2. Materials and methods
2.1.Chemicals
Ethanol absolute AnalaR NORMAPUR was purchased from VWR Chemicals (Heverlee, Belgium).
Na2CO3 was purchased from Merck (Darmstadt, Germany). Water was purified by using a Maxima
system (Elga Ltd., High Wycombe Bucks, UK).
2.2.Alcoholic beverages
Gallantry Whisky and Blanc du Blanc Wine were purchased from Aldi market (Leuven, Belgium);
Stella Artois Beer was purchased from Carrefour market (Leuven, Belgium). The characteristics of the
administered beverages are reported in Table 1. pH and osmolality were measured using a Hamilton
SlimTrode pH electrode (Bonaduz, Switzerland) and an Advanced Instruments osmometer model
3250 (Norwood, MA, USA), respectively.
2.3.In vivo study
Five healthy volunteers (3 females, 2 males) were enrolled in a cross-over study. Studies were
performed at the University Hospitals Leuven and were approved by the Committee of Medical
Ethics (ML10920). Candidate volunteers with gastrointestinal diseases, hepatitis B or C or HIV were
excluded. All volunteers gave written informed consent prior to participation. After 12 h of fasting,
two double-lumen catheters (Salem Sump Tube 14 Ch, external diameter 4.7mm; Covidien, Dublin,
Ireland) were introduced trough nose or mouth, and positioned into the stomach and the
duodenum, respectively. Positioning was checked by fluoroscopy. In a cross-over design, volunteers
were asked to drink two standard consumptions of beer, wine or whisky. One standard consumption
was defined as 250 mL beer, 100 mL wine and 40 mL whisky. Volunteers finished drinking beer within
10 minutes and wine or whisky within 5 minutes. Subsequently, gastric and duodenal fluids were
collected for 3 hours. Sample preparation was performed on site immediately after aspiration.
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2.4.Assessment of intraluminal ethanol concentration and osmolality.
Immediately after aspiration, gastric and duodenal aspirates were centrifuged (20,817g, 5 min, room
temperature). Preliminary tests demonstrated that centrifugation did not affect the measured
ethanol level. The supernatant of gastric aspirates was diluted in 0.4 mM Na2CO3 (1:50 for the wine
and whisky conditions, 1:25 for the beer condition). The supernatant of duodenal aspirates was
diluted in purified water (same dilution strength as gastric aspirates). Samples were sealed with
PTFE/Sil-caps in 20 mL crimp top vials (Perkin Elmer, Zaventem, Belgium) and analyzed by a HP6890
gas chromatography system (Wilmington, DE, USA) equipped with a Perkin Elmer (Waltham, MA,
USA) Turbomatrix 40 HS autosampler (balanced pressure system). Headspace parameters were as
follows: oven at 80°C, needle at 120°C, transfer line at 140°C and injector at 160°C. Carrier pressure
was set at 129.9 kPa. The withdrawal time was set at 0.4 s, injection time at 0.04 s and pressurization
time at 1 min. Split ratio of injection was 1/5. Separations were carried out on a ZB-624 column (30 m
x 0.53 mm, 3 µm film thickness) from Phenomenex (Utrecht, The Netherlands) with a flow of 4
mL/min helium 5.6. Detection was performed with a flame ionisation detector at 220 °C, air: 450
ml/min, H2: 40 ml/min, and make-up flow N2: 45 ml/min. Separations were carried out using the
following temperature program: holding for 7 min at 40 °C, heating 40 °C/min towards 240 °C and
holding at 240 °C for 10 min. The osmolality of gastric and duodenal aspirates of healthy volunteer
(HV) 3 was measured with the equipment described in section 2.2.
2.5.Validation
Calibration curves were made in purified water and linearity was observed between 0.8% and 0.003%
ethanol. Accuracy and precision were measured by spiking concentrations of 40, 10, 1.5 and 0.2%
ethanol in blank gastric and duodenal fluids. Following the dilution as described above, all spiked
samples could be analyzed accurately (between 95% and 110%) and precisely [RSD less than 5%
(n=5)]. Interday repeatability was less than 6.2%. Fresh calibration curves were made on each
analysis day. Quality controls of 0.08% and 0.005% ethanol were made in water and stored in the
freezer. They were thawed and analyzed together with the gastrointestinal samples. Ethanol
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concentrations in QC samples could be determined accurately (between 98% and 102%) and
precisely (RSD less than 5%).
3. Results
Average ethanol concentrations in the stomach and duodenum as a function of time after intake of
two glasses of beer, wine or whisky are depicted in Figure 1. In all conditions, the average gastric
profile shows a Tmax at 7 minutes, followed by a non-linear decline of ethanol levels over time. The
average gastric Cmax is similar for the beer and wine condition (3.6 and 3.9 % ethanol, respectively)
and higher for the whisky condition (11.1 % ethanol) which was accompanied with more variation.
The duodenal Tmax values of the average profiles for the beer, wine and whisky condition are at 20, 7
and 12 minutes, respectively. The mean duodenal profiles follow the same pattern as the
corresponding gastric profiles but depict lower percentages of ethanol. Intraluminal ethanol
concentrations appear to decline relatively rapidly in fasting conditions as stomach and duodenal
fluids contain less than 0.05% of ethanol after two hours in all conditions.
The interindividual variation in maximum ethanol concentrations and the degree of gastric dilution
are reported in Table 2. The variation is expressed by the median and the range in the observed
ethanol concentrations. The degree of dilution is calculated as the ratio of alcohol content in the
administered beverage to the gastric Cmax. In all conditions, the median duodenal Cmax is about half
than the median gastric Cmax. The observed interindividual variation on both gastric and duodenal
ethanol Cmax is most pronounced after intake of whisky, but very limited following the consumption
of beer. Maximum gastric ethanol concentrations were always lower than the ethanol content of the
beverage, resulting in a median degree of gastric dilution of 1.4 (beer) and 3.9 (wine and whisky).
The intake of alcoholic beverages resulted in a significant increase in intraluminal osmolality, as was
demonstrated for the samples collected from HV 3. The average osmolality of samples absent of
ethanol was 123 mOsm/kg (SD 51, n=18) and 187 mOsm/kg (SD 42, n=17) for stomach and duodenal
fluids, respectively. In the presence of ethanol, the osmolality increased proportionally to the ethanol
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4. Discussion
In vivo, intraluminal ethanol levels arising from the consumption of an alcoholic beverage are the
result of many interacting processes. In all conditions, the maximum gastric ethanol concentrations
were lower than the ethanol content of the corresponding beverages, indicating that at least part of
the ethanol is immediately diluted, absorbed and/or transferred upon arrival in the stomach. (Levitt
et al., 1997) Considering the relatively small residual volume in the stomach (on average 45 ml
according to Schiller et al, 2005), the observed degree of dilution was related to the volume ingested
and most distinct after intake of 80 mL of whisky and 200 mL of wine, but limited after intake of 500
mL of beer (Table 2). The relatively large degree of dilution after ingesting wine (3.85) and whisky
(3.89) contrasts the statement by Lennernäs et al. who claim gastric dilution to only minimally affect
intragastric ethanol concentrations when the ingested volume is large enough (>120 mL). (Lennernäs,
2009) Interestingly, the observed inter-individual variability in gastric dilution and maximum gastric
ethanol concentrations (Table 2) decreases when a larger volume is ingested (variability for whiskey >
wine > beer).
The highest average gastric Cmax is found in the whisky condition and amounts to 11% ethanol. The
average intragastric Cmax in the beer and wine condition are similar with 3.6% and 3.9%, respectively.
Previously reported intragastric ethanol concentrations after intake of an alcohol-containing drink
amounted up to 10%, even though the administered ethanol dose was about 2.5-fold higher
compared to the whisky condition in the present study. (Halsted et al., 1973) The gastric ethanol
peak is followed by a relatively fast decline as the average gastric profile shows less than 0.5%
alcohol after 90 minutes. Ethanol is diluted by a basal gastric fluid secretion of 1mL/min (Koziolek et
al., 2013) which is further stimulated by small alcohol concentrations (5 and 10% ethanol) and by
non-alcoholic ingredients in alcoholic beverages (particularly for beer and wine). (Lenz et al., 1983)
(Chari et al., 1993)(Peterson et al., 1986) In addition, ethanol, as a small neutral molecule, may
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passively diffuse trough gastric mucosa. Levitt et al. estimated that 10% of the administered ethanol
is absorbed by the gastric mucosa. (Levitt and Levitt, 1994)
Differences in the duodenal Tmax may indicate differences in gastric emptying rate of ethanol to the
duodenum. The duodenal Tmax in thisstudy varies from 2 to 30 minutes (Table 2). The median Tmax in
the wine and whisky condition is 12 minutes while the median Tmax in the beer condition is 7 minutes,
suggesting beer to be emptied slightly faster. Some individual profiles (5 out of 15) have a duodenal
Tmax at 2 or 7 minutes which was even shorter than the gastric Tmax; this was accompanied with a
higher ethanol concentration in the duodenum than in the stomach (data not shown) and indicates a
swift, almost instantaneous, transfer of beverage to the duodenum. The gastric emptying rate is
affected by multiple beverage characteristics. Beverages consumed in larger volumes are usually
emptied at a faster rate from the stomach. (Hunt and Spurrell, 1951)(Costill and Saltin,
1974)(Mitchell and Voss, 1991). The gastric emptying time is increased by intake of beverages with a
lower pH (Lin et al., 1990)(Chaw et al., 2001), higher caloric value (Hunt and Stubbs, 1975)(Meeroff et
al., 1975), and higher osmotic value. (Meeroff et al., 1975) Irrespective of its intrinsic caloric and
osmotic value, ethanol itself will delay gastric emptying depending on its concentration. (Franke et
al., 2004)(Kaufman and Kaye, 1979) Moreover, Franke et al. suggested that beer and wine, but not
whisky, contain non-alcoholic ingredients that may slow down gastric emptying. (Franke et al., 2004)
The beverages selected for the present study substantially vary in all of these characteristics (Table
1). No straightforward relation was found between beverage characteristics and gastric emptying. It
should be noted that such a mechanistic investigation requires a specific study design, which was
outside the scope of this study.
Following transfer from the stomach, ethanol concentrations are affected by dilution with intestinal
fluids, transit, and absorption of ethanol. The resulting average intraduodenal ethanol concentrations
are depicted in Figure 1. The highest average duodenal Cmax is found in the whisky condition and
amounts to 6.5% ethanol. An average intraduodenal Cmax of 2.7 % and 1.5% ethanol is reached in the
wine and beer condition, respectively. These observations are in line with the maximal duodenal
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concentrations reported by Halsted et al. (between 1.25 and 6.25%). (Halsted et al., 1973) After this
ethanol peak and similar to the gastric profiles, a fast decline in duodenal ethanol levels is observed.
The average duodenal profile shows less than 0.2% alcohol after 90 minutes. The interindividual
variation of these concentrations is depicted in Table 2. Whisky, with a median Cmax of 5.9% duodenal
ethanol (3.6 -17.7) has the highest variability; two volunteers even reached a duodenal Cmax of 17.7%
and 9.6% ethanol, respectively.
Interestingly, all studied beverages are highly hyperosmotic and significantly affect intraluminal
osmolality. (Meeroff et al., 1975). The strong linear correlation between ethanol and osmolality for
both gastric and duodenal samples (Figure 2.), clearly proves that ethanol is the major factor
determing intraluminal osmolality.
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5. Implications and conclusion
Intraluminal ethanol concentrations originating from the consumption of common popular alcoholic
drinks were assessed for the first time. The gastric ethanol concentrations observed in this study and
their fast decline over time contrast current FDA guidelines for evaluating ethanol resistance of
modified release formulations. Despite the fact that the administration of two standard
consumptions within only 5 (wine, whisky) or 10 minutes (beer) reflects worst-case conditions in
real-life practice, median Cmax-values were only 4.1% for beer and wine, and 11.4% for whiskey. The
FDA guideline to test formulations in the presence of 40% ethanol seems excessive as this study only
observes a maximum concentration of 21.1% ethanol after intake of whisky. In addition, the
proposed time window of two hours seems exaggerated as the stomach contains less than 0.05%
ethanol after two hours in all tested conditions. The ethanol concentrations suggested by the EMA
for in vitro testing fit better with the gastric ethanol levels observed in this study, although the gastric
ethanol level of 21.1% was only observed at one sampling point in one out of five volunteers.
Fagerberg et al. described that the presence of 20% ethanol in the stomach may significantly
increase the solubility and bioavailability of certain compounds. (Fagerberg et al., 2015) Considering
the observed rapid decrease of intragastric ethanol levels however, this is unlikely to occur in
practice. In addition, intraduodenal ethanol concentrations do not reach levels as high as needed in
order to affect local drug solubility according to Fagerberg et al. (Fagerberg et al., 2012) In our study
only two volunteers reached a duodenal Cmax of 17.7% and 9.6% ethanol after intake of whisky; in all
other cases, the duodenal Cmax never exceeded 5.6% ethanol.
In conclusion, this in vivo study is the first to present physiologically relevant ethanol concentrations
and their variation, which may serve as reference data to further investigate the impact of
intraluminal ethanol on drug formulations, solubility and permeability in fasting conditions. Further
research is needed on ethanol concentrations in the fed state.
Acknowledgment
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Figure legends
Figure 1. Mean gastric and duodenal concentration-time profiles for ethanol after the administration
of (a) 500 mL of beer, (b) 200 mL of wine, and (c) 80 mL of whisky. Black (●) and white (◌) dots depict
gastric and duodenal ethanol concentrations, respectively (±SEM, n=5).
Figure 2. Correlation between intraluminal osmolality and intraluminal ethanol concentration in
samples from HV 3. Correlations for both gastric and duodenal samples were indicated using
Pearson’s correlation coefficient (r). Dots represent the beer condition, squares represent the wine
condition and triangles represent the whisky condition. Black and white dots represent gastric and
duodenal aspirates, respectively.
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Table legends
Table 1. Characteristics of administrated beverages.
Table 2. Key parameters (Cmax, Tmax, degree of gastric dilution) of the ethanol concentration-time
profiles in stomach and duodenum (data presented as median and range).
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Tables
Table 1.
Beverage Volume administrated (mL) Alcohol content
(% ethanol)
pH Caloric Value
(Kcal)
a
Osmolality
(mOsm/kg)
Beer 500 5.2 4.09 960 2170
Wine 200 11 3.21 682 1085
Whisky 80 40 4.19 812 7208
a
According to the Dutch nutrition databank. (RIVM, 2013)
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Table 2.
Beverage Stomach Duodenum
Beer (5,2% Ethanol)
Median Cmax (min - max)
a
4.1 (3.1 - 4.1) 2.0 (0.9 - 4.3)
Median Tmax (min - max)
b
7 (2 - 12) 7 (2 - 20)
Median degree of dilution (min - max)
c
1.37 (1.27 – 1.67)
Wine (11% Ethanol)
Median Cmax (min - max)
a
4.1 (2.6 - 7.3) 2.4 (2.0 - 5.6)
Median Tmax (min - max)
b
12 (7 - 20) 12 (7 - 30)
Median degree of dilution (min - max)
c
3.85 (1.50 – 4.24)
Whisky (40% Ethanol)
Median Cmax (min - max)
a
11.4 (6.3 - 21.1) 5.9 (3.6 - 17.7)
Median Tmax (min - max)
b
20 (7 -20) 12 (7 - 30)
Median degree of dilution (min - max)
c
3.89 (1.89 – 6.34)
a
Expressed as % ethanol
b
Expressed as minutes
b
Calculated as the ratio of the alcohol content in the administered beverage to the Cmax in the stomach
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