Review

Drug interactions involving

ethanol and alcoholic beverages
Graham R Jang & Robert Z Harris

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Amgen,

1.

Introduction

2.

Body of review

3.

Expert opinion

Inc., Department of Pharmacokinetics and Drug Metabolism, One Amgen Center Dr,
Thousand Oaks, CA, 91320, USA

Ethanol is likely among the most widely and extensively used drugs in
the world. It has also been demonstrated to alter the expression or activity
of some drug-metabolizing enzymes. Thus, marked ethanol-provoked
drug interactions could be of notable clinical importance. To date, relatively
few clinically important interactions have been reported, involving
cocaine, disulfiram and tacrolimus. Limited or modest interactions with
ethanol have also been reported for drugs such as abacavir, cisapride, ecstasy
(3,4-methylenedioxymetamfetamine), -hydroxybutyrate, methylyphenidate,
metronidazole and verapamil. Most of these interactions do not seem to
involve CYP2E1, the enzyme initially characterized and cloned based on its
ability to metabolize and be induced by ethanol. Important work has
elucidated the relationship between CYP2E1-mediated formation of the
hepatotoxic metabolite of acetaminophen and alcohol consumption.
Lastly, drug interactions involving other components of alcoholic beverages
such as flavonoid and other polyphenolic components of red wine have
been reported.
Keywords: alcohol, alcohol dehydrogenase, aldehyde dehydrogenase, cocaine, disulfiram,
drug interaction, ethanol CYP2E1, tacrolimus
Expert Opin. Drug Metab. Toxicol. (2007) 3(5):719-731

1.

Introduction

Based on recent estimates from the World Health Organization, 2 billion people
worldwide regularly consume ethanol [201]. This, along with evidence of beer and
wine consumption dating to 4000 10,000 BC [1], likely renders ethanol among
the longest and most widely used drugs in human history. The chronic consumption
of alcohol can lead to marked changes in drug-metabolizing enzymes, resulting in
altered drug, other xenobiotic and metabolite concentrations. This, in turn, can
lead to differences in pharmacologic, toxicologic or carcinogenic effects between
regular ethanol consumers and those that abstain. In addition, interactions with
acute ethanol consumption may also be possible as a result of competitive inhibition
with a co-administered drug that shares the same enzyme in its metabolic fate.
The aims of this review are several-fold. For the unfamiliar, a concise but
judiciously detailed summary of ethanol disposition, the enzymes involved and the
major effects of ethanol on enzyme expression and activity is provided, paying
particular attention to CYP2E1. This will hopefully provide the reader with
sufficient insight into how varying levels of ethanol consumption might be expected
to alter concomitant drug disposition. In turn, this is anticipated to allow more
informed perusal of the specific drug interaction cases that follow, which include
examples where ethanol affects the metabolism of other drugs and, vice versa, where
ethanol is the victim. Lastly, although there is extensive literature describing the
association between alcohol consumption and particular carcinogen activation or
specific cancer risk, as well as instances of drug interactions of a pharmacodynamic
nature, these literatures are beyond the scope of this work.
10.1517/17425255.3.5.719 2007 Informa UK Ltd ISSN 1742-5255

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Drug interactions involving ethanol and alcoholic beverages

2.

Body of review

2.1

Ethanol disposition

Following consumption of ethanol, 10% or less of

the imbibed quantity or dose is eliminated by first-pass
gastric, intestinal and hepatic metabolism [2]. Ethanol is
oxidized predominantly by alcohol dehydrogenase (ADH)
enzymes (for which multiple classes exist) in the liver to
acetaldehyde. A liver microsomal ethanol-oxidizing system
(MEOS) capable of converting ethanol to acetaldehyde,
distinct from alcohol dehydrogenase, was characterized by
Lieber and colleagues in the 1970s and shown to be induced
by ethanol in rats [3-5]. The Km for converting ethanol to
acetaldehyde is roughly an order of magnitude higher for the
MEOS ( 10 mM) compared with ADH [3], suggesting that
the latter enzyme is the predominant ethanol-metabolizing
enzyme in vivo at low blood alcohol concentration (BAC). It
is generally accepted that CYP2E1 is the major component of
the MEOS, although other CYPs seem capable of oxidizing
ethanol to acetaldehyde in vitro, including CYPs 1A2
and 3A4 [6].
It is estimated that the contribution of CYP2E1 to ethanol
oxidation at low BACs (e.g., 10 mM) is 20%, but
that this proportion increases to > 50% at higher BACs
(e.g., > 0.08% [80 mg/dl or 17 mM], the legal limit for
driving in some countries) or in individuals that regularly
consume ethanol, in whom CYP2E1 levels in the liver may
be markedly induced [4]. Once ethanol-metabolizing enzymes
are saturated, the elimination of ethanol is generally described
by zero-order (i.e., constant) elimination, with the rate
of elimination determined to be higher on average in men
( 7 g/h) than women ( 5.5 g/h) [7].
Of note, the primary metabolite of ethanol, acetaldehyde,
is considered the key mediator of the unpleasant effects
(e.g., headache, flushing, nausea, vomiting) associated with
excessive (or in some individuals, even minor) alcohol
consumption. Acetaldehyde is converted to acetate by
aldehyde dehydrogenase (ALDH) enzymes, primarily those
in the liver. As noted below, there are examples of drug
interactions with ethanol that involve ALDH.
2.2

Ethanol effects on drug metabolizing enzymes

CYP2E1

2.2.1

As noted above, CYP2E1 was originally identified, characterized and cloned as a component of the ethanol-inducible
MEOS in preclinical species and, in humans, is expressed
and inducible in the liver, kidney and lung [8]. Ethanol
induces CYP2E1 via multiple mechanisms, including
stimulation of gene transcription, enhanced translational
efficiency and protein stabilization [8]. Interactions between
ethanol and other substrates of this enzyme may be
dependent on the timing of beverage consumption and drug
administration, as circulating ethanol can theoretically inhibit
CYP2E1-mediated metabolism of the coadministered drug.
Examples of other drug or xenobiotic substrates of
720

CYP2E1 are acetaminophen, tamoxifen, disulfiram, halothane,

enflurane and the muscle relaxant chlorzoxazone (CZX) [8].
The specificity of 6-hydroxy-chlorzoxazone (6-OH-CZX)
formation, the major route of CZX metabolism, to CYP2E1
warrants discussion, given the large number of studies
that have utilized this drug as a clinical probe of CYP2E1
expression and activity. Some studies with human liver
microsomes, inhibitory chemicals or antibodies, and/or
recombinantly-expressed enzymes have indicated that
6-OH-CZX formation is quite specific to CYP2E1, whereas
others have indicated the potential involvement of other
enzymes (CYP1A1, CYP1A2 and CYP3A4) [9-11]. Of note, as
discussed in Section 2.2.2, chronic ethanol administration does
not seem to markedly induce hepatic CYP3A4 activity (based
on the disposition of intravenously administered midazolam,
a prototypical CYP3A4 substrate) and CZX oral clearance
(CL) does not differ between non-smokers and smokers (in
whom CYP1A enzymes would presumably be induced). In
contrast, ethanol consumption clearly has a marked effect on
CZX disposition, suggesting a major, if not predominant,
role of CYP2E1 in the in vivo metabolism of CZX.
Following oral administration of CZX to 15 alcoholic
(mean ethanol intake 333 g/day over a mean period of
15.7 years) and 20 healthy (ethanol intake < 100 g/week)
male subjects, the oral CL of CZX was 73% higher, Cmax
37% lower and 6-OH-CZX plasma levels 2-fold greater in
alcoholics [12]. In the alcoholics, circulating levels of
liver enzymes (e.g., aspartate or alanine aminotransferases)
indicative of liver damage were on average 3- to 16-fold
those of the control subjects. This study also indicated
that differences in the 6-OH-CZX/CZX AUC ratio
(2-fold higher in alcoholics) correlate relatively well with the
6-OH-CZX/CZX ratio at a single time-point of 2 h postdose
(2.5-fold higher in alcoholics). In another study, alcoholics
(5 of 17 displaying biopsy evidence of liver lesions) displayed
an 2-fold higher oral CL and 38% lower Cmax of CZX
relative to non-alcoholics, but the same terminal-phase
half-life [13], suggesting that increased liver CYP2E1 activity
in alcoholics has a more marked effect on first-pass than
systemic CZX elimination.
Two more recent studies have evaluated the time course
and extent of induction of CYP2E1 in humans (based on
CZX disposition) with more moderate ethanol consumption
(relative to alcoholics). In one study, five male volunteers with
relatively low, baseline ethanol consumption (< 40 g/week, or
the equivalent of roughly half a 750 ml bottle of 12% ethanol
w/v wine) abstained from alcohol for 1 week, then proceeded
to consume 40 g/day (in red wine) for 4 weeks [14]. Although
the authors describe this level of ethanol intake as moderate,
it should be noted that 40 g/day exceeds recommended daily
intake in numerous countries. The subjects were administered
CZX (500 mg p.o.) and 6-OH-CZX/CZX ratios in plasma
2 h postdose were assessed at baseline and weekly through
the end of treatment. During the 4 weeks of ethanol
consumption, the median 6-OH-CZX/CZX ratio increased

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Jang & Harris

steadily up to approximately fourfold, with individual

ratios increasing greater than twofold in all but one subject.
It is of interest to note that the fold changes in the
6-OH-CZX/CZX ratio for four of the five subjects were
comparable to or greater than the difference in the ratio
noted above between alcoholics and non-alcoholics. This
would seem to suggest that the moderate level of intake
employed in this study may have resulted in maximal
or near-maximal ethanol inductive effects on CYP2E1
after 4 weeks.
The effects of lower ethanol consumption (20 30 g/day)
on CZX disposition have also been assessed based on an
across-group comparison. In the study, 20 subjects who
reported that they regularly consume ethanol 140 210 g/week
(duration 5 years) and 20 age- and sex-matched subjects
who reported lack of ethanol consumption were given an
oral dose of CZX 500 mg [15]. The mean oral CL of CZX
was 42% higher in the ethanol consuming versus abstaining
group (p < 0.05). If one assumes that the subjects in
this study accurately reported ethanol consumption of
20 30 g/day, which is within the recommended daily intake
guideline for most countries, this level of intake is associated
with an increased oral CL of CZX roughly half that observed
in alcoholics.
In one of the studies noted above [14], five alcoholics
(mean ethanol intake 282 g/day; mean duration of excess
consumption 23.4 years; two of five with evidence of cirhossis
or fibrosis) abstained from alcohol and 6-OH-CZX/CZX
ratios were determined (2 h after 750 mg p.o.) within 1 day,
then 3, 8, and 15 days after their last drink. The median
6-OH-CZX/CZX ratio decreased to a level comparable to the
baseline level for the non-alcoholics by 8 days. This result is
consistent with an earlier study, which demonstrated that
an approximately threefold higher rate of chlorzoxazone
metabolism in alcoholics (relative to nonalcoholic controls)
was essentially abolished after 8 or more days of
abstinence [16]. These data illustrate the relatively rapid rate
at which the inductive effects of ethanol on CYP2E1 are
diminished following cessation of alcohol consumption.
Collectively, these studies perhaps provide a meter by
which the interested reader can gauge the potential state of
CYP2E1 induction for subjects in some of the studies
summarized here, or indeed in themselves, based on average
daily ethanol intake.
2.2.2

CYP3A4

It is generally viewed that this enzyme is involved in the

oxidative metabolism of approximately half or more marketed
drugs, thus significant ethanol effects on its expression or
activity would have important implications to therapeutic
drug use. Studies in rats with primary human hepatocytes or
using a human hepatocellular carcinoma cell line genetically
modified to stably express CYP3A4 indicated that ethanol
was capable of inducing CYP3A enzymes in preclinical
species or in vitro [17]. In the above noted study that

enrolled 20 ethanol-consuming and 20 ethanol-abstaining

subjects [15], the pharmacokinetics (PK) of midazolam was
assessed after oral and intravenous administration. Mean CL
and half-life values after intravenous administration were
virtually identical between groups, indicating that ethanol
consumption of 20 30 g/day does not affect hepatic
CYP3A4. However, oral bioavailability of MDZ was modestly reduced (by 26%), suggesting that intestinal CYP3A4
was weakly induced. Given the wide inter-subject variability
in CYP3A4 expression, this level of intestinal CYP3A4
induction is likely of limited clinical significance.
Although it was reported that initial intravenous doses
of fentanyl (a CYP3A4 substrate) required for effective
anesthesia were 60% higher in alcoholics relative to
control subjects, maintenance doses did not differ [18].
The clearance of alfentanil, which is primarily metabolized
by CYP3A4 in vivo [19], was slightly lower on average
( 160 versus 190 ml/min) in subjects with alcoholic
liver disease relative to control subjects [20], although in such
subjects the effects of liver disease and ethanol on metabolic
enzymes may be confounded.
As noted above, in vitro studies with recombinantly
expressed CYPs and human liver microsomes have suggested
that most CYPs, including CYP3A4, are capable of oxidizing
ethanol to acetaldehyde. This finding suggests that acute
ethanol exposure could potentially inhibit the metabolism of
co-administered drugs that are CYP3A4 substrates. Two
reported interactions discussed in Section 2.3.5 suggest that
the magnitudes of such effects are small.
2.3 Effects of ethanol on the disposition
of other drugs
2.3.1 Acetaminophen

CYP2E1 is capable of activating acetaminophen to its

hepatotoxic metabolite, N-acetyl-p-benzoquinone amine
(NAPQI), although CYPs 1A2 and 3A4 may also
contribute [21,22]. Numerous studies or case reports have
assessed or described a potential increased incidence of
acetaminophen-induced hepatotoxicity in alcoholics relative
to non-alcoholics, but a correlation is not clear [23-25].
Two randomized, double-blind studies in alcoholics using
the maximum recommended daily dose of acetaminophen
did not indicate increased risk of hepatotoxicity [26,27].
Nonetheless, increased CYP2E1 levels from chronic ethanol
consumption would be expected to generate higher levels
of the toxic metabolite. However, NAPQI is detoxified via
conjugation to glutathione, therefore clinical consequences of
its increased formation would also depend upon liver
glutathione S-transferase activity (potentially impaired in
alcoholics with liver disease) and hepatic glutathione
levels (influenced by nutritional status). Furthermore,
concomitantly ingested ethanol can potentially competitively
inhibit CYP2E1-mediated formation of NAPQI, thus
counteracting an increased rate of formation by
ethanol-induced CYP2E1. Therefore, the timing of ethanol

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Drug interactions involving ethanol and alcoholic beverages

and acetaminophen administration can potentially influence

the nature and extent of the interaction.
The effect of short-term ethanol exposure, similar to that
potentially observed in a social setting, on NAPQI formation
was investigated in 10 nonalcoholic subjects [28]. Ethanol was
infused intravenously for 6 h at a target BAC of 100 mg/dl
( 20 mM), with the resulting exposure deemed to approximate that from consumption of a 750-ml bottle of wine or
a six-pack of beer. Eight hours after the end of the infusion,
acetaminophen was dosed orally. At that time, BACs
were confirmed (in 7 of 10 subjects) or estimated to be
< 10 mg/dl ( 2 mM), thus competitive inhibition of
CYP2E1 by circulating ethanol was considered minimized.
On average, ethanol administration was found to increase the
formation of NAPQI by 22% (range: 2 38%), suggesting
only a marginal increase in hepatotoxic risk. The investigators
also developed a mathematical model to describe CYP2E1
induction by ethanol, which predicted that consumption of
50 bottles of wine over 8 days would lead to an approximate
doubling in NAPQI formation. Thus, because estimates
of hepatotoxic acetaminophen doses are in the range of
8 16 g (as a single dose) [29,30], it has been suggested that
ethanol consumption, even in alcoholics, is unlikely to
increase hepatotoxic risk at the label-recommended
maximum of four 1-g doses per day [30].
2.3.2

Caffeine

Caffeine is metabolized primarily by CYP1A2, although

there is in vitro evidence that it is also metabolized by
CYPs 2E1 and 3A4 [31,32]. In addition, as noted above,
CYPs 1A2 and 3A4 are capable of oxidizing ethanol to
acetaldehyde in vitro [6]. Thus, ethanol could theoretically
inhibit caffeine metabolism through competitive inhibition
at all three CYPs. Indeed, several studies have reported
lower rates of caffeine metabolism in alcoholics [33] or
that concomitant consumption of ethanol 0.8 g/kg and
caffeine in healthy volunteers results in statistically significant
increases in caffeine exposure. In contrast, it has been
demonstrated that 3.57 ml/kg of Red Bull energy drink
( 80 mg caffeine) did not affect BACs after consumption of
ethanol 0.6 or 1 g/kg [34].
2.3.3

Cocaine

It was determined almost 30 years ago that the

coadministration of ethanol and cocaine leads to the
formation of a novel metabolite, cocaethylene [35], and more
recent studies have demonstrated that this metabolite is
formed via carboxyesterase-mediated transesterifaction between
ethanol and cocaine [36,37]. In ethanol-consuming cocaine
users, a mean ratio of circulating cocaethylene to cocaine of
1.3 was reported [38]. This interaction clearly has clinical
importance, as cocaethylene is active (either equipotent or
less potent than cocaine based on dopaminergic or serotinergic
effects, respectively) and also seems to enhance the
cardiovascular and hepatic toxicity of cocaine [39].
722

2.3.4

Methylphenidate

DL-Methylphenidate (MPH) is used in the treatment of

attention-deficit hyperactivity/disorder. In 19 healthy male

and female subjects, the consumption of ethanol (0.6 g/kg)
either 30 min prior or 30 min after an oral dose of DL-MPH
(0.3 mg/kg) resulted in 40 and 25% mean increases in
Cmax and AUC, respectively, for D-MPH when compared
with DL-MPH administration alone (p < 0.0001) [40]. The
L-enantiomer circulated at levels only 1 3% those of the
D-enantiomer and effects of ethanol on its plasma levels were
not statistically significant. The authors hypothesized that the
interaction is due to ethanol inhibition of esterase-mediated
MPH hydrolysis. In addition, the magnitude of the
interaction was proposed as clinically important due to a
reported correlation between abuse liability and higher
MPH exposure [41].
2.3.5

Ecstasy and -hydroxybutyrate

3,4-Methylenedioxymetamfetamine (MDMA or ecstasy)

is a commonly used recreational drug for its ability to produce feelings of euphoria, empathy and peacefulness [42].
Simultaneous alcohol and MDMA consumption has been
reported in a significant proportion ( 40%) of users [43],
prompting investigation of a potential drug interaction [44].
In nine male volunteers, the coadministration of ethanol
0.8 g/kg (as vodka in tonic water) with MDMA 100 mg
resulted in a statistically significant (p = 0.007), albeit modest
( 13%), increase in the mean Cmax of MDMA, with
no change in Tmax or AUC. The authors noted that the
magnitude of the effect was within inter-subject variability in
exposure, suggesting limited clinical significance of the altered
MDMA disposition. However, a pharmacodynamic interaction was observed, with the duration of euphoria for the
MDMA-alcohol combination over twice as long as that for
MDMA alone. The lack of a marked pharmacokinetic
interaction is perhaps not surprising, given that MDMA
is metabolized (in vitro) predominantly by CYP2D6, with
minor contributions from CYPs 1A2, 2B6 and 3A4 [45,46].
As noted above, CYP3A4 is capable of metabolizing ethanol
in vitro. Thus, the modest pharmacokinetic interaction
between MDMA and ethanol could theoretically be
attributable to competitive inhibition of the minor,
CYP3A4-mediated component of MDMA metabolism.
A potential interaction between ethanol and another drug
of abuse, -hydroxybutyrate (GHB), has been evaluated. A
total of 16 healthy adults were given GHB 50 mg/kg with or
without ethanol 0.6 g/kg in a crossover study design. On
average, ethanol caused a 16% higher Cmax and 29% longer
half-life for GHB, although the effects were not statistically
significant [47]. To the authors knowledge, the enzymes involved in GHB elimination have not been thoroughly evaluated
to date, although there has been report of a life-threatening
interaction between the HIV protease inhibitors ritonavir and
saquinavir and both MDMA and GHB [48]. Ritonavir and
saquinavir are potent inactivators of CYP3A4 [49], suggesting

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Jang & Harris

that GHB, similar to MDMA, is at least partly metabolized

by this enzyme. If GHB is metabolized primarily by CYP3A4,
these data suggest that acute alcohol intake does not
markedly affect CYP3A4 activity.

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2.3.6

Interaction at alcohol dehydrogenase

One study has demonstrated an interaction between ethanol

and another drug that involves ADH and not CYP2E1. In
24 adults infected with HIV, the effects of coadministration
of ethanol 0.7 g/kg on the pharmacokinetics of abacavir, a
nucleoside analog metabolized predominantly by ADH
and UDP glucuronosyltransferase enzymes, were assessed [50].
On average, the Cmax and AUC of abacavir were increased
15 and 41%, respectively, and its half-life prolonged by
26%. This was accompanied by a marked ( 66%) decrease
in urinary excretion of the carboxylate (ADH-generated)
metabolite and an increase ( 45%) in urinary excretion
of the glucuronide. The increased abacavir exposures with
ethanol were noted to be within the range observed with
previous monotherapy, and were thus deemed of little clinical
concern. No effects of abacavir on ethanol pharmacokinetics
were observed. Thus, in this example of an ADH-based interaction involving ethanol and another drug, inhibition of the
ADH-meidated pathway led to a larger fraction metabolized
via the alternate metabolic pathway (glucuronidation). It
seems likely, however, that for a drug that is entirely or largely
metabolized by ADH, a more marked and perhaps clinically
important drug interaction with ethanol could occur.
2.3.7

Isoniazid and dapsone

A major route of metabolism for isoniazid and dapsone

is acetylation, thus it was hypothesized that increased
acetyl-coenzyme A following ethanol ingestion (derived from
acetaldehyde oxidation to acetate) would lead to their more
rapid elimination due to enhanced acetyltransferase activity.
The effect of consuming ethanol 0.73 g/kg 1 h prior to
receiving oral isoniazid, followed by consumption of ethanol
0.11 g/kg every hour for 7 h, was evaluated in 16 healthy
male subjects in a crossover study design [51]. This ethanol
regimen was not found to affect isoniazid half-life nor the
ratio of acetylated metabolite to parent (3 h postdose). The
unaffected 3 h postdose metabolite/parent ratio was noted to
be similar to results published 10 years earlier for dapsone [52].
Thus, it seems unlikely that ethanol consumption, at the levels
assessed in these studies, will affect the pharmacokinetics of
drugs eliminated primarily via acetylation.
2.3.8

Warfarin

In studies published over 20 years ago, it was demonstrated

that acute consumption of ethanol 41 g (in wine) or daily
consumption of ethanol 28 56 g (in wine) had no effects
on warfarin levels or prothrombin time in healthy adults
or patients undergoing anticoagulation therapy [53-55].
More recently, there was a case report of a 58-year old
man on long-term, stable anticoagulation therapy whose

international normalized ratio (INR; a measure of warfarins

antithrombotic effect) markedly increased when he began
consuming half a can of beer (ethanol 5 g) every other day
for its purported cardiovascular benefits [56]. It should be
noted that, at the time, the individual suffered from a host of
other medical complications and was taking eight other medications daily, including metoprolol, aspirin, rosiglitazone,
atorvastatin, gemfibrozil and levothyroxine. The authors of
the report offer several hypotheses to explain the interaction,
such as ethanol inhibiting the binding of warfarin to albumin
or the inhibition of CYP1A2, the principal enzyme involved
in warfarin metabolism, by ethanol or prenylflavonoids in
beer. Interference with warfarin binding to albumin, which
has been demonstrated in vitro [57], would indeed lead to a
higher fraction of unbound warfarin that could in theory
increase its pharmacologic activity, but it would also lead to
more rapid elimination of the drug, potentially offsetting the
effects of protein displacement. Although it has been demonstrated in vitro that CYP1A2 is capable of oxidizing ethanol
to acetaldehyde, the small amount of ethanol consumed renders it likely that ADH-mediated metabolism predominated
(i.e., if only a very small proportion of ethanol were being
oxidized by CYP1A2, competitive inhibition would be minimal). Prenylflavonoids in beer (also discussed in Section
2.6.2) are capable of inhibiting CYP1A2 in vitro, thus this
could have contributed to reduced warfarin elimination. It
seems likely that, given the results of the earlier controlled
trials with wine, ethanol per se was not the sole mediator of
the reported interaction. The reported interaction may have
also involved the large number of concomitant medications
in the individuals system when the beer was consumed.
2.3.9 An extended-release formulation
(hydromorphone HCl)

Co-ingestion of ethanol (even as little as the equivalent

of two thirds of a typical beer) with an extended-release
(24 h) formulation of hydromorphone hydrochloride
(Palladone XL) resulted in an increase in peak concentrations
of the opioid ranging from approximately two- to sixfold [58].
However, it was subsequently reported that such marked
ethanol effects were not observed for four other extendedrelease formulations of codeine, hydromorphone, morphine
or oxycodone; it was also conveyed that the concomitant
administration of any CNS depressant with alcohol is
uniformly ill-advised [59]. Palladone XL was subsequently
withdrawn from the market. Nonetheless, the interaction
may be of clinical importance if similar extended-release
formulations are potentially susceptible to such interactions.
2.4 Effects of other drugs on the disposition
of ethanol
2.4.1 Aspirin, acetaminophen, and H2-receptor
antagonists

An extensive number of clinical studies have been conducted

over the last two to three decades investigating the potential

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Drug interactions involving ethanol and alcoholic beverages

effects of aspirin, acetaminophen and H2-receptor antagonists

on ethanol pharmacokinetics, due to in vitro evidence that
they inhibit ADH enzymes [60-62]. Clearly, if they were
to potently inhibit intestinal and/or hepatic ADH in vivo,
the very wide-spread use of these drugs and alcohol would
be expected to result in common and clinically important
elevations in BACs. Monroe and Doering provided a
thorough and relatively recent review of these extensive
studies [63], subsequent to which, to the authors knowledge,
no additional clinical studies have been reported that
would alter their general conclusions. Briefly, it was found
that there are conflicting evidence supporting a consistent
and marked increase in BACs by aspirin and the H2-receptor
antagonists (ranitidine, cimetidine, nizatidine and famotidine), and that in the studies that demonstrated statistically
significant elevations in BACs, the increases observed
were either not reproducible (in other studies of similar
design) or were likely of limited clinical significance.
Regarding the latter point, results of a meta-analysis
were summarized in which mean estimates for H2-receptor
antagonist-induced increases in BACs were in the range of
0.3 7 mg/dl [64]. These increases of 0.0003 to 0.007%
perhaps seem miniscule when considered on the scale
by which a driving BAC limit is commonly defined
(0 0.08%). Nonetheless, although important interactions
thus seem improbable, individual risk may vary with susceptibility to the intoxicating effects of ethanol or be increased
with lower ethanol doses (i.e., potentially greater effects
at lower BAC, where ADH metabolism predominates).
With regard to acetaminophen, no changes in the Cmax
or AUC of ethanol were observed in the single study
reviewed that assessed the effect of coadministration of
acetaminophen 1 g.
2.4.2

Cisapride

In a crossover design study, the effects of cisapride treatment

(10 mg t.i.d. for 4 days) on ethanol (0.3 g/kg) pharmacokinetics were assessed in 10 healthy male volunteers [65].
Cisapride was found to increase the mean Cmax and AUC of
ethanol by 47 and 25%, with the effect on Cmax reaching
statistical significance. However, it was concluded that this
interaction was likely of limited clinical significance.
Moreover, cisapride was subsequently withdrawn from
worldwide markets due to adverse cardiovascular events.
2.4.3

Disulfiram

2.4.4

Metronidazole

The numerous case reports of an interaction between

this antimicrobial and ethanol, in which some of the
symptoms described were similar to those observed in
the disulfiramethanol reaction noted above, were
reviewed recently and it was concluded that none of
the reports provided clear mechanistic evidence of the
interaction [67]. Subsequently, a randomized, double-blind,
placebo-controlled study was conducted in which six healthy
males received either placebo or metronidazole (200 mg) t.i.d.
for 5 days [68]. One hour after the last dose of placebo or
metronidazole, the subjects consumed 0.4 g/kg ethanol and
blood ethanol and acetaldehyde levels were measured. In
addition, changes in heart rate, blood pressure and facial
temperature were monitored. There were no differences in
blood ethanol or acetaldehyde levels, heart rate, blood
pressure or facial temperature between treatments, nor were
there differences in reported subjective signs of a reaction
(e.g., headache, nausea). The authors suggest that the above
noted case reports may have resulted from an interaction in
susceptible individuals at a locus other than hepatic ALDH.
2.4.5

Tacrolimus

There have been numerous case reports (five adults and three
children) of facial flushing when using tacrolimus ointment
on the face and ingesting ethanol (the children consumed
ethanol in vitamin D or antihistamine formulations) [69-72].
In addition, a small study was conducted in six adults that
had reported facial flushing with concomitant tacrolimus and
ethanol exposure, and the flushing responses were reproduced
in the clinic [73]. A potential mechanism proposed was
tacrolimus-mediated increases in cutaneous acetaldehyde
levels; however, the authors assessed in vitro inhibition of
aldehyde or alcohol dehydrogenases and were unable to
demonstrate altered enzyme activities (no data shown).
Thus, although this mechanism seems plausible, it remains
unconfirmed. Alternatively, it is possible that this is not a case
of tacrolimus altering the metabolism of ethanol or its
metabolite (acetaldehyde) but rather an instance of ethanol
affecting tacrolimus disposition or a pharmacodynamic
interaction between the two compounds.
2.4.6

The metabolism of disulfiram leads to multiple metabolites

that are capable of inhibiting both CYP2E1 and ALDH.
Inhibition of the latter following concomitant consumption
of disulfiram and ethanol leads to very high systemic levels
of acetaldehyde and rapid experience of its toxic effects,
which, as noted previously, include facial flushing, headache,
nausea and vomiting. For this reason, disulfiram is at times
administered to alcoholics as a deterrent to continued ethanol
consumption. However, this practice is the subject of
724

debate and there has been at least one report of a fatal

disulfiramalcohol interaction [66].

Verapamil

The calcium channel blocker verapamil is not a CYP2E1

substrate, but is metabolized by CYP3A4, CYP1A2
and enzymes of the CYP2C subfamily [74,75]. In vitro,
verapamil was found not to inhibit CYP2E1 or alcohol
dehydrogenase, although its major metabolite, norverapamil,
moderately inhibited CYP2E1 [76]. Single oral doses of
verapamil did not influence ethanol pharmacokinetics or
pharmacodynamics [77,78], suggesting that norverapamil
concentrations from a single dose of verapamil are insufficient

Expert Opin. Drug Metab. Toxicol. (2007) 3(5)

Jang & Harris

to inhibit CYP2E1 in vivo. In contrast, three-times daily

administration for 5 days resulted in 17 and 30% increases
in ethanol Cmax and AUC, respectively, and prolongation of
ethanol pharmacodynamic effects [79]. These data suggest
that norverapamil may have accumulated following multiple
dosing, eventually leading to modest CYP2E1 inhibition.
Other interactions involving ethanol
2.5.1 Phenethyl isothiocyanate (watercress)
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2.5

Eating watercress results in exposure to phenethyl

isothiocyanate, which has been demonstrated in vitro to be
a mechanism-based inactivator of CYP2E1 [80,81]. A total of
10 healthy volunteers received CZX orally before and 11 h
after consuming a homogenate containing 50 g of watercress.
The watercress consumption caused 28 and 56% increases in
mean Cmax and AUC, respectively, as well as a 53% prolongation in CZX half-life (all p < 0.05) [82]. In contrast, a
subsequent study by the same investigators indicated that
watercress consumption (50 g in homogenate) either 1
or 10.5 h prior to ethanol (0.5 g/kg) consumption did not
significantly alter the Cmax or AUC of ethanol [83]. In
both studies, the healthy volunteers reported that they either
did not drink alcohol or did so in relatively small amounts
(< 40 g/week). The authors pointed out that, unlike CZX,
which is metabolized predominantly by CYP2E1, ethanol is
likely metabolized predominantly by ADH in subjects such
as those enrolled in these studies (i.e., in whom CYP2E1 is
likely not induced). Indeed, a watercressethanol interaction
study in subjects that consume moderate or greater amounts
of ethanol may yield different results.
2.5.2

Honey

It has been reported that the consumption of honey

(1 1.25 ml/kg) either 2 min [84] or 30 40 min [85] after
consuming ethanol 0.5 g/kg causes significant reductions in
ethanol Cmax and AUC. In the latter case, consumption of
honey either 40 (in men) or 30 (in women) min after ethanol
consumption (assumed to be 10 min prior to peak BAC)
was intended to prevent an impact on ethanol absorption,
although its absorption continues after Cmax (which,
by nature, is attained when the rates of absorption and
elimination are equal). Interestingly, apparent differences in
mean BACs between treatments were observed right at the
time of honey consumption in men or prior to honey
consumption in women (at the first BAC measure 20 min
after ethanol intake) [85]. Marked reductions in ethanol
exposure by food have been extensively studied, although
typically feeding precedes ethanol intake (e.g., by 15 min [86]).
Importantly, one experiment has demonstrated an 45%
increase in the elimination rate of intravenously administered
ethanol in the fed versus fasted state [7]. Thus, food seems to
reduce BACs by altering both absorption (delay of gastric
emptying) and elimination (potentially via increased
hepatic blood flow). Although in theory particular
components of the honey used in the studies could rapidly

accelerate ADH or CYP2E1 activities (e.g., via enzyme

activation), at least part of the interaction may be attributable
to a food effect.
2.6 Interactions due to other alcoholic beverage
components

Consumption of alcoholic beverages can affect the activity

of drug metabolizing enzymes via mechanisms that are
independent of ethanol. This occurs because certain alcoholic
beverages contain xenobiotics that are capable of modulating
the synthesis and activity of drug-metabolizing enzymes.
2.6.1

Red wine

Red wine is a beverage rich in antioxidant molecules

including flavonoids and other polyphenols [87]. Some of
these complex, nucleophilic molecules seem to interact with
CYP enzymes involved in drug metabolism, resulting in
potentially clinically relevant effects.
A number of studies have assessed the effect of red
wine components on the activity of CYP3A4. An in vitro
study has demonstrated that red wine solids inhibited
CYP3A4 in a time- and concentration-dependent
manner [88]. In contrast, white wine solids did not
affect CYP3A4 activity, presumably because white wine
is lacking in the flavonoids and other antioxidant molecules
that are present in red wine [88]. Subsequent studies
have demonstrated that a major component of red wine,
trans-resveratrol
(3,5,4-trihydroxy-trans-stilbene),
may
noncompetitively inhibit [89] or inactivate [90,91] CYP3A4
and CYP3A5 and may thus be a principle mediator of
this interaction.
Resveratrol may also affect CYP enzymes other than
CYP3A4. In addition to inhibiting CYP3A4 with an IC50 of
1 M, resveratrol was shown to inhibit CYP2C19 with an
IC50 of 12 M [92]. The activities of 1A2, 2C9, 2C19 or 2D6
did not seem to be markedly affected in this study and the
3-sulfate conjugate of resveratrol did not inhibit any of the
major CYP enzymes [92]. In another study, resveratrol was
shown to selectively inhibit CYP1A1 activity in vitro with an
IC50 of 10 20 M, a value 50-fold lower than the IC50
value against CYP1A2 [93]. Consistent with these results,
Chang and colleagues found that resveratrol more potently
inhibited CYP1A1 than CYP1A2, but they also found that
the compound could mediate mechanism-based inactivation
of CYP1A2 [94]. E-viniferin, a resveratrol dimer, was also
found to inhibit CYP activities including 1A1, 1B1 and
2D6 [95]. In vitro studies by Mikstacka et al. demonstrated
that natural analogs of resveratrol inhibit CYP1A2 with
Ki values < 1 M [96].
Resveratrol may also modulate CYP activity at the level
of gene transcription [97]. The compound has been shown
to inhibit the transactivation of dioxin-inducible genes
including CYP1A1 and CYP1B1 [98], presumably via
interaction with the aryl hydrocarbon (AhR) receptor [99].
In human cell culture models, the antagonism of AhR by

Expert Opin. Drug Metab. Toxicol. (2007) 3(5)

725

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Drug interactions involving ethanol and alcoholic beverages

resveratrol can result in suppression of CYP mediated activation of xenobiotics into reactive species, thereby reducing
cytotoxicity [100]. Thus, it has been speculated that resveratrol
can act as a chemopreventive against chemical-induced
carcinogenisis in vivo [101].
In addition to resveratrol, other components of red wine
may affect drug metabolism. For example, gallic acid, an
agent found in wine and tea, reversibly inhibited CYP3A4,
but did not affect the activities of CYPs 1A and 2E [102]. The
inhibition of CYP3A4 was postulated to be driven by a gallic
acid metabolite, most likely a free radical species [102]. It is
likely that other electron-rich macromolecules found in red
wine also modulated CYP activity.
To investigate whether these in vitro observations with red
wine and resveratrol correlated with clinical effects, a study to
assess the effect of acute consumption of 12 oz of red wine on
the pharmacokinetics of the CYP3A4 and P-glycoprotein
substrate ciclosporin was initiated [103]. Surprisingly, instead
of causing an increase in ciclosporin exposure, which would
be expected for a CYP3A4 inhibitor, acute red wine
consumption caused a statistically significant 30% decrease in
the ciclosporin AUC, and a 40% decrease in Cmax, with no
change in half-life. This decrease in ciclosporin exposure after
a single administration of red wine is of a magnitude that
could be clinically important and may result in acute organ
rejection. The mechanism for the decrease is not understood,
although it is possible that there is a direct binding interaction between ciclosporin and constituents in red wine that
limits solubility and lowers the extent of absorption. It is also
possible that the decrease in exposure is due to stimulation of
the activity of P-glycoprotein or another drug transporter,
although in vitro data suggest that P-glycoprotein activity is
not affected by red wine.
In a follow-up study, the effect of chronic administration
(12 oz for 7 days) of red wine on ciclosporin pharmacokinetics was assessed [104]. For this assessment, ciclosporin
was administered 12 h after red wine consumption, greatly
reducing the chance that an observed interaction would be
due to acute, reversible inhibition of intestinal CYP3A4 or
direct binding of red wine to ciclosporin. Consistent with the
inactivation that was observed in vitro, it was found
that chronic administration of red wine resulted in a
13% increase in mean ciclosporin exposure, with one
subject showing an 82% increase. In addition, consistent with
the in vitro data, neither acute nor chronic white wine
consumption had a notable effect on the pharmacokinetics
of ciclosporin, suggesting that the effects observed were
due to constituents in red wine and not a result of
alcohol consumption.
In addition to these red wineciclosporin studies, it was
reported that a single administration of red wine caused an
average increase in cisapride AUC of 15%, although this
increase was not statistically significant [105]. One of the
12 subjects displayed a two-fold increase in cisapride exposure,

726

suggesting that the magnitude of the interaction can vary

across individuals. The authors suggested that individuals
with high intestinal CYP3A4 content may experience
clinically relevant drug interactions with red wine. In
contrast, red wine did not appear notably affect the systemic
elimination of the CYP3A4 substrate felodipine [106].
Interestingly, consumption of red wine did seem to slow the
absorption of this agent, resulting in apparent dose
dumping in some individuals [106]. An effect of wine on drug
absorption was also observed with doxycycline, where cheap
red wine was shown to affect the absorption characteristics of
the drug. This effect was attributed to the relatively high
acetic acid content of the inexpensive wine [107].
Based on the limited clinical data described above, it seems
that the modulation of drug-metabolizing systems by red
wine that occurs in vitro can, to some extent, occur in vivo,
and could lead to clinically important interactions in
particularly susceptible individuals. It should be noted that
different types of wine displayed different inhibitory
potentials towards CYP3A4 in vitro [88], suggesting that the
magnitude of the effects of red wine on the pharmacokinetics
of CYP3A4 substrates may be dependent on both the amount
and also the type of red wine consumed.
2.6.2

Other alcoholic beverages

Beverages other than wine may also contain components that

modulate CYP activity. Nonvolatile components of Cognac
(XOS and VSS) were found to moderately inhibit multiple
CYP enzymes including CYP1A with a Ki of 2 10 mg/l [91].
The compounds viniferin and resveratrol accounted for only
a modest proportion of this inhibition. In addition, in vitro
data suggest that flavonoids from hops, a component in
beer, are selective inhibitors of human CYP enzymes. The
prenylated chalcone xanthohumol, a component of hops was
found to potently inhibit human CYPs 1A1 and 1B1 and
two prenylated flavonoids found in hops, 8-prenylnaringenin
and isoxanthohumol, were found to potently inhibit
CYP1A2 [108]. In contrast, these flavonoids did not seem to
affect CYP2E1 or CYP3A4. In a separate report, prenylflavonoids from hops were found to inhibit CYP1A2 in vitro
resulting in decreased activation of a potentially carcinogenic
heterocyclic amine [109].
Crankshaw demonstrated that feeding beer to rats inhibits
CYP2E1 and possibly other CYP enzymes via metabolic
intermediate complex formation, and that this inhibition was
strong enough to reverse the induction of CYP2E1 by
alcohol [110]. Similarly, Hidestrand and colleagues found that
in rats, consumption of stout (a dark beer) modulated the
expression of CYP enzymes, whereas lager (a light beer) did
not [111]. In contrast, Lechevrel, demonstrated that the effects
on CYP activity in rats treated for 3 days with ethanol alone,
whisky, brandy, beer, cider or wine were primarily attributed
to alcohol mediated CYP2E1 induction rather than other
effects on CYP enzymes [112].

Expert Opin. Drug Metab. Toxicol. (2007) 3(5)

Jang & Harris

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3.

Expert opinion

Several high-level conclusions can be drawn based on the

collective results of the studies summarized above: i) further
investigation of ethanol effects on drug-metabolizing enzymes
is warranted; ii) some risks of drug interaction due to
chronic or concomitant ethanol use have been very
effectively studied and appropriately characterized, whereas
others are perhaps exaggerated; iii) data generated with
probe substrates cannot always be extrapolated to other
drugs metabolized by the enzyme for which the probe is
(at least relatively) specific; and iv) instances of marked,
ethanol-provoked drug interactions seem to be rare, but can
be clinically important.
Although, in general, it does not seem that ethanol is
a potent inducer of CYP3A4 in vivo (based on lack of
effect of moderate consumption on IV midazolam PK), the
findings cited for fentanyl and the results noted for alfentanil
(potentially confounded by hepatic impairment) suggest
that further study may be warranted. A study comparing the
intravenous disposition of midazolam in heavy alcohol
consumers without liver disease versus alcohol-abstaining
subjects should confirm or refute the fentanyl findings.
It seems possible that any ethanol effects on this enzyme
are reflected, along with myriad other factors, in the
generally observed wide variability in CYP3A4 expression
and activity across individuals, but it remains perhaps of
scientific interest given the importance of this enzyme in
xenobiotic metabolism.
Extensive and rigorous work has been conducted not
only identifying NAPQI as the hepatotoxic acetaminophen
metabolite, but also studying the effects of varied ethanol

consumption on its production in humans. The work has

elucidated an important toxicologic mechanism and,
seemingly, defined the probable increased risk for moderate
or heavy alcohol consumers that take label-prescribed doses
of the analgesic. In contrast, case reports of marked
interactions between ethanol and warfarin or metronidazole
describe situations of likely complex etiology (i.e., involving
multiple disease conditions and co-medications) and, in
the case of metronidazole, contradicted by results of a randomized, controlled trial. This suggests that alcohol-related
case reports must at times be interpreted with caution before
assigning ethanol as culprit.
The studies indicating a marked effect of watercress
on CZX but not ethanol disposition indicate that caution
must also be given in extrapolating results between two
substrates of the same enzyme. In the case of ethanol,
its elimination is clearly less susceptible to CYP2E1 inhibition (by phenethyl isothiocyanate and, likely, any other
inhibitor) than CZX, given the primary role of ADH in
ethanol clearance.
Lastly, although alcohol consumption has clearly been
associated with increased risk of particular cancers, but also
decreased cardiovascular risk, it seems to provoke relatively
rare, clinically important therapeutic drug interactions.
Altered metabolism of cocaine, facial flushing with tacrolimus
and caustic acetaldehyde toxicity with disulfiram seem to
be the most marked and uniformly observed interactions.
Other interactions in which ethanol is the precipitant or
victim are perhaps lessened, to a large extent, by the
promiscuity in the enzymes metabolizing both ethanol and
the concomitantly administered agents and resulting alternate
metabolic pathways.

Expert Opin. Drug Metab. Toxicol. (2007) 3(5)

727

Drug interactions involving ethanol and alcoholic beverages

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DEVALARJA R, SHEDLOFSKY S:
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Website
201. http://www.who.int/substance_abuse/
publications/global_status_report_2004_
overview.pdf
World Health Organization Global Status
Report on Alcohol (2004).

Affiliation
Graham R Jang1 PhD, Director &
Robert Z Harris2 PhD, Director
Author for correspondence
1Amgen, Inc.,
Department of Pharmacokinetics and
Drug Metabolism, One Amgen Center Dr,
Thousand Oaks, CA, 91320, USA
Tel: +1 805 447 6897; Fax: +1 805 376 1867;
E-mail: gjang@amgen.com
2Amgen, Inc.,
Department of Regulatory Affairs and Safety,
One Amgen Center Dr, Thousand Oaks,
CA, 91320, USA

731

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