Clin Pharmacokinet (2014) 53:1115–1136

DOI 10.1007/s40262-014-0190-x

REVIEW ARTICLE

Pharmacokinetic and Pharmacodynamic Drug Interactions

with Ethanol (Alcohol)
Lingtak-Neander Chan • Gail D. Anderson

Published online: 30 September 2014

 Springer International Publishing Switzerland 2014

Abstract Ethanol (alcohol) is one of the most widely that a significantly higher volume of clinical studies have
used legal drugs in the world. Ethanol is metabolized by focused on the pharmacokinetic interactions of ethanol and
alcohol dehydrogenase (ADH) and the cytochrome P450 other drugs. The data on pharmacodynamic interactions are
(CYP) 2E1 drug-metabolizing enzyme that is also more limited and future research addressing pharmacody-
responsible for the biotransformation of xenobiotics and namic interactions with ethanol, especially regarding the
fatty acids. Drugs that inhibit ADH or CYP2E1 are the non-central nervous system effects, is much needed.
most likely theoretical compounds that would lead to a
clinically significant pharmacokinetic interaction with
ethanol, which include only a limited number of drugs.
Key Points
Acute ethanol primarily alters the pharmacokinetics of
other drugs by changing the rate and extent of absorption,
Ethanol (alcohol) primarily alters the
with more limited effects on clearance. Both acute and
pharmacokinetics of other drugs by altering
chronic ethanol use can cause transient changes to many
absorption, with more limited effects on clearance.
physiologic responses in different organ systems such as
hypotension and impairment of motor and cognitive func- The most commonly reported symptoms related to
tions, resulting in both pharmacokinetic and pharmacody- pharmacodynamic interactions with ethanol are
namic interactions. Evaluating drug interactions with long- sedation, tachycardia, and general increased
term use of ethanol is uniquely challenging. Specifically, it intoxication.
is difficult to distinguish between the effects of long-term
ethanol use on liver pathology and chronic malnutrition.
Ethanol-induced liver disease results in decreased activity
of hepatic metabolic enzymes and changes in protein 1 Introduction
binding. Clinical studies that include patients with chronic
alcohol use may be evaluating the effects of mild cirrhosis Ethanol (alcohol) is one of the most widely used legal
on liver metabolism, and not just ethanol itself. The defi- drugs in the world. In the USA, 87.6 % of the population
nition of chronic alcohol use is very inconsistent, which over 18 years of age reported that they consumed alcohol
greatly affects the quality of the data and clinical appli- at some point in their lifetime, 71 % reported that they
cation of the results. Our study of the literature has shown drank in the past year, and 56.3 % reported that they drank
in the past month [1]. Ethanol is also a compound with high
potential for abuse. Data from the World Health Organi-
zation (WHO) show that about 3.3 million deaths were
attributable to the harmful use of alcohol in 2012 alone [2].
L.-N. Chan  G. D. Anderson (&) Binge drinking is reported in about 17 % of the US pop-
Department of Pharmacy, University of Washington,
Box 357630, Seattle, WA 98195, USA ulation [3]. Chronic, heavy alcohol consumption is asso-
e-mail: [email protected] ciated with a number of negative effects on general health.
1116 L.-N. Chan, G. D. Anderson

More importantly, chronic ethanol use can alter the body’s primary hepatic isoenzymes responsible for metabolizing
ability to metabolize xenobiotics. With the widespread use ethanol in humans. These enzymes are highly saturable
of ethanol in society and the increase in the aging popu- since their Michaelis-Menten constant (Km) for ethanol is
lation taking multiple medications for chronic diseases, it is approximately 1 mmol/L. ADH4 and ADH5 (also known
important to understand the significance of interactions as class II and III ADH, respectively) have a higher Km for
between ethanol and commonly used medications. The aim ethanol, although the expression level is usually lower than
of this article is to review the effect of ethanol on the ADH1, 2, and 3. ADH6 (class V ADH) is present in both
pharmacokinetics of commonly used drugs, and to discuss the liver and epithelial lining of the stomach and contrib-
the effect of those drugs on the pharmacokinetics of alco- utes partially to the pre-systemic metabolism of ethanol.
hol along with their clinical implications. ADH7 is found in the stomach and its primary substrate is
retinol [5, 10, 11].
In addition to ADH, cytochrome P450 (CYP) 2E1 is
2 Pharmacokinetics and Metabolic Profile of Ethanol another important enzyme responsible for the metabolism
(Alcohol) of ethanol [12]. The Km of CYP2E1 for ethanol is about
tenfold (10 mmol/L) higher than that of ADH1–3 but is
After oral ingestion, ethanol is absorbed from the gastro- still within the range of blood alcohol concentration
intestinal tract exclusively by passive diffusion. Concen- obtained with social drinking. It is estimated that the
tration gradient is the most important driving force for contribution of ethanol oxidation by CYP2E1 at lower
luminal absorption of ethanol. Therefore, the rate of blood alcohol concentrations is about 10–20 %. However,
absorption of ethanol correlates with the concentration of when the blood alcohol concentration has exceeded the
alcohol consumed [4, 5]. In the US, a standard drink is legal limit (i.e., 80 mg/dL or 0.08 % or 17 mmol/L), the
equal to 14.0 g or 0.2 g/kg for a 70 kg person (17.7 mL) of contribution of CYP2E1 is likely approaching or has
pure alcohol. This amount of pure alcohol is equivalent to exceeded 50 % [5, 13]. Therefore, the role of CYP2E1 on
355 mL of beer (5 % alcohol content), 237 mL of malt ethanol metabolism is more significant after a large amount
liquor (7 % alcohol content), 148 mL of wine (12 % of ethanol is consumed. It is also important to note that
alcohol content), or 44.4 mL or a ‘shot’ of 80-proof (40 % CYP2E1 expression is induced by chronic ethanol use,
alcohol content) distilled spirits or liquor (e.g., gin, rum, fasting, obesity, and diabetes mellitus [14–18]. It appears
vodka, whiskey) [3]. Although a small fraction of the that the mechanism of CYP2E1 induction by ethanol is
consumed ethanol is absorbed in the stomach, the rate of primarily post-transcriptionally regulated through messen-
absorption is more rapid in the duodenum and jejunum [5]. ger RNA and protein stabilization and increased transla-
The gastric emptying rate is therefore an important factor tional efficiency, which results in an increased elimination
in regulating the rate of ethanol absorption from the gas- half-life (t‘) for CYP2E1 [19, 20]. Altered CYP2E1
trointestinal tract. This is the primary reason why concur- activities with these chronic conditions and co-morbidities
rent food intake, especially with meals high in fat content, may further impact the risk and clinical significance of an
can decrease the rate of absorption and possibly the extent interaction between ethanol and prescription medications.
of pre-systemic metabolism of ethanol, whereas intoxica- Acetaldehyde, the primary metabolite of ethanol
tion occurs more rapidly when ethanol is consumed on an through oxidation, is further metabolized by aldehyde
empty stomach. dehydrogenase (ALDH) to acetate, which can be converted
Ethanol undergoes extensive pre-systemic metabolism to acetyl coenzyme A (acetyl-CoA) in the presence of
and its elimination generally follows Michaelis–Menten coenzyme A and becomes a substrate for the tricarboxylic
kinetics [6, 7]. The average metabolic capacity of ethanol, acid cycle. Each gram of ethanol provides 7 kcal (or 29 kJ)
including the extent of pre-systemic metabolism, varies [12, 21]. Other minor metabolic pathways for ethanol
greatly due to nutritional status, diet, ethnicity, genetics, include conjugation with glucuronic acid to form ethyl
the type and quality of concurrent food intake, and the glucuronide, and formation of fatty acyl ester by fatty acid
frequency and amount of ethanol consumed [8]. In a person ethyl ester synthases [5, 22].
who does not consume alcohol regularly, the average rate Women generally have higher blood ethanol concen-
of ethanol clearance is approximately 7 g/h [5]. The pri- trations after consuming equivalent amounts to men [23]
mary metabolic pathway for ethanol oxidation is by alcohol due to a smaller volume of distribution (Vd) and a
dehydrogenase (ADH). ADH is a large family of zinc- decreased gastric ADH resulting in a decreased first-pass
containing cytosolic enzymes found primarily in the liver metabolism and increased bioavailability [24]. A study
[9, 10]. Extrahepatic ADH enzymes are also present in the evaluating the effect of the menstrual cycle on ethanol
gastrointestinal tract, kidneys, nasal mucosa, testes, and pharmacokinetics in ten Caucasian women found that the
uterus. ADH1, 2, and 3 (formerly class I ADHs) are the pharmacokinetics of ethanol were not different between the
PK and PD Drug Interactions with Ethanol (Alcohol) 1117

luteal and the menstrual phases within the menstrual cycle 4 Literature Search
[25]. Age is possibly another factor that may affect the
pharmacokinetics of ethanol. After consuming equal Both authors conducted a comprehensive literature search
amounts of ethanol [0.3 g/kg in 8 ounces (*236 mL) of independently and then compared and reviewed the results.
fruit juice over 10 min] on an empty stomach, the mean We searched PubMed, from inception to June 2014, for
area under the plasma concentration–time curve (AUC) relevant studies. The search terms were ‘‘Ethanol/alcohol
from time zero to 6 h (AUC6) of ethanol was higher in AND Metabolism, Ethanol/alcohol AND Pharmacokinetic
older men (over 60 years of age) than in younger men AND Interaction’’, ‘‘Ethanol/alcohol AND Pharmacody-
(between 21 and 40 years of age) [26]. More interestingly, namic AND Interaction’’. The reference lists of included
both the maximum plasma concentration (Cmax) and AUC papers were assessed for additional relevant studies.
were found to be higher in older women than in younger
women. However, the age-related differences in ethanol 4.1 Inclusion and Exclusion Criteria
pharmacokinetics were not observed when ethanol was
consumed after a meal, or through an intravenous route. We considered all clinical studies published with pharma-
cokinetic or pharmacodynamic data using human subjects.
Exclusion criteria included animal data only, studies
3 Pharmacodynamics of Ethanol with no quantifiable measurement of pharmacokinetic or
pharmacodynamic parameters, case reports, in vitro stud-
Ethanol affects a number of physiological systems. It ies, and simulation modeling studies. We also excluded
exhibits a dose-dependent depressive effect on the central studies that were aimed at evaluating the impact of alco-
nervous system (CNS). The clinical response ranges from holism on the disposition of another drug, as the focus of
mild anxiolytic effect, disinhibition of behavior, to sedation the review is on the impact of the concurrent use of ethanol
and respiratory depression, depending on the dose and a (acute or chronic) on the disposition of other drugs.
number of host factors such as age, body composition,
intrinsic clearance capacity for alcohol, diet, and interact- 4.2 Outcome Measures
ing agents. Drugs that can cause CNS depression, such as
benzodiazepines, barbiturates, opioids, and antidepressants The outcome measures used in this review are listed below.
may therefore potentiate the clinical effects of ethanol and
• Pharmacokinetic parameters for assessment included
vice versa. The impact of ethanol on the cardiovascular
Cmax, AUC, t‘, clearance, and plasma/serum concen-
system is more complex. Although a mild coronary vaso-
trations, if available.
dilatation occurs within hours after ethanol consumption,
• Pharmacodynamic parameters that are relevant to the
long-term heavy ethanol use is associated with a persistent
pharmacological effects of the interacting drugs or
increase in diastolic and systolic blood pressure [27–29].
ethanol.
Ethanol at high doses also prolongs the QT interval and
ventricular repolarization. Other observed cardiovascular Evaluating pharmacokinetic and pharmacodynamic drug
changes associated with chronic alcohol use include interactions with ethanol is uniquely challenging. Specifi-
supraventricular tachyarrhythmias, atrial fibrillation, and cally, it is difficult to distinguish between drug interactions
cardiomyopathy [30–34]. Therefore, drug interaction and the effects of long-term ethanol use on liver pathology,
potential exists between alcohol and drugs affecting car- which can result in acute alcoholic hepatitis, chronic cir-
diac conductance, such as tricyclic antidepressants and rhosis, hyperbiliruinemia, hypoalbuminemia, and chronic
sodium channel antagonists. Other well-documented malnutrition. Ethanol-induced liver disease results in
pharmacodynamic effects associated with ethanol use decreased activity of hepatic metabolic enzymes and
include diuresis, decreased lower esophageal sphincter changes in protein binding. In subjects without overt signs
pressure, disruption of the gastrointestinal epithelial of liver cirrhosis, clinical studies that include patients with
architecture and barrier function, pancreatitis, fatty liver, chronic alcohol use may be evaluating the effects of mild
hepatitis, and cirrhosis. Unfortunately, studies specifically cirrhosis on liver metabolism, and not just ethanol, itself.
designed to investigate the pharmacodynamic interactions Unfortunately, a large majority of the clinical research
between alcohol and other drugs are very limited. There is includes small sample sizes (4–14), primarily male sub-
a need for new studies in this area to understand the clinical jects, variable ethanol doses, large inter-subject variability,
significance of these potential pharmacodynamic and poorly controlled clinical factors including the pre-
interactions. sence of liver disease and other medications.
1118 L.-N. Chan, G. D. Anderson

5 Drugs that Affect the Central Nervous System (CNS) 5.1.2 Bupropion

5.1 Antidepressants Bupropion is a substrate and a probe drug for CYP2B6

[42]. Its potential interaction with ethanol was evaluated in
5.1.1 Amitriptyline a two-phase, randomized crossover trial with eight healthy
male subjects. In the first phase, the subjects were ran-
Amitriptyline is metabolized by CYP2C9, CYP2D6, and domized to receive a single 100 mg oral dose of bupropion
CYP3A4 [35]. Scott et al. [36] evaluated the interaction hydrochloride. Ethanol 16 % (v/v) in orange juice or an
between amitriptyline 75 mg and ethanol (50 g) in six equal volume of plain orange juice was consumed 30 min
healthy male subjects. Amitriptyline pre-treatment was before, and 90 and 210 min after taking bupropion. Plasma
not found to alter the pharmacokinetics of ethanol. bupropion concentrations and blood alcohol concentrations
However, amitriptyline increased the sedative effect were measured. The pharmacokinetics of bupropion were
caused by ethanol and resulted in a marked increase in not altered by ethanol. After a washout period, the same
the horizontal movement of the center of gravity even subjects received the same treatments but in reverse
when a person is standing still (body sway).The finding sequence (i.e., ethanol in orange juice or plain orange juice
suggests that there is a clinically significant pharmaco- with and without bupropion pre-administration at 3.5 h
dynamic interaction with amitriptyline and ethanol. The prior to consuming ethanol). The blood alcohol concen-
positive pharmacodynamic interaction between amitrip- tration was measured using a breathalyzer for 5 h. Overall,
tyline and ethanol in the absence of a pharmacokinetic ethanol pharmacokinetics were not altered by bupropion
interaction is consistent with the results shown by [43]. These data suggest that a pharmacokinetic interaction
Warrington et al. [37] Amitriptyline (50 mg) failed to between bupropion and alcohol is absent.
alter the pharmacokinetics of ethanol (0.5 mL/kg) and
vice versa in six subjects. However, compared with 5.1.3 Fluvoxamine
ethanol alone, concurrent administration of amitriptyline
and ethanol is associated with a more significant The potential pharmacokinetic and pharmacodynamic
impairment of manual dexterity. The mechanism of interaction between ethanol and fluvoxamine have been
interaction is likely mediated by different pathways: investigated in two different studies. Fluvoxamine is
amitriptyline causes sedation by blocking histamine H1 extensively metabolized by CYP1A2 and CYP2D6 [44]
receptors in the CNS, whereas ethanol probably enhances and is an inhibitor of CYP1A2, CYP2C19, and CYP3A4
a GABA-mediated mechanism. [45, 46]. Overall, fluvoxamine 50 mg, given both as single
However, the lack of pharmacokinetic interactions in dose or multiple doses to twelve healthy male subjects, did
the above studies contradicts the results presented by not alter the pharmacokinetics of ethanol (40 g intrave-
Dorian et al. [38]. In five healthy subjects (2 male, 3 nously or orally). Orally administered ethanol slightly
female), concurrent ethanol intake showed [0.9 g/kg increased the rate of fluvoxamine absorption, but not the
loading dose followed by 0.18 g/kg every 30 min as overall oral bioavailability [47]. Fluvoxamine did not
needed to maintain a blood ethanol concentration between interact significantly with alcohol or potentiate alcohol-
80 and 100 mg/dL (0.08–0.1 %) as measured by a related impairment of cognitive function in ten healthy
breathalyzer] significantly increased amitriptyline male subjects [47, 48].
unbound plasma concentrations by a logarithmic mean of
204, 186, and 127 % at 1.5, 2, and 2.5 h, respectively. 5.1.4 Venlafaxine
Both the total and unbound amitriptyline AUC from time
zero to 8 h (AUC8) were significantly increased with Venlafaxine is primarily metabolized by CYP2D6 [49] and
concurrent ethanol consumption (44.4 %, range there is evidence to suggest that N-desmethylvenlafaxine is
6.8–87.4 %; and 48 %, range 10.8–78.2 %, respectively). formed via CYP3A4 [50]. Troy et al. [51] evaluated the
The AUC8 for nortriptyline, a metabolite of amitriptyline, potential for a pharmacokinetic and pharmacodynamic
was also increased by 26 %. The increase in unbound interaction between venlafaxine and ethanol in six healthy
amitriptyline was more pronounced during the absorption subjects. Subjects took venlafaxine 50 mg or placebo every
phase. At the time of peak amitriptyline plasma concen- 8 h for 5 days before receiving ethanol 0.5 g/kg. The eth-
trations, ethanol co-administration increased the mean anol Cmax and AUC were unaltered by venlafaxine. The
postural sway by an additional 90 % and decreased mean results of the psychometric tests also failed to demonstrate
short-term memory (word recall) by an additional 34 % any clinical significant pharmacodynamic interaction
than without ethanol [38]. Further investigations should between venlafaxine and ethanol. Likewise, the pharma-
be conducted to confirm these results [39–41]. cokinetics of venlafaxine were not affected by ethanol [51].
PK and PD Drug Interactions with Ethanol (Alcohol) 1119

5.1.5 Trazodone drowsiness is a common dose-dependent adverse effect of

gabapentin. Bisaga and Evans investigated the potential
The potential interaction between trazodone and ethanol pharmacodynamic interaction between gabapentin and
was investigated in the amitriptyline study by Warrington ethanol [57]. Seventeen subjects without alcohol depen-
et al. [37] The time to reach Cmax (tmax) for trazodone dence were tested using a double-blind design with three
(single dose 100 mg) was prolonged by ethanol (0.5 mL/ 3-day long inpatient phases, each separated by at least a
kg), from 45 min to 2 h after dosing, but the other phar- 1-week washout period. Gabapentin pre-treatment at three
macokinetic parameters for trazodone were unaffected. different doses (0, 1,000, or 2,000 mg) was administered
Pharmacodynamic effects of trazodone, as measured by 4 h before alcohol (0.75 g/kg), given in four divided doses
depressant effects on critical flicker fusion frequency every 20 min. Gabapentin impaired the ability to balance
threshold, choice reaction time, manual dexterity, and on without producing changes in subjective, physiological, or
the rating scales for drowsiness, ‘clear-headedness’, other performance measures. Gabapentin also enhanced
aggression, and disinhibition, were not significantly tachycardia associated with ethanol in a dose-dependent
increased by the addition of ethanol. manner; however, it did not significantly alter subjective
and performance effects of ethanol. These data suggest
5.2 Anti-Seizure Drugs that, other than tachycardia, a clinically significant inter-
action between ethanol and gabapentin is absent.
5.2.1 Carbamazepine
5.2.4 Phenytoin
Carbamazepine is primarily a substrate for CYP3A4 with
minor metabolism by CYP1A2 and CYP2C8 [52]. There was Phenytoin is eliminated predominantly by CYP2C9 with
no effect of ethanol (25 g) on the pharmacokinetics of a single minor metabolism by CYP2C19 and minimal excretion of
400 mg dose of carbamazepine in eight healthy subjects when unchanged drug [58]. Sandor et al. [59] evaluated phe-
given concurrently [53]. In seven chronic users of ethanol, the nytoin pharmacokinetics in 11 chronic users of ethanol
AUC from time zero to 12 h (AUC12) after receiving a during an alcohol ingestion phase (6 days) followed by an
400 mg dose of carbamazepine on day 1 was significantly alcohol withdrawal phase. Subjects received ethanol [20 %
higher (20 %) than AUC after receiving carbamazepine for (v/v) in orange juice] every 2 h while awake to maintain a
9 days after ethanol withdrawal [53]. As carbamazepine blood ethanol concentration of 50–80 mg/dL. Phenytoin
induces its own metabolism, the effect on AUC is presumably was administered as 300 mg intravenously plus 300 mg
due to auto-induction by carbamazepine and not de-inhibition orally followed by 150 mg twice daily for 20 days. Aver-
due to alcohol withdrawal. The limited evidence suggests that age median (range) total phenytoin concentrations were 7.0
neither acute nor chronic ethanol use will significantly alter (3.3–21.9) mg/L, 9.7 (4.4–22.7) mg/L, 5.6 (3.1–25.4) mg/L,
the pharmacokinetics of carbamazepine. and 4.7 (4.1–29.9) mg/L on days 4–6 (during ethanol
treatment), days 7–9 (early withdrawal), days 10–12
5.2.2 Ezogabine (Retigabine) (withdrawal), and days 18–20 (late withdrawal), respec-
tively. Despite this large inter-subject variability, statisti-
Ezogabine is eliminated by hepatic metabolism through cally significant differences were found using the signed
formation of an N-acetyl metabolite and through N-glucu- rank test and the authors suggested that chronic ethanol
ronidation [via uridine 50 -diphospho-glucuronosyltransfer- increases phenytoin clearance. However, two patients were
ase (UGT) 1A1, 1A3, and 1A9] and renal excretion of outliers with a significant decrease in phenytoin elimina-
unchanged drug (20–30 %) [54]. The effect of ethanol tion on withdrawal, most probably due to genetic poly-
(1 g/kg) on single-dose ezogabine (200 mg) pharmacoki- morphisms of CYPC9 and/or CYP2C19. Also, the average
netics was determined in a double-blind, placebo-con- phenytoin total clearance in the nine remaining subjects
trolled crossover study in 17 healthy male and female receiving ethanol were in the same range as normal sub-
moderate alcohol drinkers [55]. Ethanol treatment signifi- jects not drinking ethanol (0.023 ± 0.006 vs.
cantly increased the Cmax and AUC of ezogabine by 23 and 0.025 ± 0.003 L/kg/h). Albumin concentrations and liver
36 %, respectively. There was no effect of ezogabine on function tests were within the normal range. The free
the pharmacokinetics of ethanol. fraction of phenytoin ranged from 9.1 to 17.5 % and the
ratio of AUC unbound to AUC total was 13.1 ± 1.2 %.
5.2.3 Gabapentin The unbound oral clearance of phenytoin was decreased
during treatment with ethanol compared with during
Gabapentin is primarily eliminated renally [56] and has a withdrawal (0.153 ± 0.059 vs. 0.196 ± 0.100, p \ 0.05).
relatively low drug–drug interaction potential. However, These results suggest that chronic ethanol treatment
1120 L.-N. Chan, G. D. Anderson

inhibits phenytoin metabolism rather than inducing it as temazepam, and oxazepam. Desmethyldiazepam is formed
suggested by Sandor and colleagues. by CYP2C19 (major pathway) and CYP3A4 [71]. The
Kater et al. determined the t‘ of phenytoin (n = 15), effect of acute ethanol (0.7 g/kg) on intravenous diazepam
tolbutamide (n = 31), and warfarin (n = 15) in chronic (10 mg) in six healthy male subjects resulted in a 27 %
ethanol users. Phenytoin, tolbutamide, and warfarin are all average increase in unbound diazepam AUC. The AUC of
primarily metabolized by CYP2C9 and are highly protein its primary metabolite N-desmethyldiazepam decreased by
bound drugs. Patients had a normal liver function test and 50 %, suggesting that acute ethanol may inhibit CYP2C19
albumin concentrations, and no jaundice or ascites. The [72]. Hayes et al. [73] administered diazepam (0.07 mg/kg)
phenytoin t‘ determined after patients received phenytoin orally with water or 50 % ethanol to seven healthy subjects
100 mg three times daily for 3 days was 16.3 ± 6.8 versus and found a significantly increased bioavailability resulting
23.5 ± 11 h in 76 healthy control subjects [60]. The t‘ of in doubling of the Cmax. In contrast, two larger placebo-
tolbutamide after a 1 g oral dose was 165 ± 34 min controlled crossover studies failed to demonstrate an effect
compared with 351 ± 131 min in 13 healthy control sub- of ethanol on diazepam pharmacokinetics. In 24 healthy
jects. The t‘ of warfarin in subjects receiving a 40 mg oral men, ethanol (0.8 g/kg) administered immediately after
dose was 26.5 ± 13.2 h compared with 41.1 ± 19.2 h in taking an oral dose of diazepam (5 mg) did not signifi-
11 healthy control subjects. As the t‘ is dependent on cantly alter the pharmacokinetics [74]. There was an
clearance and Vd, a decrease in the t‘ could occur with additive effect with ethanol on decreasing skilled perfor-
either an increased clearance and/or a decrease in the Vd mance measures including eye tracking and body balance
due to ethanol-induced changes in tissue perfusion and and sedation. Similarly, in a study in 12 healthy subjects,
drug binding to tissue and/or proteins. It is not possible to administration of a single oral dose of diazepam (10 mg)
separate out the effects of chronic ethanol on clearance or after an intravenous infusion of ethanol (target blood
Vd. In addition, the activity of CYP2C19 is significantly alcohol concentration of 0.5 g/L or 0.05 %) found that
decreased in mild liver cirrhosis [61]. Clinical studies that ethanol treatment resulted in a significant decrease in
include patients with chronic alcohol use may be evaluat- performance measures (body sway, eye tracking, and
ing the effects of mild cirrhosis and not just ethanol itself. sedation), with no effects on diazepam pharmacokinetics
Therefore, overall, the effect of ethanol on phenytoin is compared to placebo control [75]. Therefore, the studies
unclear based on the limited and conflicting data. with the largest number of subjects both found only a
pharmacodynamic interaction, with no effect of ethanol on
5.3 Benzodiazepines diazepam pharmacokinetics.
The unbound clearance of chlordiazepoxide (0.6 mg/kg
There is an association between the use of benzodiazepines intravenous) decreased by 37 % when a single dose of
and road traffic accidents and the incidence is increased ethanol was administered 1 h prior to dosing in five healthy
with the use of ethanol in combination with benzodiaze- male subjects. Ethanol also decreased plasma protein
pines [62–64]. There have been numerous studies demon- binding and increased the t‘ of chlordiazepoxide. The CYP
strating the combination of ethanol and benzodiazepines isoenzyme involved in the demethylation of chlordiaz-
altering the psychomotor skills associated with driving, epoxide has not been identified. Clobazam is extensively
primarily due to an additive effect on reaction and coor- metabolized to multiple metabolites, mostly by CYP3A4
dination [65–68]. Short-acting benzodiazepines without and to some extent by CYP2C19 [76]. N-desmethylcloba-
active metabolites appear to cause less impairment than zam, the primary metabolite, is pharmacologically active
longer-acting benzodiazepines [69]. The effect of acute and and predominantly metabolized by CYP2C19. Eight heal-
chronic ethanol on the pharmacokinetics of the benzodi- thy male subjects received clobazam (20 mg orally)
azepines is less clear. administered with and without ethanol (administered as a
combination of beer and brandy designed to produce an
5.3.1 Acute Ethanol alcohol Cmax of 1,000 lg/mL) [77]. Ethanol increased
clobazam Cmax and AUC by 59 and 54 % on average,
In general, studies conducted using single-dose ethanol and respectively. Clobazam did not alter the pharmacokinetics
single-dose benzodiazepines suggest that acute ethanol of ethanol. Despite the increase in clobazam concentra-
increases the blood concentrations of the benzodiazepines tions, the effect of ethanol plus clobazam on pharmaco-
metabolized by CYP oxidation (clobazam, chlordiazepox- dynamic measures showed no difference between ethanol
ide, desmethyldiazepam, and diazepam), with minimal to alone or ethanol plus clobazam on measures of body sway,
no change for those metabolized by UGT conjugation coordination, and reaction time.
(oxazepam, lorazepam) [70]. Diazepam is metabolized to Lorazepam is extensive metabolized to a glucuronide
several active metabolites including desmethyldiazepam, conjugate by UGT2B15 [78]. Lorazepam clearance was
PK and PD Drug Interactions with Ethanol (Alcohol) 1121

shown to be decreased by an average of 18 % in seven CNS and respiratory depressant effects (for review, see
healthy male subjects treated with ethanol (0.8 g/kg) in Gudin et al. [86]). Unlike the additive pharmacodynamic
orange juice administered 1 h prior to a dose of lorazepam interaction with benzodiazepines and ethanol, ethanol may
(2 mg intravenous) and then every 5 h for four doses. potentiated the effects of the opioid by decreasing the
There was no effect on t‘, Vd, or protein binding [79]. The ventilator response to hypercapnia [87]. Concurrent use of
psychomotor impairment of lorazepam (2.5 mg) and ethanol does not appear to alter the pharmacokinetics of the
buspirone (10 and 20 mg) administered with and without opioids [87].
ethanol (1 g/kg) was determined in 12 healthy males [68].
Lorazepam, but not buspirone, significantly impaired psy- 5.4.1 Morphine
chomotor skills (body sway, tracking, flicker recognition)
and ethanol significantly increased the impairment. In 24 Due to reports of co-ingestion of ethanol with a sustained-
healthy subjects (12 males, 12 females), ethanol (0.6 g/kg) release opioid product (PalladoneTM, hydromorphone ER)
significantly decreased recall memory based on an imme- resulting in a premature and unintended rapid release of the
diate and delayed word frequency test compared with lor- opioid from the product (dose dumping), the US Food and
azepam (2 mg) alone [80]. Drug Administration recommended that all extended-
release opioid products be evaluated with acute ethanol
5.3.2 Chronic Ethanol consumption to determine the risk of this potential inter-
action. The effect of ethanol [40 % (v/v)] on extended-
There is limited and conflicting data on the effects of chronic release morphine sulfate (100 mg) and immediate-release
ethanol on the pharmacokinetics of chlordiazepoxide and morphine solution (20 mg) compared with water was
diazepam. Chlordiazepoxide (25 mg) pharmacokinetics evaluated in an open-label, randomized, 3-way crossover
were determined in a group of seven male patients admitted design in 32 healthy male subjects [88]. There was no
for diagnosis of acute intoxication and compared with five effect of single-dose ethanol on the pharmacokinetics of
healthy male subjects [81]. The clearance of chlordiaz- either morphine formulation. A 4-way crossover study of
epoxide was significantly lower in the chronic ethanol the effects of dose escalation of ethanol on an extended-
patients than in the controls (36.4 ± 9.7 vs. 25.4 ± 15 mL/ release combination product of morphine sulfate and nal-
min), although the clearance was not weight normalized. In trexone hydrochloride was conducted in 32 healthy male
contrast, in patients undergoing ethanol withdrawal evalu- and females. There was no effect of a 4 or 20 % ethanol
ated on day 1 and day 6 [82], the AUC of chlordiazepoxide dose on the pharmacokinetics of either morphine or nal-
(50 mg) significantly decreased from 55.6 ± 5.8 to trexone. Concurrent dosing with a 40 % ethanol dose
21.0 ± 5.1 lgh/mL after withdrawal of ethanol. Sellers increased the absorption rate and resulted in a twofold
et al. also reported that the chlordiazepoxide and des- increase in the Cmax and 55.5 % decrease in tmax (from 9 to
methylchlordiazepoxide concentrations were significantly 4 h) with no significant effect on the AUC. In order to
lower on day 6 than on day 2 after ethanol withdrawal when evaluate the pharmacokinetic and pharmacodynamic
measured 4 h after dosing [83]. However, changes in the rate effects of rapid dose dumping of morphine, a crossover
or extent of absorption could also explain the results as only study in ten subjects received two doses of morphine (50
one timepoint was evaluated. and 80 mg) as an oral solution with and without ethanol
After a 10 mg intravenous dose, the plasma concentra- 20 % (0.7 g/kg) [89]. There was no effect on the phar-
tions and AUC from time zero to 24 h (AUC24) of diaze- macokinetics of morphine or morphine metabolites. There
pam were significantly lower in 14 male patients with were also no serious adverse events, including no clinically
chronic ethanol use who were 1–3 days ethanol free than in relevant decrease in vital signs or oxygen saturation. The
13 healthy subjects [84]. This suggests that chronic ethanol investigators concluded that at the doses used in the
use is associated with induction of diazepam metabolism. extended-release formulations, even if dose dumping of
The same group of investigators administered a 10 mg oral morphine occurred, the effects would be minimal.
dose of diazepam in 12 (11 male, 1 female) patients with Morphine is primarily eliminated by UGT2B7 [90] to
chronic ethanol use who ranged from 1 to 7 days ethanol two glucuronide metabolites, morphine 6-glucuronide
free and found that the Cmax and AUC12 were lower, with (M6G) and morphine 3-glucuronide (M3G), accounting for
no difference in the t‘ [85]. approximately 65 % of the dose [91]. There is limited
evidence that chronic ethanol may inhibit morphine glu-
5.4 Opioids curonidation. In vitro studies in isolated rat hepatocytes
have demonstrated an inhibition of morphine glucuroni-
The combination of ethanol and opioid use increases the dation by ethanol [92, 93]. Clinically, the ratios of M6G
risk of fatal overdose, presumably due to a combination of and M3G to morphine concentrations were evaluated in a
1122 L.-N. Chan, G. D. Anderson

series of samples obtained from suspected drunk and/or methylphenidate (0.3 mg/kg). The control arm included
drugged drivers [94]. The ratio of the M3G and M6G to methylphenidate taken 30 min before orange juice and
morphine concentration was significantly lower (27 and soda. Concurrent ethanol consumption, regardless of the
35 %, respectively) in the samples obtained from the timing, was associated with a significant increase in both
morphine plus ethanol subjects than in those from the the Cmax and AUC from time zero to infinity (AUC?) of
morphine alone subjects, suggesting that chronic ethanol the d-methylphenidate concentration in the plasma. The
may decrease morphine glucuronidation. There are no mean increases in Cmax were 37 and 39 % and the mean
published studies evaluating morphine pharmacokinetics in increases in AUC were 27 and 23 %, respectively, when
chronic users of ethanol. As M6G is the major active ethanol was administered before methylphenidate dosing.
metabolite responsible for significant analgesic effect [95] More interestingly, although men had higher Cmax and
and M3G may be responsible for the excitatory effects of AUC values than women, women were more likely to
morphine [96], it is not clear how a decrease in the for- experience the stimulant effects based on subjective
mation of the metabolites would alter the overall pharma- reporting using a visual analog scale with nine questions.
cologic effect of morphine. Ethanol co-administration significantly increased the for-
mation of ethylphenidate in both sexes compared with
5.4.2 Oxycodone taking methylphenidate alone. The mean plasma l-ethyl-
phenidate concentration was higher in men than in women.
Oxycodone is metabolized primarily by CYP3A4 with minor The active enantiomer, d-ethylphenidate, was only detect-
metabolism by CYP2D6 [97]. In a randomized, placebo- able in women if ethanol was administered after methyl-
controlled crossover study designed to evaluate the potential phenidate [104]. In a separate study using 20 mg of
of ethanol to increase the abuse effects of oxycodone, 14 male methylphenidate and 0.8 g/kg of ethanol in nine male
and female subjects received placebo, oxycodone (10 mg), subjects, the methylphenidate concentration was not altered
two doses of ethanol (0.3 and 0.6 g/kg), or the combination significantly by ethanol regardless of the administration
[98]. Oxycodone significantly reduced the breath alcohol sequence. Ethanol consumed before administration of
concentrations at 15 and 30 min after the lower ethanol dose, methylphenidate was associated with a significant reduction
and at 15, 20, and 60 min after the higher dose of ethanol. of plasma ritalinic acid concentrations [105]. The con-
There was no pharmacokinetic effect of ethanol on oxyco- tradicting results between the two studies may be due to the
done concentrations as estimated by miosis, which has been presence of intrinsic fast and poor metabolizers of methyl-
shown to be strongly correlated with oxycodone concentra- phenidate, as shown by Patrick et al. [104]. Further under-
tions. There has been no effect of other opioids, propoxy- standing of the metabolic profile of methylphenidate is
phene, [99] morphine [89], and hydromorphone [100] on the needed in order to more accurately evaluate the potential
breath alcohol concentrations in similar studies. interaction with ethanol. In summary, conflicting informa-
tion exists with regard to any pharmacokinetic interaction
5.5 Stimulants between methylphenidate and ethanol. Based on one study,
the concurrent use of methylphenidate and ethanol may be
5.5.1 Methylphenidate associated with an increased stimulant effect in women.

The primary metabolic pathway for methylphenidate is 5.6 Miscellaneous CNS Agents
hydrolysis by esterases to ritalinic acid, which is pharma-
cologically inactive. Other minor metabolites include 5.6.1 Almotriptan
p-hydroxymethyl-phenidate and lactam, which can undergo
further oxidation. However, the enzyme involved in the Almotriptan is a serotonin 5-HT1B/1D receptor agonist for
oxidation of the lactam is unknown [101]. Ethylphenidate, the treatment of migraine. It is a substrate of monoamine
an active metabolite, has been detected in people who have oxidase-A, CYP3A4, and CYP2D6 [106], and its metabolic
methylphenidate overdose with alcohol co-ingestion. It has profile suggests that it should not have a significant inter-
been postulated that in the presence of ethanol, methyl- action potential with ethanol. In a pharmacokinetic inter-
phenidate can undergo transesterification to form ethyl- action study by Cabarrocas et al. [107], 16 healthy male
phenidate [102, 103]. Therefore, the potential for a subjects received an oral dose of almotriptan (12.5 mg)
clinically important interaction between ethanol and with and without concomitant alcohol intake (0.8 g/kg).
methylphenidate is high. In an open-label, 3-way, ran- Ethanol appeared to alter the tmax without significantly
domized crossover study involving 20 healthy subjects (ten affecting the Cmax and AUC of almotriptan. The results
men and ten women), ethanol (0.6 g/kg) was administered suggest that ethanol may alter the rate but not the extent of
30 min before and after immediate-release oral absorption of almotriptan.
PK and PD Drug Interactions with Ethanol (Alcohol) 1123

5.6.2 Triazolam, Zolpicone, and Zolpidem 6.1.1 Felodipine

Triazolam, zolpicone, and zolpidem are predominately Felodipine is metabolized by CYP3A4 [114]. The phar-
eliminated by CYP3A4. In a small study of six healthy macokinetic and pharmacodynamic interaction between
subjects (five males, one female), triazolam 0.25 mg with felodipine and ethanol was evaluated by Bailey et al. [115].
ethanol was administered 1 h prior and 7.5 h after dosing Ten patients with untreated borderline hypertension
to maintain breath concentrations of 800–950 mg/L received felodipine 5 mg with placebo or 0.75 g/kg of
[108]. Ethanol administration increased the AUC of ethanol based on lean body weight in a randomized,
triazolam by an average of 21 % (-6 to 42 %), with no crossover double-blind study. Changes in cardiovascular
effect on the t‘ with a large inter-subject variability. responses, such as cardiac indices, total peripheral resis-
There was a significant increase in psychomotor tance, blood pressure and heart rate, were evaluated for up
impairment with the combination. An additional study in to 4 h. Compared with placebo, coadministration of felo-
five healthy subjects by the same investigators evaluated dipine with ethanol is associated with a more profound
the effect of a single dose of ethanol (60 mL of vodka reduction in supine total peripheral resistance (13 ± 2 vs.
administered with 60 mL of water) with a higher oral 17 ± 2 dyns/cm5) and diastolic blood pressure (68 ± 3
dose of triazolam (0.5 mg) and found no effect on the vs. 75 ± 2 mmHg) with a resultant increase in heart rate
Cmax, tmax, t‘, or oral clearance [109]. Similar results (72 ± 3 vs. 67 ± 2 bpm) and cardiac index (3.7 ± 0.4 vs.
were found in a study of 12 healthy subjects receiving 3.0 ± 0.3 L/min/m2). More subjects experienced light-
triazolam (0.25 mg) or zopiclone (7.5 mg) with ethanol headedness with felodipine plus ethanol. The pharmaco-
(0.8 g kg); ethanol enhanced and prolonged the sub- kinetics of felodipine did not appear to be affected by the
jective and objective performance tests with no effect on coadministration of ethanol. Therefore, ethanol appears to
the plasma concentrations of triazolam or zopiclone have a pharmacodynamic interaction with felodipine but
[110]. Therefore, there are conflicting data on a possible not a pharmacokinetic interaction.
pharmacokinetic drug interaction; however, the additive
effect on performance skills and sedation is consistent, 6.1.2 Nifedipine
supporting a pharmacodynamic interaction. Twenty-four
male subjects received a single oral dose of zolpidem The interaction between ethanol and nifedipine, a substrate
(10 or 15 mg) with and without an alcoholic beverage of CYP3A4 [116], was evaluated in ten healthy subjects in
designed to achieve a blood alcohol concentration of a crossover study [117]. The subjects received 20 mg of
0.08 %. The sedative effect as measured by performance nifedipine with 75 mL of orange juice or an equal volume
skill was additive [111]. In a study in 18 healthy male of ethanol (0.8 g/kg). Concurrent ingestion of ethanol was
subjects, there was also an additive sedative effect of not associated with any significant change in the Cmax, tmax,
zaleplon (10 mg) with ethanol (0.75 g/kg) without a or t‘ of nifedipine. Interestingly, the investigators also
pharmacokinetic interaction [112]. Therefore, as would reported a 54 % increase in the AUC from time zero to
be predicted from a pharmacodynamic perspective, con- 16 h (AUC16) of nifedipine (533 vs. 346 ngh/mL) with
current administration of ethanol with a hypnotic seda- concurrent ethanol administration. Since nifedipine is a
tive results in an additive effect on sedation on CYP3A4 substrate and ethanol is not known to affect
performance tests. CYP3A4 activity or expression, the exact mechanism is
unclear. Although no significant changes in systolic and
diastolic blood pressures were detected, an increase in heart
6 Drugs that Affect the Cardiovascular System rate was more pronounced in the ethanol group.

6.1 Antihypertensive Agents 6.1.3 Verapamil

Ethanol ingestion is associated with a fall in supine Verapamil is metabolized by CYP3A4, whereas its
blood pressure and vasodilatation in the superior mes- metabolite, norverapamil, appears to be partially metabo-
enteric artery. Cardiac output and blood flow to the lized by CYP2E1 [118]. This is consistent with the finding
forearm muscle are not affected [113]. However, as from clinical studies showing a lack of interaction between
hypertension is one of the most common co-morbidi- ethanol and a single dose of verapamil [119]. However,
ties, especially among older adults, the potential when ethanol (0.8 g/kg) was given to ten healthy male
interaction between ethanol and cardiovascular agents subjects after receiving multiple doses of verapamil (80 mg
has been the focus of intense investigations in the past every 8 h for 6 days), significantly higher blood ethanol
three decades. Cmax (106.45 ± 21.40 vs. 124.24 ± 24.74 mg/dL) and
1124 L.-N. Chan, G. D. Anderson

AUC (365.67 ± 93.52 vs. 475.07 ± 97.24 mgh/dL) val- associated with a mean increase of NAPQI formation by
ues were found than with placebo [120]. From a pharma- 22 % [128]. This suggests that acute ingestion of a large
codynamic perspective, verapamil also increased the amount of ethanol may also increase the risk of acetamino-
subject’s perception of ethanol intoxication as measured by phen hepatotoxicity.
a simple visual analog scale. The increase in ethanol AUC
correlated with the AUC of verapamil. The findings sug- 7.2 Aspirin (Acetylsalicylic Acid)
gest that norverapamil may have accumulated at steady
state to cause a clinically significant interaction with eth- The interaction between aspirin (acetylsalicylic acid) and
anol, likely through inhibition of CYP2E1. ethanol has been investigated in different settings. In vitro
data using both human and rat gastric mucosal tissues
6.2 Anti-Arrhythmic Agents suggested that aspirin inhibits gastric ADH activities
through non-competitive inhibition with an inhibition
6.2.1 Procainamide constant (Ki) of 8 mmol/L [129]. Incubation of human
gastric mucosal tissue with aspirin at 10 mmol/L was
Ethanol alters the pharmacokinetics of procainamide, associated with a 54 % reduction of ADH activities. In five
which is metabolized by the polymorphic enzyme N-ace- healthy male subjects who received a standard breakfast,
tyltransferase (NAT2) [121]. Ethanol (0.73 g/kg) admin- pretreatment with aspirin 1 g 1 h prior to consuming 0.3 g/
istered 1.5 h after procainamide taken orally caused a kg of ethanol over 10 min was associated with a 39 %
significant reduction in the t‘ (171 vs. 125 min) and an increase in the Cmax and a 26 % increase in the mean AUC
increase in the total clearance of procainamide (532 vs. of ethanol. In contrast, no change in ethanol pharmacoki-
711 mL/min) without affecting the renal clearance of either netics was detected in rats after intravenous administration
procainamide or N-acetylprocainamide [122]. The inter- when pre-treated with aspirin orally. These findings appear
action was observed in both fast (n = 6) and slow (n = 5) to be supported by the study by Truitt et al. [130], which
acetylators. The proposed mechanism for this interaction is showed that aspirin pre-treatment (640 mg) was associated
that ethanol use leads to increased formation of acetyl- with decreased alcohol-induced flushing and intoxication
CoA, which is an important co-substrate for the enzyme with a small reduction in blood acetaldehyde concentra-
NAT2. Therefore, ethanol consumption can increase the tion. A follow-up study showed that the relative oral bio-
drug elimination via the acetylation reaction. availability of ethanol was increased by 39 % after pre-
treatment with 1 g of aspirin. Using the technique of
scintigraphy, it was shown that aspirin did not alter the
7 Anti-Inflammatory and Analgesic Agents gastric emptying time [131]. However, when two different
groups later repeated the same clinical experiments, they
7.1 Acetaminophen were unable to replicate the increase in ethanol absorption
[132, 133]. Ethanol pre-treatment did reduce the Cmax of
Acetaminophen is metabolized by glucuronidation and sul- aspirin by 25 %. In summary, it appears that a pharmaco-
fation with minor metabolism by CYP2E1 and CYP3A4 kinetic interaction between aspirin and ethanol exists.
[123]. It is well-documented that chronic ethanol consump- Mechanistic investigation suggests that aspirin inhibits
tion increases the risk of acetaminophen hepatotoxicity. The ethanol oral bioavailability by decreasing pre-systemic
mechanism primarily involves the induction of CYP2E1 by metabolism in the stomach. However, clinical studies
ethanol, which increases the fraction of an acetaminophen failed to produce consistent results. It is likely that this
dose converted to its toxic metabolite, N-acetyl-p-benzo- interaction is confounded by other factors that affect eth-
quinone imine (NAPQI) [124, 125]. Although earlier studies anol pharmacokinetics, such as genetics, diet, and baseline
in animal models have suggested that acute ethanol admin- activities of ADHs and CYP2E1.
istration might inhibit the activities of CYP2E1 and possibly In addition to a pharmacokinetic interaction, pharma-
had a protective effect on acute acetaminophen intoxication, codynamic interactions exist between aspirin and ethanol.
this interaction appeared to be more complex and dependent Concurrent ethanol intake at any concentration increases
on the time of administration of both compounds as well as the risk of upper gastrointestinal bleeding associated with
the number of doses of acetaminophen ingested [126, 127]. A aspirin [134]. The likely explanation for this interaction
subsequent study showed that the administration of a single includes the reversal of the inhibition of vascular prosta-
dose of acetaminophen 500 mg 8 h after attainment of a cyclin synthesis by ethanol, which promotes bleeding, as
blood alcohol concentration of 100 mg/dL through contin- well as the additive effect of both aspirin and ethanol on
uous ethanol infusion (equivalent to consumption of one gastrointestinal mucosal blood flow, oxygenation, and
750 mL bottle of wine or six 12-ounce cans of beer) was also integrity [135].
PK and PD Drug Interactions with Ethanol (Alcohol) 1125

7.3 Ibuprofen ethanol preparation may have affected the magnitude of

interaction with the precipitant drugs in these studies [105,
The impact of ibuprofen, which is metabolized by 107]. Likewise, the choice of meal prior to ethanol inges-
CYP2C9 [136], coadministration on ethanol pharmacoki- tion varies from a standard breakfast (e.g., 2 eggs, 2 strips
netics was investigated in 19 healthy subjects [137]. of bacon, 2 pieces of toast, and coffee) to pasta with des-
Blood ethanol concentrations were monitored every sert. A clinical study using omeprazole as the precipitant
30–60 min for up to 4 h with or without pre-treatment drug showed that it did not alter the bioavailability and
with ibuprofen. The mean elimination rate as calculated pharmacokinetics of ethanol [145].
based on Widmark’s elimination factor was similar in the In summary, despite the implication from in vitro data,
two groups (0.018 ± 0.006 g/dL for ethanol and H2RBs given at the typical therapeutic doses should not
0.017 ± 0.007 g/dL/h for ethanol with ibuprofen). Over- lead to a clinically significant increase in ethanol concen-
all, the pharmacokinetic profiles of ethanol were similar tration after oral administration. Proton pump inhibitors
with or without ibuprofen. such as omeprazole are now the preferred drugs of choice
in the management of most gastric acid-related illnesses
such as gastroesophageal reflux disorder and peptic ulcer
8 Drugs that Affect the Gastrointestinal System disease and, based on both their metabolic profile and
mechanism of action, we would not expect any clinically
8.1 Gastric Acid-Reducing Agents significant interaction with ethanol.

The potential interaction between acid-reducing agents and 8.1.1 Aprepitant

ethanol has been investigated extensively. The rationale for
the investigation is based on the data from in vitro studies Aprepitant is a neurokinin 1 (NK1) receptor antagonist.
suggesting that histamine H2 receptor antagonists (block- Although it is primarily metabolized by CYP3A4 [146] and
ers) (H2RBs) inhibit ADH enzymes [129, 138, 139]. a pharmacokinetic interaction is unlikely, there is a
Cimetidine, ranitidine, and nizatidine all appeared to potential for pharmacodynamic interaction with ethanol
inhibit ADH in the gastric epithelial tissues. In a study of since it affects neurotransmitters. Healthy subjects of both
20 healthy male subjects, Gupta et al. [140] showed that sexes (n = 16) were recruited to compare the pharmaco-
cimetidine administered at a therapeutic dose (400 mg kinetic and pharmacodynamic effect of aprepitant with or
twice daily) was associated with a clinically significant with intravenous ethanol (target blood alcohol concentra-
increase in the ethanol Cmax. The average increase in eth- tion 65 mg/dL) [147]. Amitriptyline was used as the
anol Cmax was 45 % with three subjects’ Cmax more than positive control for pharmacodynamic changes because of
doubled after cimetidine coadministration. Ethanol was its effects on the impairment of the CNS. The results
administered orally at 0.6 g/kg after a meal in 3–4 drinks showed that there was no clinically significant interaction
over 135 min. The pharmacokinetic interaction is due to between ethanol and aprepitant, and that coadministration
inhibition of gastric ADH resulting in increased oral bio- of both drugs was not associated with additive effects in
availability of ethanol. The magnitude of the increase in impairing psychomotor and cognitive function. The phar-
ethanol Cmax with cimetidine positively correlated with the macokinetics of neither drug was affected with concurrent
baseline pre-systemic metabolism of ethanol. Nevertheless, drug administration.
subsequent clinical studies showed that while the typical
therapeutic dose of ranitidine (150 mg twice daily) could 8.1.2 Orlistat
increase the Cmax and AUC of ethanol, the corresponding
change in blood alcohol concentration was less than Orlistat is primarily eliminated unchanged in the urine and
0.01 % and was not clinically significant. The dose of is poorly absorbed by the gastrointestinal tract [148]. A
ethanol in these studies ranged from 0.15 to 0.6 g/kg and randomized, double-blind, placebo-controlled study in 30
the number of study subjects ranged from 8 to 23 [141– normal weight, male healthy subjects was conducted to
145]. The magnitude of the interaction is further con- evaluate the potential interaction between orlistat and
founded by the timing of ethanol consumption, the type of ethanol by Melia et al. [149] in a parallel study with three
ethanol used, the quality and the quantity of concurrent treatment groups (orlistat with placebo, orlistat with etha-
meal intake, and the diversity of the study subjects’ ethnic nol, and placebo with ethanol). Each group of ten subjects
background. For example, ethanol was prepared as a 10 % received a high-calorie (2,500 kcal/day) and high-fat
(v/v) beverage in one study, whereas 4.8 % beer was used (30 % fat) diet. Orlistat administration (120 mg three times
in another. Since the rate of ethanol absorption is affected daily) did not alter the ethanol pharmacokinetics. Similarly,
by the concentration of ethanol consumed, the difference in concomitant ingestion of ethanol (40 g) did not alter the
1126 L.-N. Chan, G. D. Anderson

efficacy of orlistat on inhibition of dietary fat absorption parenteral cefpirome and ethanol was assessed in 22
during short-term treatment (6 days) with orlistat. healthy male subjects [154]. After an overnight fast, the
subjects received cefpirome 2 g intravenously and ethanol
0.5 g/kg. There were no statistically significant differences
9 Anticoagulants in mean values for the various pharmacokinetic parameters
for plasma alcohol between the cefpirome and placebo
9.1 Warfarin treatment groups. Pharmacodynamic interactions, includ-
ing disulfiram-like reaction, were not observed following
Warfarin is a compound with high potential for drug–drug consumption of alcohol. Overall, clinically significant
interactions. It is primary metabolized by CYP2C9 with interactions between b-lactam antibacterials and ethanol
minor pathways through CYP1A2, CYP2C8, CYP2C18, appear to be absent.
CYP2C19, and CYP3A4 [150]. Interestingly, despite the
potential clinical significance of the interaction, the impact 10.1.2 Ciprofloxacin
of ethanol on warfarin metabolism has not been evaluated.
A single case report exists in the literature involving a The impact of ciprofloxacin (500 mg twice daily for
58-year-old man with no history of liver disease, who 3 days) on the pharmacokinetics of ethanol (30 g) was
required long-term therapy with warfarin for the prevention evaluated in 12 healthy subjects [155]. Compared with
of ischemic stroke. When he began consistent consumption placebo, ciprofloxacin did not alter the Cmax, tmax, or AUC
of one-half can of light beer every other day (5.35 g), his of ethanol. Additionally, ciprofloxacin did not intensify the
international normalized ratio (INR) increased from a pharmacodynamic effect of ethanol as measured by psy-
baseline of 2.18 to 8.0. After discontinuing his low-dose chomotor tests, such as the critical flicker fusion threshold,
beer consumption, his INR returned to baseline with the choice reaction time, pursuit rotor, tapping rate, digit
previously prescribed warfarin regimen [151]. Although symbol substitution, and digit span. Subjective feelings of
the timing of the event may appear to support a drug concentration, vigilance, and relaxation based on visual
interaction between warfarin and ethanol, the change of analog scales were also unchanged. The author concluded
INR from baseline of 2.18 to 8.0 seems too dramatic. It is that a clinically significant interaction between ciproflox-
likely that the sharp increase in INR was precipitated by acin and ethanol is absent. This finding is consistent with
other transient events. At this point, there is insufficient the metabolic profile of ciprofloxacin, which is an inhibitor
evidence to suggest a single ingestion of a moderate of CYP1A2 but not CYP2E1 [156].
amount of ethanol alone may significantly alter warfarin
pharmacokinetics and clinical response in patients who are 10.1.3 Erythromycin
not malnourished or with extensive liver diseases.
Erythromycin is metabolized by CYP3A4 and is a potent
inhibitor of CYP1A2 and CYP3A4 [157]. Morasso et al.
10 Antimicrobial Agents [158] investigated whether the pharmacokinetics of eryth-
romycin are altered by ethanol (approximately 0.5 g/kg,
10.1 Antibacterial Drugs administered as 150 mL of pisco sour, a Peruvian nation
beverage containing lemon juice, sugar and pisco, an
10.1.1 b-Lactams alcoholic beverage obtained by distillation of fermented
grapes) in nine healthy male and female subjects. Ethanol
The effect of ethanol on the pharmacokinetics of penicillin was consumed with and then 2.5 h after erythromycin.
(administered orally as 2 million units of phenoxymethyl- Compared with water, ethanol co-ingestion led to a 136 %
penicillin) was evaluated in healthy subjects (n = 6; three increase in lag time (0.28 ± 0.07 vs. 0.66 ± 0.33 h), 15 %
men and three women) [152]. Ethanol (1 g/kg) had no decrease in Cmax (0.89 ± 0.32 vs. 0.76 ± 0.29 mg/L), and
effect on the Cmax, tmax, t‘, AUC, or 24-h urinary excretion 27 % decrease in erythromycin AUC (3.38 ± 1.01 vs.
of penicillin. Similarly, the potential interaction between 2.48 ± 0.84 lgmin/mL). The mechanism of this interac-
amoxicillin (500 mg) and ethanol was studied in eight tion is unclear. The impact of erythromycin pre-treatment
healthy subjects [153]. Ethanol altered the absorption rate on the pharmacokinetics of ethanol was not determined.
constant, lag time, and tmax of amoxicillin without signif- Since erythromycin increases the gastric emptying rate
icantly affecting the Cmax and AUC. Therefore, it appears [159], it can be speculated that it would lead to an
that ethanol alters the rate but not on the extent of increased rate and possibly extent of ethanol absorption
absorption of amoxicillin. The interaction between resulting in a lower tmax and possible higher Cmax.
PK and PD Drug Interactions with Ethanol (Alcohol) 1127

10.1.4 Tetracycline in AUC8 of ethanol. However, only the change in AUC

reached statistical significance. Despite the overall reduction
The impact of ethanol on the pharmacokinetics of tetra- of ethanol exposure with efavirenz, the subjects demon-
cycline was studied in nine healthy subjects [160]. Con- strated a lack of decline in ratings of intoxication and
current ingestion of alcoholic beverage in the form of pisco drowsiness consistent with a pharmacodynamic interaction.
sour 150 mL (equivalent to approximately 0.27 g/kg)
caused a significant increase in the Cmax (9.31 vs. 10.2.3 Maraviroc
12.36 mg/L) and AUC (62.65 vs. 94.28 mgh/L) of tetra-
cycline, suggesting an increased bioavailability. Maraviroc is an HIV entry inhibitor and is a substrate of
CYP3A4 [169]. In ten healthy male and female subjects
10.1.5 Isoniazid receiving ethanol (1 g/kg) and maraviroc, ethanol did not
alter the pharmacokinetics of maraviroc, whereas maravi-
Isoniazid is a commonly prescribed anti-tuberculosis drug roc coadministration was associated with a 12 % increase
and is primary metabolized by NAT2 [161]. It has a in ethanol AUC8 [170].
complex inhibition–induction profile on various CYP
enzymes. It is a mechanism-based inhibitor for CYP1A2, 10.2.4 Ritonavir
CYP2C9, CYP2C19, and CYP3A4 [162]. Interestingly,
data also showed that isoniazid induces CYP2E1 via post- The same study that investigated the interaction between
transcriptional protein stabilization [163]. The effect of ethanol and efavirenz also evaluated the potential interac-
acute ethanol ingestion (0.73 g/kg 1 h before isoniazid, tion between ethanol and ritonavir [168], which is a sub-
followed by 0.11 g/kg every hour for 7 h) on the phar- strate and a mechanism-based inhibitor of CYP3A4 [171].
macokinetics of isoniazid (200 mg orally) was evaluated in During the 8-h blood sampling period, blood alcohol con-
16 healthy male subjects [164]. Concurrent ethanol centrations were consistently lower with ritonavir than with
administration did not change the pharmacokinetics of ethanol alone (1 g/kg), suggesting that ritonavir decreased
isoniazid. The Cmax, tmax, AUC, and apparent oral clear- the bioavailability of ethanol. A pharmacodynamic inter-
ance of isoniazid were all similar with or without ethanol action was not in evidence based on the subjective
administration in both slow and fast acetylators. The results assessment of the patient’s intoxication or drowsiness
suggest that a pharmacokinetic interaction between isoni- score. Ethanol consumption did not alter the pharmacoki-
azid and ethanol is absent. netics of ritonavir.

10.2 Antiviral Drugs

11 Miscellaneous Drugs
10.2.1 Abacavir
11.1 D9-Tetrahydrocannabinol
Abacavir is a nucleoside analog used in the treatment of
HIV infection. The primary metabolic pathways for ab- 11.1.1 Effect of D9-Tetrahydrocannabinol on Ethanol
acavir are oxidation by ADH and glucuronidation [165].
Therefore, the potential for interaction with ethanol is high. There have been several studies evaluating the effect of D9-
McDowell et al. [166] evaluated this interaction in 25 male tetrahydrocannabinol (THC) on the pharmacokinetics of
HIV-infected patients who received abacavir 600 mg and ethanol. The interaction has been evaluated by either
ethanol 0.7 g/kg. Abacavir did not alter the pharmacoki- administration of THC by oral capsules [172–174] or by
netics of ethanol. Conversely, ethanol did increase abacavir smoking standardized marijuana cigarettes (inhaled) [175,
AUC12 by 41 %, Cmax by 15 %, and t‘ by 26 %. 176]. Benowitz and Jones [172] evaluated the effects of
chronic THC (10–30 mg given every 4 h for 10–17 days)
10.2.2 Efavirenz on ethanol pharmacokinetics in a crossover placebo-con-
trolled study in eight healthy male and female subjects.
Efavirenz is extensively metabolized by CYP2B6 and Ethanol was administered orally (95 % ethanol, 1 mL/kg in
CYP3A4/5 [167]. Ten HIV-infected patients not currently orange juice) in seven subjects and intravenously (0.4 g/
receiving ritonavir were recruited to receive efavirenz with kg) in one subject. The rate of ethanol elimination was
or without ethanol (1 g/kg) [168]. Efavirenz treatment was decreased in five subjects and increased in three subjects,
associated with a lower blood alcohol concentration with a resulting in no overall significant change. Belgrave et al.
12 % decrease in ethanol Cmax, a 62.5 % decrease in blood [173] administered THC (300 lg/kg) or placebo 60 min
alcohol concentration at 8 h, and an overall 14 % reduction after 15 subjects received either ethanol (0.54 g/kg) or
1128 L.-N. Chan, G. D. Anderson

placebo in a factorial design (n = 3–4 subjects/treatment THC was evaluated in regular users of cannabis in a dou-
arm). They found no significant effect of THC on ethanol ble-blind, placebo-controlled 3-way study design [178–
blood concentrations. Consroe et al. [174] studied the 180]. The initial dose of ethanol (95 % in orange juice)was
effect of THC (200 mg oral capsule) on ethanol (1 g/kg in 0, 0.5, or 0.7 g/L and subsequent additional doses were
orange juice) administered concurrently in ten healthy given every 30 min to maintain blood alcohol concentra-
males and females in a double-blind, placebo-controlled tions of 0, 0.5, and 0.7 g/L for 4.5 h. Subjects smoked THC
crossover design. Ethanol blood concentrations were sig- (400 lg/kg, 11 %) 3 h after the first dose of alcohol. There
nificantly decreased at 30, 60, and 120 min by an average was no effect of ethanol on the AUC of THC. The t‘ of
of 5–10 mg/dL. Perez-Reyes et al. [175] evaluated the THC in the higher-dose ethanol group was significantly
pharmacokinetics of two doses of ethanol (0.425 or 0.85 g/ longer than placebo (2.4 ± 1.5, 1.9 ± 0.6, and
kg) in a crossover placebo-controlled study in six male 1.6 ± 0.4 h) and the Cmax was lower (94 ± 40, 98 ± 50,
subjects. There was no effect of THC (2.4 %) on the tmax, and 112 ± 48 g/L for the high-dose, low-dose, and placebo
Cmax, or AUC when THC was administered by inhalation groups, respectively) [179]. There was no significant effect
15 min after the dose of ethanol. Lukas et al. [176] eval- of ethanol on the salivary concentrations of THC obtained
uated a low dose (1.26 %) and high dose (2.53 %) of THC up to 4 h after the THC inhalation [180]. Overall, the
and two doses of ethanol (0.35 g/kg, 0.7 g/kg) compared quantitative relationship between THC concentrations in
with placebo. Each subject (n = 5) received the same dose whole blood and oral fluid has been shown to be only
of THC 30 min after all three doses of ethanol. There was weakly correlated [181]. Neurocognitive assessment to
no effect of THC on the lower dose of ethanol. In contrast, evaluate critical tracking, divided attention, and motor
both doses of THC significantly decreased plasma ethanol impulsivity was performed up to 7 h after the ethanol
concentrations after the 0.7 g/kg dose during the 120 min dosing. Both low and high doses of ethanol significantly
after dosing, suggesting that marijuana smoking signifi- impaired all performance measures. THC alone did not
cantly decreases the oral absorption of ethanol. The Cmax impair the performance on the critical tracking task and
decreased from 78 ± 5 to 61 ± 11 mg/dL and 55 ± 8 mg/ motor impulsivity. Ethanol plus THC significantly
dL and the tmax increased from 50 min to 85 min and increased the effects on divided attention than was found
104 min after the placebo and 1.26 or 2.53 % THC dose, with ethanol alone [178].
respectively. The study duration was insufficient to eval- In general, THC has been shown to cause impairment on
uate the effect of THC on the elimination of ethanol. In cognitive studies with little or no impairment on experi-
conclusion, due to the varied treatments evaluated (dose, mental studies (for review, see Sewell et al. [182]). A meta-
routes, duration and timing of administration), it is not analysis concluded that THC impaired tracking, motor
possible to conclude whether or not THC alters ethanol coordination, visual functions, and complex text that
pharmacokinetics. require divided attention, with automatic functions
impaired at lower THC doses and more complex functions
11.1.2 Effect of Ethanol on D9-Tetrahydrocannabinol only impaired at higher does [183]. Overall, experimental
studies have found that the effects of the combination of
Lukas and Orozco [177] evaluated the effect of two doses ethanol and THC on cognitive function are additive [184,
of ethanol (0.35 and 0.7 g/kg) administered in orange juice 185], with a few reports suggesting possible synergy [175,
compared to placebo on the serum concentration of THC 186].
after two doses of THC (1.26 and 2.53 %) in 22 healthy In contrast, studies evaluating THC and ethanol using
male subjects. The higher dose of ethanol significantly driving simulators have found little or no effect of a dose of
increased the slope of the THC concentration–time curve THC up to 250 lg/kg or low-dose ethanol (\0.10 g/dL);
from 0 to 15 min, increased the Cmax, and decreased tmax however, additive effects with THC and ethanol were
by 5 min, suggesting a possible increased THC absorption. found when combined [187]. In a series of single-blind,
There was no effect of ethanol on the immediate post- randomized crossover studies evaluating the dose effect of
absorption phase (15–90 min). The duration of sampling THC and low-dose ethanol in actual driving, 16 or 24
was not sufficient to determine an effect on the elimination subjects received THC (0, 100, 200, and 300 lg/kg) with
of THC. The latency and duration of the effects of THC and without low-dose ethanol (blood alcohol concentration
were also evaluated subjectively using an instrumental of 0.04 g/dL) [188]. The effect of THC on driving per-
joystick device. Ethanol decreased the latency to detecting formance was small (100 lg/kg) or moderate (200 and
THC effect and increased the duration of euphoria signif- 300 lg/kg) when taken alone. The combination of THC
icantly for both doses of THC. with the low-dose ethanol resulted in severe impairment in
The effect of ethanol on the serum concentrations, sal- driving ability. In their review, Sewell et al. suggest that
ivary concentrations, and neurocognitive performance of alcohol impairs tasks requiring cognitive control more than
PK and PD Drug Interactions with Ethanol (Alcohol) 1129

automatic functions, while THC has the reverse effect. 9 %, respectively. Compared to ethanol or MDMA alone,
Therefore, the combination of ethanol and THC is additive the combination produced a longer-lasting euphoria, well-
or possibly synergistic [182]. being, and subjective sedation with no effect on the effect
of alcohol on psychomotor abilities.
11.2 Cocaine
11.5 Vardenafil
Cocaine is metabolized by hepatic carboxyltransferases to
norcocaine, cocaethylene, and norcocaethylene [189]. A Vardenafil is a phosphodiesterase-5 inhibitor that is
randomized, placebo-controlled crossover study evaluat- metabolized by CYP3A4 and CYP3A5 [193]. Its potential
ing the effect of acute ethanol intoxication (0.8 g/kg) on interaction with ethanol was evaluated in a randomized,
the effects of intranasal cocaine (100 mg) was performed single-dose, double-blind, placebo-controlled crossover
in eight healthy male subjects [190]. Ethanol increased trial with 12 healthy male subjects [194]. There were three
the Cmax and AUC6 of cocaine by 21 and 20 %, respec- treatment arms: vardenafil 20 mg plus ethanol 0.5 g/kg,
tively. The AUC6 of norcocaine was also increased by vardenafil plus placebo, and ethanol plus placebo. Varde-
39 %. There was no effect of cocaine on the pharmaco- nafil, vardenafil metabolite M-1, and ethanol pharmacoki-
kinetics of ethanol. Plasma concentrations of cocaethyl- netics were assessed. Pharmacodynamic parameters
ene, an active metabolite, and norcocaethylene were only including heart rate and systolic and diastolic blood pres-
present when ethanol was administered in combination sures were measured in a supine position for up to 24 h.
with cocaine. The combination resulted in significantly Overall, the pharmacokinetic parameters of vardenafil were
higher pleasurable-related effects including euphoria and not altered with concurrent ethanol intake. Additionally, no
reduced the alcohol-induced sedation. Heart rate and significant differences in systolic and diastolic blood
plasma cortisol concentrations were also higher with the pressures were found among treatment arms. Significantly
combination. The investigators suggests that the higher heart rates were observed in both treatment arms
enhancement of cocaine effects by ethanol may be due to that included ethanol; however, the difference between the
the higher initial cocaine concentrations and the additive ethanol only and ethanol plus vardenafil arm was not sig-
effects of cocaethyene, but could not rule out a pharma- nificant. Since the other phosphodiesterase-5 inhibitors,
codynamic effect. such as sildenafil, tadalafil, and avanafil, all share similar
metabolic pathways, it is likely that as a class of drugs, they
11.3 Methamphetamine do not have a pharmacokinetic interaction with ethanol.

The pharmacokinetic/pharmacodynamic effects of the

combination of methamphetamine (30 mg) and ethanol 12 Other Direct Inhibitors of Ethanol Metabolism
(1 g/kg) were evaluated in a double-blind placebo-con-
trolled study in eight methamphetamine and ethanol users 12.1 Fomepizole
[191]. There was no significant effect of ethanol on the
pharmacokinetics of methamphetamine or an effect of Fomepizole, also known as 4-methylpyrazole, is a syn-
methamphetamine on breath ethanol concentrations. The thetic ADH inhibitor. It is indicated as an antidote for
combination decreased the subjective effects of perceived ethylene glycol or methanol poisoning. Theoretically,
ethanol intoxication without affecting the subjective effects fomepizole can also inhibit ethanol metabolism. In a study
of methamphetamine (i.e., euphoria, alertness). Addition of involving 12 healthy men, the typical therapeutic dose of
ethanol to methamphetamine did increase heart rate and fomepizole (10–20 mg/kg) was associated with an average
decreased systolic blood pressure, resulting in potential 40 % reduction of ethanol clearance. Inhibition of ethanol
harmful cardiovascular effects. clearance by fomepizole was dose dependent. Ethanol was
dosed at 0.5 and 0.7 g/kg and administered as 20 % (w/v)
11.4 3,4-Methylenedioxymethamphetamine in orange juice. Interestingly, when the subjects were given
0.6 g/kg of ethanol first before administering fomepizole,
Nine healthy male 3,4-methylenedioxymethamphetamine fomepizole clearance was significantly decreased [195].
(MDMA; ecstasy) and ethanol users received placebo, These results suggest that there is a bidirectional pharma-
MDMA (100 mg), ethanol (0.8 g/Kg), or the combination cokinetic interaction between ethanol and fomepizole.
in a double-blind, randomized crossover study [192]. Eth- From a clinical perspective, it appears that the concurrent
anol increased the Cmax of MDMA by 12 % with no sig- administration of both fomepizole and ethanol may have a
nificant effect on the AUC6. MDMA decreased the Cmax synergistic effect as an antidote for methanol and ethylene
and AUC6 of the blood ethanol concentration by 15 and glycol intoxication.
1130 L.-N. Chan, G. D. Anderson

12.2 Disulfiram is the object drug, pharmacokinetic interactions can gen-

erally be predicted based on the metabolic profile of the
Disulfiram, or tetraethylthiuram, is a prodrug. After oral drug in question, and that the number of precipitant drugs
administration, it is rapidly converted to diethyldithiocar- are fairly limited (Table 1). Drugs that inhibit ADH or
bamic acid (DDC), which is further metabolized to die- CYP2E1 are the most likely compounds to lead to a clin-
thyldithiomethylcarbamate (Me-DDC). Me-DDC then ically significant pharmacokinetic interaction with ethanol,
undergoes oxidative biotransformation to S-methyl N,N- but pharmacodynamic interactions are more difficult to
diethylthiocarbamate (Me-DTC). Me-DTC is mechanism- predict (Table 2). The most commonly reported symptoms
based inhibitor of ALDH 1. Additionally, Me-DTC is also related to pharmacodynamic interactions are sedation,
metabolized to its sulfoxide and sulfone metabolites by tachycardia, impaired psychomotor performance, and
CYP2A6, CYP2E1, and CYP3A4, which are potent general intoxication. On the other hand, as a precipitant
inhibitors of both ALDH 1 and 2 in the cytosol and drug, ethanol can interact with a wide variety of com-
mitochondria [196, 197]. Inhibition of ALDH after ethanol pounds through a number of mechanisms, including alter-
ingestion leads to a five to tenfold increase in the blood ing the rate of absorption, changing the total amount
aldehyde concentration, which precipitates symptoms absorbed, changing the clearance, and increasing the gen-
similar to aldehyde poisoning such as peripheral vasodi- eration of toxic metabolites (Table 1). In many studies
latation, flushing, throbbing, tachycardia, headache, nau-
sea, and dizziness. In severe cases, syncope, confusion, and
Table 1 Pharmacokinetic interactions with ethanol (alcohol)
shock may also occur. The severity of the adverse reactions
related this interaction combination limits that viability of Object drug Interaction
conducting pharmacokinetic and pharmacodynamic inter-
Effect of ethanol on other drugs
action in humans. The published data, therefore, are pri-
Acetaminophen : Formation of NAPQI
marily from animal studies. In a dose-escalation study with
Amitriptyline Possible : in AUC and
52 healthy subjects, after a 14-day course of disulfiram pre- Cmax
treatment with 100, 200, and 300 mg daily, an ethanol Aspirin ; Cmax
challenge resulted in median plasma acetaldehyde con- Abacavir : Cmax, : AUC, ; t‘
centrations of 8, 32, and 46 lmol/L, respectively (range Chlordiazepoxide Acute: ; CL, : AUC
7–197 lmol/L). The presence of a disulfiram–alcohol
Chronic: ; AUC
reaction was always accompanied by at least 97 % inhi-
Diazepam Acute: ; CL, : AUC
bition of ALDH in the erythrocytes [197]. Additionally,
Chronic: ; AUC
although the pharmacokinetics of ethanol are similar,
Ezogabine : Cmax, : AUC
alcoholics with biopsy-proven alcoholic liver disease
Erythromycin : tmax, ; AUC
actually had lower overall exposure to acetaldehyde and
Fluvoxamine : Rate of absorption
fewer disulfiram–alcohol symptoms than alcoholics with-
3,4-Methylenedioxymethamphetamine : Cmax
out liver disease. The Cmax values of acetaldehyde in
Morphine Chronic: ; formation of
individuals with and without alcoholic liver disease were glucuronides
33.46 ± 21.52 and 110.87 ± 56.00 lmol/L, respectively,
Nifedipine : AUC
and the AUC values were 1,463.8 ± 762.5 and
Procainamide : CL, ; t‘, :
4,162.0 ± 2,424.6 lmoLmin/L, respectively [198]. These N-acetylation
results suggest that the patients with liver disease are less Tetracycline : Cmax, : AUC
likely to experience the same magnitude of disulfiram– Effect of other drugs on ethanol
alcohol symptoms with this drug interaction combination. Aspirin : Cmax, : AUC
Other drugs that may interact with ALDH causing disul- Cimetidine : Cmax
firam-like symptoms after alcohol ingestion include met- Disulfiram ; CL, : AUC
ronidazole, a number of cephalosporin antibiotics including Fomepizole ; CL, : AUC
cefoperazone, cefotetan and cefuroxime, chloramphenicol,
Maraviroc : AUC
chlorpropamide, and nitrofuratoin.
Oxycodone ; Breath alcohol
concentration
Verapamil : Cmax, : AUC
13 Conclusion
AUC area under the plasma concentration–time curve, CL clearance,
Cmax maximum concentration, NAPQI N-acetyl-p-benzoquinone
Our comprehensive review of the clinical literature focus- imine, t‘ elimination half-life, tmax time to Cmax, : indicates increase,
ing on acute ingestion of ethanol shows that when ethanol ; indicates decrease
PK and PD Drug Interactions with Ethanol (Alcohol) 1131

Table 2 Pharmacodynamic interactions with ethanol (alcohol) Acknowledgments No sources of funding were used to assist in the
preparation of this review. L.-N. Chan and G. D. Anderson have no
Object drug Adverse effect conflicts of interest to declare.

Acetaminophen : Risk of hepatotoxicity

Amitriptyline Sedation
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