THE AMERICAN JOURNAL OF GASTROENTEROLOGY
1, 2000
© 2000 by Am. Coll. of Gastroenterology
Published by Elsevier Science Inc.
Alcohol Levels Are Increased in
Social Drinkers Receiving Ranitidine
Satish Arora, M.D., Enrique Baraona, M.D., and Charles S. Lieber, M.D.
Alcohol Research and Treatment Center, Bronx Veterans Affairs Medical Center and
Mount Sinai School of Medicine, New York, New York
OBJECTIVE: Ranitidine increases blood alcohol concentra-
tions by decreasing the first pass metabolism of ethanol. The
effect of ranitidine on alcohol levels has been found to be
variable when using large doses of alcohol or conditions in
which its first pass metabolism is known to be minimal.
Despite a consensus that the drug increases alcohol levels
after small doses of ethanol, this effect has been considered
inconsequential, because of the low alcohol levels. How-
ever, social drinking comprises repetitive consumption of
small doses of alcohol and the ranitidine effect could
thereby be potentiated.
METHODS: To study this factor, alcohol levels were deter-
mined by breath analysis in nine men (social drinkers), after
four drinks of 0.15 g/kg ethanol given postprandially every
45 min, before and after ranitidine (150 mg b.i.d. for 7 days).
RESULTS: Their blood alcohol increased with repeated
doses, reaching peak values of 24 ⫾ 3 mg/dl before raniti-
dine and 33 ⫾ 2 after ranitidine (p ⫽ 0.04). In seven of the
nine subjects blood alcohol exceeded 25 mg/dl, a level at
which impairment of judgment and of finely tuned skills
occurs and which exceeds legal limits of driving in some
European countries. Moreover, the high levels persisted for
a longer time with than without the drug. These effects were
associated with a 62% decrease in first pass metabolism.
CONCLUSION: Under conditions mimicking social drinking,
ranitidine increases blood alcohol to levels known to impair
psychomotor skills needed for driving. (Am J Gastroenterol
2000;95:208 –213. © 2000 by Am. Coll. of Gastroenterol-
ogy)
INTRODUCTION
We previously reported that the H2-receptor antagonists
cimetidine and ranitidine (but not famotidine) increase
blood alcohol concentrations (BAC) by decreasing the first
pass metabolism (FPM) of ethanol (1, 2). Whereas the effect
of cimetidine appears to be linked to its capacity to inhibit
gastric alcohol dehydrogenase (ADH) activity (3– 6), the
inhibitory effect of ranitidine on FPM is primarily associ-
ated with an acceleration of the gastric emptying of ethanol
(due to its anticholinesterase activity), which shortens the
exposure of the enzyme to alcohol (7).
Vol. 95, No.
ISSN 0002-9270/00/$20.00
PII S0002-9270(99)00745-5
The effect of these drugs on BAC has been found to be
variable when using single large doses of alcohol or condi-
tions such as fasting or dilute alcohol solutions, in which
FPM has been reported to be minimal (8, 9). While there is
a general consensus that ranitidine increases BAC after a
single small dose of ethanol (150 mg/kg) (10), this effect has
been considered clinically inconsequential because the re-
sulting BAC are low. However, social drinking encom-
passes repetitive consumption of small doses of alcohol. In
this setting, the inhibitory effect of cimetidine on FPM was
potentiated and clinically relevant differences in BAC were
achieved after several drinks (11). Because ranitidine and
cimetidine affect the FPM by different mechanisms, this
study was undertaken to determine to what extent ranitidine
affects BAC under conditions of repetitive consumption of
small alcohol doses, mimicking social drinking.
MATERIALS AND METHODS
After approval by the Institutional Review Board and ob-
taining informed consent, 12 healthy men (30 to 45 yr old)
who drank ⬍60 g of alcohol (less than five standard drinks)
per week, were used in this study.
Ethanol Administration
Because we previously showed that 20 –30% of apparently
healthy subjects display minimal or no FPM (11, 12), we
first screened the 12 volunteers for FPM, using a single dose
of ethanol (300 mg/kg) randomly administered by the oral
route (as a 15% solution in orange juice) or intravenously
(as a 5% solution in isotonic dextrose). Each alcohol dose
was given 1 h after a standard meal to avoid the inhibitory
effects of fasting on FPM (8). All experiments were initiated
in the morning, but we previously did not find diurnal
differences in FPM (12).
In nine of the subjects, who displayed a substantial FPM,
we determined the alcohol levels and calculated the amount
of ethanol reaching the systemic blood after postprandial
administration of four small drinks (150 mg/kg) given at
45-min intervals and alternating with potato chips to simu-
late social drinking. This procedure was repeated after 1 wk
of ranitidine administration.
AJG – January, 2000
Ranitidine Administration
After completion of the baseline measurements, 150 mg of
ranitidine were given orally twice a day for 1 wk. Subjects
were given the weekly dose of ranitidine and asked to keep
it with them at all times to assess compliance by pill count.
Blood Ethanol Concentrations
To obtain a large number of measurements, the blood alco-
hol levels were determined at 5-min intervals by breath
analysis with a calibrated breathalizer, with a sensitivity of
0.1 mmol/L (13). This procedure was previously validated
by comparison with direct blood measurements by gas chro-
matography in the same subjects (11). After drinking, the
mouth was washed and the first breath sample was obtained
15 min thereafter to avoid the early contamination of ex-
pired air with alcohol remaining in the mouth.
First Pass Metabolism of Ethanol
The first pass metabolism of ethanol was quantified by the
difference between the amount of ethanol reaching the sys-
temic blood after intravenous and after oral administration
of the same dose (14). To calculate these amounts, we used
the Michaelis-Menten kinetics of ethanol elimination (15,
16). In each subject, we first obtained their parameters of
ethanol elimination, Vmax (maximal elimination velocity),
and Km (Michaelis constant) by curve fitting of an appro-
priate expression of the Michaelis-Menten function [t ⫽
⫺(Ct/Vmax) ⫹ (Km/Vmax) ⫻ ln(Co/Ct) ⫹ Co/Vmax] to
the decreasing blood levels after the intravenous infusion of
ethanol (300 mg/kg). The best fitting was generally obtained
after 60 min, once most of the ethanol had distributed in the
total body water. The volume of alcohol distribution (Vd)
was calculated by dividing the dose by the concentration at
time zero, which was obtained by extrapolation of the
Michaelis-Menten function to zero time. As reported previ-
ously (7), Vmax, Km, and Vd did not change after raniti-
dine; therefore, for each subject, the same values were used
before and after ranitidine administration.
The quantity of ethanol reaching the blood (Qabs) was
calculated as the sum of the amount present in body water
(Ct ⫻ Vd) plus the amount eliminated up to that time. The
amount of alcohol eliminated from the systemic blood after
intravenous and oral administration of the dose was calcu-
lated by integration of a more classical expression of the
Michaelis-Menten equation: Qelim ⫽ Vd ⫻ 兰[(Ct ⫻
Vmax)/(Ct ⫹ Km)] ⫻ dt. After administration of a single
dose of alcohol, the total amount reaching the systemic
blood becomes equal to that eliminated once ethanol has
disappeared from the circulation. The difference between
either of these two amounts (Qabs or Qelim) after the same
intravenous and oral dose indicates the magnitude of the
FPM, expressed in milligrams per kilogram body weight.
After multiple doses, FPM was assessed from the difference
between the quantity of alcohol imbibed and that reaching
the systemic blood because the quantity reaching blood after
intravenous administration should be equal to the dose.
Alcohol Levels and Ranitidine 209
Statistics
All values were expressed by their means ⫾ SEM. The
significance of the ranitine effect (factor A) was tested as
repeated measures at four levels of the number of drinks
(factor B) by a two-factor analysis of variance. Other dif-
ferences were analyzed by Student’s t test for paired com-
parisons.
RESULTS
Before ranitidine administration, 9 of the 12 men screened
displayed a substantial FPM (⬎30 mg ethanol/kg body
weight) after a single postprandial dose of ethanol (300
mg/kg). They were selected to assess the inhibitory effects
of ranitidine on FPM after repetitive drinking of small
alcohol doses. The other three subjects displayed none or
minimal FPM (⬍10% of the dose) before ranitidine and,
therefore, they were excluded.
In the nine selected subjects, the BAC after intravenous
administration were considerably higher than those after
oral administration of the same dose (300 mg/kg) (Fig. 1). In
every subject, the parameters of ethanol elimination (Vmax,
Km, and Vd) were calculated by fitting the Michaelis-
Menten function to the descending blood alcohol levels after
intravenous administration. Vmax was 193 ⫾ 9 mg ⫻
kg⫺1 ⫻ h⫺1; Km was 2.20 ⫾ 0.02 mmol/L; and Vd was 0.65
⫾ 0.02 L/kg. Using these parameters, the total quantity of
ethanol eliminated from the blood was calculated. After
intravenous administration, the calculation of the amount of
ethanol eliminated was equal to the dose (300 mg/kg),
confirming the validity of the parameters used. In contrast,
after oral administration, only two-thirds of the dose (about
200 mg/kg) entered the systemic blood and was eliminated
in 3 to 3.5 h. The difference between the intravenously and
orally produced amounts of ethanol reaching the blood (94
⫾ 17 mg/kg) indicates the average magnitude of the FPM in
the nine subjects selected.
Before and after 1 wk of ranitidine administration (150
mg twice a day), the same subjects were administered four
small alcohol drinks (150 mg/kg) in the postprandial state at
45-min intervals and the calculated amount of ethanol
reaching the systemic blood was compared with the imbibed
dose (Fig. 2). Before ranitidine, the amount of alcohol
reaching the systemic blood increased with each subsequent
drink, but only two-third of the total dose imbibed (600
mg/kg) reached the blood, documenting again in these sub-
jects a FPM of about one-third of the dose (201.4 ⫾ 20.8
mg/kg). The fraction of the alcohol dose reaching the sys-
temic blood (bioavailability) after the four small drinks was
similar to that found after the single ethanol dose (300
mg/kg) given to the same subjects 1 wk before (68 ⫾ 5% vs
74 ⫾ 5%; p ⫽ not significant).
After 1 wk of treatment with ranitidine, the subjects were
given the same four doses of alcohol under the same con-
ditions. Now, after each drink, the amount of alcohol en-
tering the blood was greater than before ranitidine, reaching
210 Arora et al. AJG – Vol. 95, No. 1, 2000

Figure 1. Baseline first pass metabolism (FPM) in the nine subjects selected to study the inhibitory effects of ranitidine. FPM was assessed
with an alcohol dose (300 mg /kg) given, on alternate days, either by the oral (p.o.) or the intravenous (i.v.) route. Blood alcohol levels
were higher after i.v. than p.o. Curve fitting of an expression of the Michaelis-Menten function over the descending blood levels after i.v.
administration provides the pharmacokinetic parameters (Vmax, Km, and Vd) to calculate the cumulative elimination from blood (Qiv and
Qpo). At the completion of the alcohol curves, the quantities of ethanol eliminated (Qpo and Qiv) became equal to those reaching the blood
and Qiv ⫺ Qpo quantifies the FPM.

a maximum of five-sixth of the alcohol dose. Thus, the FPM
after ranitidine (77.3 ⫾ 4.1 mg/kg) was 38% of that before
the drug.
The blood ethanol levels also increased with each drink
(Fig. 3). After ranitidine, the peak BAC (33 ⫾ 2 mg/dl) were
significantly higher than before (24 ⫾ 3; p ⫽ 0.043, on
paired t test). Their 95% confidence intervals were 20.0 to
38.2 and 15.5 to 28.5, respectively. Moreover, the period
during which BAC exceeded 15 mg/dl was greater after than
before ranitidine (165 ⫾ 16 min vs 98 ⫾ 26; p ⫽ 0.040).
Similarly, BAC ⬎25 mg/dl persisted for a longer time after
ranitidine (54 ⫾ 15 min) than before (25 ⫾ 12; p ⬍ 0.05).
Also the areas under the curve were greater after ranitidine
(72 ⫾ 6 mg/dl per h) than before (51 ⫾ 9; p ⫽ 0.023). The
increased BAC were associated with an apparent change in
mood; whereas only three of the nine subjects were euphoric
before ranitidine, eight of the nine manifested clear euphoria
after ranitidine.
DISCUSSION
Our results indicate that, under conditions mimicking social
drinking, ranitidine strikingly increased blood alcohol con-
centrations. This effect was associated with a 60% reduction
in FPM. In terms of BAC, the effect of ranitidine was
potentiated by the repetitive drinking of small alcohol doses.
Moreover, after ranitidine, blood alcohol reached levels
known to be associated with impairment of psychomotor
skills, and these levels persisted for periods of time consid-
erably longer than in the absence of the drug.
Since the initial reports of inhibitory effects of H2-recep-
tor antagonists on the FPM of alcohol (1– 4, 17), their effects
on BACs after oral administration have been the subject of
controversy (for a review, see Ref. 18). However, the neg-
ative studies consistently used conditions known to be as-
sociated with minimal FPM, such as fasting (8), dilute
alcohol solutions (9), or high alcohol doses (5-fold or more
than the FPM). Furthermore, except for a negative study
(19), which unfortunately did not provide individual values,
all the other studies did not assess the presence and magni-
tude of FPM before the treatment. In this study, as well as
in previous ones (11, 12), 25–30% of the volunteers dis-
played minimal or no FPM at baseline. Under these condi-
tions, one would expect no modifications of BAC by drugs
that primarily decrease the FPM of alcohol. This has been
documented in the case of cimetidine, which increased BAC
in subjects with substantial FPM, but did not enhance BAC
when given to subjects with minimal or no FPM at baseline
AJG – January, 2000 Alcohol Levels and Ranitidine 211

Figure 2. Effect of ranitidine on the amount of ethanol entering the systemic blood in nine subjects taking four alcohol drinks. Here, at
each point in time, the quantity of ethanol reaching the blood (sum of ethanol present in body water [Ct ⫻ Vd] and that already eliminated)
was compared with the imbibed dose. The total amount of ethanol reaching the blood was 68% of the dose before (open circles) and 87%
after ranitidine (solid circles).

Figure 3. Effect of ranitidine (150 mg b.i.d. for 7 days) on blood alcohol levels after four small drinks in nine normal men. After repetitive
drinking, blood alcohol levels reach clinically relevant concentrations. The decrease in FPM produced by ranitidine was associated with
significant increase in blood alcohol to reached levels that are known to be associated with impairments of skills and judgment.
212 Arora et al.
(11). Therefore, in the present study, we excluded the sub-
jects with minimal (⬍30 mg/kg) or no FPM.
It has been claimed that ranitidine affects BAC only when
given in small doses, resulting in inconsequential changes of
BAC (10). However, the repetitive drinking of small alcohol
doses (often alternating with snacks), which is common
during social drinking, could potentiate the effects of rani-
tidine on BAC. This was shown to be the case with cime-
tidine (11), an H2-receptor antagonist that inhibits gastric
ADH activity. Because ranitidine decreases FPM primarily
by a different mechanism, namely by accelerating the gas-
tric emptying of ethanol, we wondered whether its effect
would nevertheless be potentiated after repetitive drinking.
A previous study used three drinks, the first one in the fasted
state and the other two postprandially and found no differ-
ences in BAC after ranitidine (20). However, the marked
effect of fasting on gastric emptying and FPM of alcohol
may have obscured the smaller effect of the drug. Therefore,
in the present study we administered the alcohol dose 1 h
after a standard meal and maintained the postprandial status
with potato chips.
Traditionally, FPM has been assessed by differences in
areas under the curve of blood concentrations between those
produced by intravenous and oral administration of the same
dose. This is valid for substances with a rate of elimination
proportional to their BAC (first order kinetics), but ethanol
elimination follows Michaelis-Menten kinetics, which re-
sembles the first order only at very low ethanol concentra-
tions and becomes independent of concentration (zero order
kinetics) at higher, clinically more relevant, concentrations.
Under the latter conditions, the rate of elimination is virtu-
ally constant and the BAC depends not only on the amount
but, principally, on the rate of entry of ethanol into the
blood. Indeed, marked differences in areas under the curve
of BAC were produced by changes in the rate of infusion
despite an equal amount of ethanol entering the blood (14).
Thus, the ranitidine-induced acceleration of gastric empty-
ing of alcohol (7) could increase BAC by enhancing either
the speed or the amount of ethanol entering the blood. To
dissociate both mechanisms, the FPM was quantified by
calculating the difference in the quantities of ethanol reach-
ing the blood (regardless of the rate of entry), through the
intravenous and the oral route, using Michaelis-Menten
kinetics of elimination (14) (Fig. 1).
After demonstrating that the calculated amount of ethanol
given intravenously is equal to the dose and that the param-
eters of elimination are not affected by ranitidine (7), we
calculated the FPM as the difference between the dose and
the amount reaching the blood (Fig. 2). This amount in-
creased with each drink and this effect was exaggerated after
treatment with ranitidine, indicating a marked decrease in
FPM. In a previous study (7), there was significant corre-
lation between the acceleration of the gastric emptying of
alcohol and the decrease in FPM. Indeed, the rapid transit of
ethanol through the stomach or the liver can decrease the
amount of alcohol metabolized before reaching the systemic
AJG – Vol. 95, No. 1, 2000
blood (FPM) by shortening the exposure of ADH to optimal
concentrations of ethanol. Although the role of hepatic
oxidation has not been excluded in these experiments, it
would be unlikely that the FPM persists or increases at
ethanol concentrations higher than those found to produce
saturation of the ethanol extraction in the human liver (21).
For hepatic FPM to occur, the extraction rate must be higher
at ethanol concentrations resulting from absorption than
from recirculation, which typically occurs with very small
doses.
These effects of ranitidine on FPM were associated with
clinically relevant changes in BAC. One hour after a stan-
dard breakfast, the repetitive drinking of four small doses at
45-min intervals resulted in stepwise increases of BAC (Fig.
3). After 1 wk of treatment with ranitidine, the increases in
BAC after each drink were greater than before ranitidine,
and BAC reached levels known to be associated with im-
pairment of skills needed to perform complex tasks (15
mg/dl) (22, 23) or to exercise judgment (25 mg/dl) (24).
Moreover, after ranitidine, the blood alcohol levels ex-
ceeded legal limits for driving in some countries, such as
Sweden, and they were maintained for almost 2 h. There-
fore, social drinkers treated with ranitidine should be
warned of the possibility of developing unexpected func-
tional impairment when drinking amounts of alcohol they
might consider safe.
ACKNOWLEDGMENT
This study was supported by National Institutes of Health
grants AA 05934 and AA07275, Department of Veterans
Affairs and Kingsbridge Research Foundation.
Reprint requests and correspondence: Charles S. Lieber, M.D.,
Alcohol Research Center, Veterans Affairs Medical Center, 130
West Kingsbridge Road, Bronx, NY 10468.
Received Jan. 8, 1999; accepted Aug. 4, 1999.
REFERENCES
1. Caballerı́a J, Baraona E, Rodamilans M, et al. Effects of
cimetidine on gastric alcohol dehydrogenase activity and
blood ethanol levels. Gastroenterology 1989;96:388 –92.
2. DiPadova C, Roine R, Frezza M, et al. Effects of ranitidine on
blood alcohol levels after ethanol ingestion. Comparison with
other H2-receptor antagonists. JAMA 1992;267:83– 6.
3. Caballerı́a J, Baraona E, Deulofeu R, et al. Effects of H2-
receptor antagonists on gastric alcohol dehydrogenase activity.
Dig Dis Sci 1991;36:1673–9.
4. Hernández-Muñoz R, Caballerı́a J, Baraona E, et al. Human
gastric alcohol dehydrogenase: Its inhibition by H2-receptor
antagonists, and its effect on the bioavailability of ethanol.
Alcoholism: Clin Exp Res 1990;14:946 –50.
5. Pozzato G, Stebel M, Lunazzi G, et al. Influence of acid-
secretion blockers on gastric and hepatic alcohol-dehydroge-
nase in rat. Scand J Clin Lab Invest 1992;52:747–52.
6. Stone CL, Hurley TD, Peggs CF, et al. Cimetidine inhibition
of human gastric and liver alcohol dehydrogenase isoenzymes:
AJG – January, 2000
Identification of inhibitor complexes by kinetics and molecular
modeling. Biochemistry 1995;34:4003–14.
7. Amir I, Anwar N, Baraona E, et al. Ranitidine increases the
bioavailability of imbibed alcohol by accelerating gastric emp-
tying. Life Sci 1996;58:511– 8.
8. DiPadova C, Worner TM, Julkunen RJK, et al. Effects of
fasting and chronic alcohol consumption on the first-pass
metabolism of ethanol. Gastroenterology 1987;92:1169 –73.
9. Roine RP, Gentry RT, Lim RT Jr, et al. Effect of concentration
of ingested ethanol on blood alcohol levels. Alcohol Clin Exp
Res 1991;15:734 – 8.
10. Fraser AG, Hudson M, Sawyerr AM, et al. Short report: The
effect of ranitidine on post-prandial absorption of a low dose
of alcohol. Aliment Pharmacol Ther 1992;6:267–71.
11. Gupta AM, Baraona E, Lieber CS. Significant increase of
blood alcohol by cimetidine after repetitive drinking of small
alcohol doses. Alcohol Clin Exp Res 1995;19:1083–7.
12. Sharma R, Gentry RT, Lim RT, et al. First pass metabolism of
alcohol: Absence of diurnal variation and its inhibition by
cimetidine after an evening meal. Am J Gastroenterol 1995;
40:2091–7.
13. Falkensson M, Jones W, Sörbo B. Bedside diagnosis of alco-
hol intoxication with a pocket-size breath-alcohol device:
Sampling from unconscious subjects and specificity for etha-
nol. Clin Chem 1989;35:918 –21.
14. Gentry RT, Sharma R, Lim RT Jr, et al. A new method to
quantify first pass metabolism of alcohol: Application to the
effects of H2-blockers on alcohol bioavailability. Gastroenter-
ology 1992;92:A811.
Alcohol Levels and Ranitidine 213
15. Lundquist F, Wolthers H. The kinetics of alcohol elimination
in man. Acta Pharmacol Toxicol 1958;14:265– 89.
16. Wagner JG, Wilkinson PK, Sedman AJ, et al. Elimination of
alcohol from human blood. J Pharm Sci 1976;65:152– 4.
17. Seitz HK, Veith S, Czygan P, et al. In vivo interactions
between H2-receptor antagonists and ethanol metabolism in
man and in rats. Hepatology 1984;4:1231– 4.
18. Baraona E, Gentry RT, Lieber CS. Bioavailability of alcohol:
Role of gastric metabolism and its interaction with other drugs.
Dig Dis 1994;12:351– 67.
19. Casini A, Pizzigallo AM, Mari F, et al. Prolonged bedtime
treatment with H2-receptor antagonists (ranitidine and famo-
tidine) does not affect blood alcohol levels after ethanol in-
gestion in male patients with duodenal ulcer. Am J Gastroen-
terol 1994;89:745–9.
20. Kleine M, Ertl D. Comparative trial in volunteers to investi-
gate possible ethanol-ranitidine interaction. Ann Pharmacother
1993;27:841–5.
21. Keiding S, Johansen S, Midtbfll I, et al. Ethanol elimination
kinetics in human liver and pig liver in vivo. Am J Physiol
1979;237:E316 –24.
22. Klein KE, Breuker K, Brüner H, et al. Blutalkohol und Flu-
guntüchtigkeit. Versuch einer Erarbeitung von Richtwerten für
die allgemeine Luftfahrt. Int Z angew Physiol 1967;24:254 –7.
23. Moskowitz H, Burns MM, Williams AF. Skill performance at
low blood alcohol levels. J Stud Alcohol 1985;46:482–5.
24. Modell JG, Mountz JM. Drinking and flying—The problem of
alcohol use in pilots. N Engl J Med 1990;323:455– 61.