THE AMERICAN JOURNAL OF GASTROENTEROLOGY
1, 2000
© 2000 by Am. Coll. of Gastroenterology
Published by Elsevier Science Inc.
Twenty-Four-Hour Intragastric pH:
Tolerance Within 5 Days of
Continuous Ranitidine Administration
Leonard Lachman, M.D., and Colin W. Howden, M.D., F.A.C.G.
Phoenix International (formerly IBRD Center for Clinical Research), Neptune, New Jersey; and Rush
University and Rush-Presbyterian-St. Luke’s Medical Center, Chicago, Illinois
OBJECTIVE: To investigate further the phenomenon of phar-
macological tolerance to H2-receptor antagonists, we un-
dertook a study of the antisecretory effect of ranitidine with
continuous daily administration.
METHODS: A total of 28 healthy male volunteers were given
ranitidine 150 mg q.i.d. for 5 days. Twenty-four-hour intra-
gastric pH monitoring was performed predosing and on days
1 and 5 of ranitidine administration. Serial blood samples
were collected on days 1 and 5 of ranitidine administration
for pharmacokinetics.
RESULTS: Mean 24-h intragastric pH was 2.62 predosing,
4.22 on day 1 of ranitidine administration and 3.28 on day
5 (p ⫽ 0.001, ranitidine day 1 vs day 5). Intragastric pH was
⬎3, 4, and 5 for 69.9%, 54.3%, and 35.9%, respectively, on
day 1 of ranitidine administration and was 45.8%, 30.1%,
and 20.8% on day 5 (p ⬍ 0.005 for each comparison).
Subjects’ Helicobacter pylori status did not affect the anti-
secretory effect of ranitidine. There was no alteration in
ranitidine pharmacokinetics to account for its reduced anti-
secretory effect.
CONCLUSION: This study has demonstrated a statistically
significant reduction in the antisecretory effect of ranitidine
within 5 days of continuous administration which is not
explained by altered ranitidine pharmacokinetics. This is
further evidence for the development of a form of phar-
macological tolerance to an H2-receptor antagonist
within a few days of continuous daily dosing. (Am J
Gastroenterol 2000;95:57– 61. © 2000 by Am. Coll. of
Gastroenterology)
INTRODUCTION
Gastroesophageal reflux disease (GERD) is often managed
with maintenance acid inhibitory therapy to control symp-
toms and to prevent complications that could result from
exposure of the esophageal mucosa to acidic gastric con-
tents. Previous short term studies have suggested the devel-
opment of tolerance to the pH-raising effects of H2-receptor
antagonists (H2RAs) within a few days of continuous ad-
ministration (1– 8). This may be particularly likely to occur
Vol. 95, No.
ISSN 0002-9270/00/$20.00
PII S0002-9270(99)00760-1
when H2RAs are given in high dose, such as those some-
times recommended for GERD. This study compared the
24-h gastric antisecretory effect of ranitidine 150 mg q.i.d.
after 1 and 5 days of administration.
MATERIALS AND METHODS
A total of 29 healthy male volunteers were enrolled in the
study. Subjects (22 black, five white, one Asian, and one
mixed race) were nonsmokers with a mean age of 34 yr
(range 25– 45), a mean height of 69.3 inches (range 63–75),
and a mean weight of 176 pounds (range 125–226). Subjects
had no evidence of clinically significant medical disease at
the time of recruitment, had no history of drug or alcohol
abuse, required no concurrent medications that were ex-
pected to affect the outcome of the study, and had not
donated blood within 30 days before study initiation. A
serum sample was obtained at the screening visit for the
determination of the presence of IgG antibodies to Helico-
bacter pylori (H. pylori) (FlexSure, SmithKline Diagnos-
tics, San Jose, CA). The Investigational Review Board used
by Phoenix International (formerly IBRD Center for Clini-
cal Research) approved the study. All subjects gave written
informed consent before participation. A total of 28 subjects
completed the entire study; statistical analysis is based on
the results from these 28.
Subjects had three separate 24-h intragastric pH studies
performed. The first was 2 days before ranitidine adminis-
tration. The second and third were during days 1 and 5 of
dosing with ranitidine 150 mg q.i.d. After the baseline,
predosing study, subjects received a single iron-gray opaque
capsule containing 150 mg of crushed ranitidine q.i.d. at
0800, 1200, 1700, and 2100 h for 5 days. This preparation
of ranitidine had been previously shown to have similar
bioavailability to the marketed product. Doses were ingested
with approximately 180 ml of water and were administered
1 h before meals and snacks. Study personnel performed a
thorough hand and mouth check on each subject to ensure
ingestion of each dose. The primary evaluation endpoints
were the effects of ranitidine on ambulatory 24-h intragas-
58 Lachman and Howden
tric pH after 1 and 5 days of continuous daily administra-
tion.
Intragastric pH monitoring was performed using a Digi-
trapper MD ambulatory pH monitoring system (Sandhill
Scientific, Highland Ranch, CO) with built-in lower esoph-
ageal sphincter (LES) identifier and a graphite/antimony pH
and pressure sensor probe that was accurately calibrated.
The intragastric pH probe was inserted via the nose, and its
tip placed in the gastric antrum approximately 15– 60 min
before the start of pH recording and before 0800 h. The LES
identifier within the Digitrapper unit located the LES man-
ometrically; the tip of the probe was then placed 15 cm
below the LES. At each pH monitoring session, intragastric
pH was sampled every 10 s during the 24-h period. The
median of these values over 15-min intervals was calculated
and used in all data analyses.
During the study period, subjects were confined to the
study facility and consumed only scheduled meals, stan-
dardized with regard to content. Xanthine-containing food
and beverages were prohibited. Meals were served at ap-
proximately 0900 (breakfast), 1300 (lunch), 1800 (dinner),
and 2200 h (snack).
Safety evaluations included complete and interim medical
histories and physical examinations, monitoring of adverse
events, vital signs, and clinical laboratory determinations
including hematology, fasting serum chemistry, and urinal-
ysis.
On days 1 and 5 of ranitidine dosing, blood samples for
drug assay were collected before (h 0) the morning dose and
at 0.5, 1, 1.5, 2, 3, 4 (before the 1200 h dose), 5, 6, 7, 8, 9
(before the 1700 h dose), 10, 11, 12, 13 (before the 2100 h
dose), 14, 15, and 24 h after administration of the 0800 h
dose. The 3-ml blood samples were collected in heparinized
tubes and immediately placed in ice. All blood samples were
centrifuged at about 5°C within 2 h after sample collection.
The plasma was then separated, transferred to appropriately
labeled plastic tubes, and frozen immediately to a maximum
temperature of ⫺20°C until assayed. Plasma samples were
analyzed using a high pressure liquid chromatographic
method with ultraviolet detection under the direction of
Abbott Laboratories’ Pharmaceutical Products Division
Drug Metabolism Department.
Individual and mean plasma concentrations for ranitidine
on days 1 and 5 of dosing were tabulated. The following
pharmacokinetic parameters were determined: the maxi-
mum observed plasma concentration (Cmax), time to max-
imum observed concentration (Tmax), terminal phase
elimination rate constant (␤), corresponding half-life (T1/
2), and area under the plasma concentration-time curve
(AUC0 –24).
It was planned that ⱖ24 subjects would complete the
study. All statistical tests were two tailed, with values of p ⱕ
0.05 regarded as significant. Intragastric pH values on days
1 and 5 of ranitidine dosing were compared using paired
Student’s t tests. These analyses were carried out on mean
intragastric pH (calculated as the mean of the 15-min me-
AJG – Vol. 95, No. 1, 2000
dians) and on the percentage of time (based on the 15-min
median) that pH was ⬎3, 4, 5, and 6 during each of the 24-h
monitoring periods and over each of the following time
intervals: 0 –5, 6 –10, 11–15, and 16 –24 h after the morning
dose.
Pharmacokinetic variables (Cmax, Tmax, T1/2, and AUC0 –24)
were determined by noncompartmental methods. An anal-
ysis of variance was performed with effects for day, period,
and subject nested within period.
The number and percentage of subjects having adverse
events beginning during the dosing period or within 3 days
of the last dose of study drug were tabulated for each dosing
regimen by COSTART term and body system. Tabulation
was performed for all possible or probable treatment-related
adverse events, regardless of timing, with a further break-
down by the rating of severity (mild, moderate, or severe).
RESULTS
Mean 24-h intragastric pH was 2.62 predosing, 4.22 on day
1, and 3.28 on day 5 of ranitidine dosing (p ⫽ 0.001 for day
1 vs day 5 of ranitidine; Fig. 1). Similarly, lower mean pH
values were found for all postdosage time intervals on day
5 than on day 1 of dosing (Fig. 2). On day 1 of ranitidine,
intragastric pH was ⬎3, ⬎4, and ⬎5 for 69.9%, 54.3%, and
35.9%, respectively, of the recording period. Corresponding
values after 5 days were 45.8%, 30.1%, and 20.8% (p ⬍
0.005 for each comparison). Individuals’ mean pH values
predosing and after 1 and 5 days of ranitidine are depicted
in Figure 3.
Six subjects were H. pylori-positive and 22 were H.
pylori-negative at screening. Mean 24-h intragastric pH
values at baseline were comparable at 2.80 and 2.57, re-
spectively (p ⫽ 0.760). On day 1 of dosing with ranitidine,
intragastric pH in the six H. pylori-positive subjects in-
creased to 4.99 (p ⫽ 0.063). In the 22 H. pylori-negative
subjects, mean pH increased to 4.01 (p ⬍ 0.001). The rise in
mean pH seen with 1 day of dosing was not significantly
greater in the H. pylori-positive than in the H. pylori-
negative subjects (p ⫽ 0.074). After 5 days of continuous
ranitidine administration, the mean 24-h intragastric pH
decreased in the H. pylori-positive subjects from 4.99 to
3.91 (p ⫽ 0.355). In the H. pylori-negative subjects, mean
pH decreased from 4.01 to 3.11 (p ⬍ 0.001). After 5 days of
continuous ranitidine administration, the mean pH in the H.
pylori-positive subjects was not significantly higher than in
the H. pylori-negative subjects (p ⫽ 0.203).
Details of the pharmacokinetic parameters are summa-
rized in Table 1. Statistically significant increases occurred
in the natural logarithm of Cmax (p ⫽ 0.0033) and in the
natural logarithm of AUC0 –24 (p ⫽ 0.0041) between days 1
and 5 days of ranitidine administration. No statistically
significant differences were observed for Tmax or ␤.
Adverse events were reported by 11% of subjects. All
AJG – January, 2000 Tolerance in 5 Days to Continuous Ranitidine 59

Figure 1. Mean intragastric pH levels on ranitidine 150 mg q.i.d. after 1 and 5 days of dosing

adverse events reported were considered mild or moderate sults, hematology, serum chemistry, or urinalysis. No clin-
in severity. No subject discontinued the study prematurely ically or statistically significant differences were observed
because of an adverse event. There were no clinically sig- from baseline to the last day of ranitidine administration for
nificant differences observed in physical examination re- any hematology, chemistry, or urinalysis parameter.

Figure 2. Adjusted mean of intragastric pH levels by postdosing interval before ranitidine and after 1 and 5 days of dosing with ranitidine
150 mg q.i.d.
60 Lachman and Howden
Figure 3. Individuals’ mean intragastric pH values predosing and after 1 and 5 days of ranitidine 150 mg q.i.d.
DISCUSSION
After day 1 of dosing, ranitidine produced a substantial
increase in 24-h intragastric pH. However, the magnitude of
the initial effect diminished after 5 days of continuous
administration. By day 5 of dosing, the mean 24-h intragas-
tric pH was significantly lower than that seen on day 1.
Most of our subjects were H. pylori-negative, which
would have been expected given their age distribution. The
initial rise in intragastric pH seen with ranitidine appeared to
have been less in this group, although the absolute change
was not significantly different from that seen in the smaller
group who were infected with H. pylori. The decrement in
pH seen within 5 days of continuous ranitidine administra-
tion was of greater magnitude in the H. pylori-positive than
in the H. pylori-negative subjects, although this difference
was not statistically significant. Given the small number of
subjects who were H. pylori-positive, it is reasonable to
conclude that H. pylori status plays little or no role in the
Table 1. Mean (⫹ SD) Pharmacokinetic Parameters for Ranitidine
Day of Cmax Tmax
Dosing (ng/ml) (h)
1 495 (161) 7.7 (4.2)
5 561 (129)* 8.3 (5.5)
* p ⬍ 0.005 between days 1 and 5 of dosing.
† Reported as harmonic mean and pseudostandard deviation.
AJG – Vol. 95, No. 1, 2000
development of pharmacological tolerance to ranitidine.
This has not been addressed in previous studies (1– 8).
This decreased acid-inhibitory effect occurred despite
small, but statistically significant, increases in ranitidine log
Cmax and AUC0 –24 observed after 5 days of administration.
The clinical significance of these observed changes is highly
questionable. What is of relevance is that there was no
evidence for decreased absorption or increased elimination
of ranitidine to account for its diminished antisecretory
effect.
This diminished effectiveness has been previously docu-
mented with H2RAs and considered to represent the devel-
opment of pharmacological tolerance (1– 8). Early hypoth-
eses suggested that this was due to up-regulation of gastrin
and/or H2-receptors, with or without an increase in parietal
cell mass (9 –12). Current experimental data suggest that the
reduced effect observed with continuous H2RA therapy is
due to a gastrin-induced up-regulation of enterochromaffin-
AUC0⫺24 ␤ T1/2
(ng 䡠 h/ml) (h⫺1) (h)†
6052 0.144
4.80 (1.98)
(1240) (0.059)
6821* 0.174
3.99 (1.47)
(1330) (0.064)
AJG – January, 2000
like cell synthesis of histamine, which then competes with
the antagonist at the parietal cell. This may also be respon-
sible for the rebound acid hypersecretion without hypergas-
trinemia that has been reported after withdrawal of H2RAs
(7, 13).
Maintenance of the intragastric pH at ⱖ4.0 for most of
the day reduces GERD symptoms and heals erosive esoph-
agitis. PPIs are more effective than the H2RAs in raising
and maintaining intragastric pH to ⬎4 (14 –19). The ability
of the PPIs in maintaining intragastric pH at ⱖ4 for longer
than the H2RAs has been associated with greater relief of
GERD symptoms and more rapid healing of esophagitis (20,
21). The ability of the H2RAs to control 24-h intragastric
pH diminishes with continuous administration. In clinical
practice, GERD patients on continuous H2RA treatment
might be expected to experience breakthrough symptoms or
recurrence of esophagitis based on this reduction in phar-
macological effect.
This study has demonstrated a marked reduction in the
acid-inhibitory effect of an H2RA in normal healthy volun-
teers within 5 days of continuous administration. This ob-
servation may in part explain the disappointing effect of
continuous treatment with H2RAs that is seen in GERD
patients (22, 23).
ACKNOWLEDGMENT
This work was supported by a grant from TAP Pharmaceu-
ticals, Deerfield, IL.
Reprint requests and correspondence: Colin W. Howden, M.D.,
F.A.C.G., Division of Digestive Diseases, Rush-Presbyterian-St.
Luke’s Medical Center, 1725 West Harrison Street, Suite 206,
Chicago, IL 60612.
Received Apr. 20, 1999; accepted Sep. 7, 1999.
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